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Zhao W, Li Y, Zhou Y, Zhao J, Lu Y, Xu Z. AdipoRon attenuates depression-like behavior in T2DM mice via inhibiting inflammation and regulating autophagy. Brain Res Bull 2025; 224:111308. [PMID: 40096914 DOI: 10.1016/j.brainresbull.2025.111308] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Revised: 02/23/2025] [Accepted: 03/12/2025] [Indexed: 03/19/2025]
Abstract
Adiponectin, an adipocyte-derived adipokine, exerts anti-inflammatory effects in the brain, but its specific function in type 2 diabetes mellitus(T2DM) has not been elucidated. Based on the common physiological and pathological mechanisms of T2DM and depression, this study revealed the protective effect of AdipoRon on T2DM-related depressive behavior and its molecular biological mechanism in vivo. Our results showed that AdipoRon treatment enhanced the sucrose consumption of T2DM mice in sucrose preference experiment, reduced the immobility time in the forced swimming experiment, and increased the total movement distance and cross times in the open field experiment. AdipoRon treatment inhibited the apoptosis of hippocampal cells, increased the number of synapses in the prefrontal cortex and hippocampus, and enhanced the density of dendritic spines in CA1 region of T2DM mice. AdipoRon could reduce NLRP3, ASC and IL-1β levels in the hippocampus and prefrontal cortex, increase the ratio of p-AMPK/AMPK and decrease p-mTOR/mTOR expression in T2DM mice. Furthermore, AdipoRon treatment increased the ratio of LC3II/LC3I and the expression of AdipoR1 in the prefrontal cortex and hippocampus of T2DM mice. All of these findings support the idea that AdipoRon reduces neuroinflammation and stimulates autophagy in T2DM mice via activating the AdipoR1/AMPK/mTOR pathway. AdipoRon may be a novel therapeutic agent for T2DM complicated depression.
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Affiliation(s)
- Wenyan Zhao
- Department of Neuropsychology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China; Department of Neurology,Tangdu Hospital, Air Force Medical University, Xi'an, Shanxi, China
| | - Yahong Li
- Department of Applied Psychology, South-Central Minzu University, Wuhan, Hubei, China
| | - Yuliang Zhou
- Department of Neuropsychology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
| | - Jinying Zhao
- Department of Neuropsychology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
| | - Yanyu Lu
- Department of Applied Psychology, South-Central Minzu University, Wuhan, Hubei, China
| | - Zhipeng Xu
- Department of Neuropsychology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China.
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Alimohammadi S, Mohaddes G, Keyhanmanesh R, Athari SZ, Azizifar N, Farajdokht F. Intranasal AdipoRon mitigates motor and cognitive deficits in hemiparkinsonian rats through neuroprotective mechanisms against oxidative stress and synaptic dysfunction. Neuropharmacology 2025; 262:110180. [PMID: 39393589 DOI: 10.1016/j.neuropharm.2024.110180] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2024] [Revised: 09/27/2024] [Accepted: 10/07/2024] [Indexed: 10/13/2024]
Abstract
While motor symptoms are the most well-known manifestation of Parkinson's disease (PD), patients may also suffer from non-motor signs like cognitive impairments. The adiponectin receptor agonist AdipoRon (Adipo) has shown neuroprotective effects in preclinical studies. The objective of this study was to determine the potential benefits of chronic intranasal treatment of Adipo on motor function and cognitive performance in a hemiparkinsonian rat model caused by injecting 6-hydroxydopamine (6-OHDA) into the left forebrain bundle. After one week, PD rats were given either a vehicle or one of three dosages of Adipo (0.1, 1, and 10 μg) or levodopa (10 mg/kg orally) daily for 21 days. Recognition and spatial memory were determined using the novel object recognition test (NORT) and the Barnes maze test, respectively. The hippocampal tissues of the animals were harvested to examine oxidative stress status as well as the protein expressions of brain-derived neurotrophic factor (BDNF) and postsynaptic density protein 95 (PSD-95). In hemiparkinsonian rats, motor impairments, recognition memory, and spatial memory were all improved by chronic intranasal Adipo at 1 and 10 μg. Furthermore, we found that unilateral 6-OHDA injection elevated hippocampal oxidative stress (ROS) while concurrently reducing total antioxidant capacity (TAC), BDNF, PSD-95, and antioxidant enzymes (SOD, GPx). However, Adipo 10 μg significantly reduced these biochemical alterations in the hippocampus of 6-OHDA-lesioned rats. Chronic intranasal Adipo ameliorated spatial and recognition memory deterioration in hemiparkinsonian rats, presumably by increasing hippocampal synaptic protein levels, reducing oxidative stress, and increasing BDNF.
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Affiliation(s)
- Soraya Alimohammadi
- Neurosciences Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Gisou Mohaddes
- Department of Biomedical Education, California Health Sciences University, College of Osteopathic Medicine, Clovis, CA, USA
| | - Rana Keyhanmanesh
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Physiology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Seyed Zanyar Athari
- Neurosciences Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Physiology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Negin Azizifar
- Neurosciences Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Fereshteh Farajdokht
- Neurosciences Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Physiology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
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Athari SZ, Keyhanmanesh R, Farajdokht F, Karimipour M, Azizifar N, Alimohammadi S, Mohaddes G. AdipoRon improves mitochondrial homeostasis and protects dopaminergic neurons through activation of the AMPK signaling pathway in the 6-OHDA-lesioned rats. Eur J Pharmacol 2024; 985:177111. [PMID: 39515564 DOI: 10.1016/j.ejphar.2024.177111] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Revised: 10/07/2024] [Accepted: 11/05/2024] [Indexed: 11/16/2024]
Abstract
The progressive decline of dopaminergic neurons in Parkinson's disease (PD) has been linked to an imbalance in energy and the failure of mitochondrial function. AMP-activated protein kinase (AMPK), the major intracellular energy sensor, regulates energy balance, and damage to nigral dopaminergic neurons induced by 6-hydroxydopamine (6-OHDA) is exacerbated in the absence of AMPK activity. This study aimed to examine the potential therapeutic advantages of AdipoRon, an AMPK activator, on motor function and mitochondrial homeostasis in a 6-OHDA-induced PD model. Male Wistar rats were subjected to unilateral injection of 6-OHDA (10 μg) into the left medial forebrain bundle at two points, and after 7 days, they were treated with intranasal AdipoRon (0.1, 1, and 10 μg) or Levodopa (10 mg/kg, p. o.) for 21 successive days. Following the last treatment day, motor behavior was evaluated through the Murprogo's test, bar test, beam walking test, and apomorphine-induced rotation test. After euthanasia, the left substantia nigra (SN) was separated for evaluation of ATP, mitochondrial membrane potential (MMP), and protein expressions of AMPK, p-AMPK, and mitochondrial dynamics markers (Mfn-2 and Drp-1). Moreover, the number of tyrosine hydroxylase-positive (TH+) cells was quantified in the left substantia nigra. Intranasal AdipoRon effectively reversed muscle rigidity, akinesia, bradykinesia, and rotation caused by 6-OHDA. Moreover, AdipoRon increased the phospho-AMPK/AMPK ratio, mitigated mitochondrial dysfunction, and improved mitochondrial dynamics in the SN. Furthermore, AdipoRon increased the number of TH+ cells in the SN of PD animals. These findings suggest that AdipoRon could protect dopaminergic neurons by activating the AMPK pathway and improving mitochondrial dysfunction.
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Affiliation(s)
- Seyed Zanyar Athari
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Neurosciences Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Rana Keyhanmanesh
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Fereshteh Farajdokht
- Neurosciences Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Karimipour
- Department of Anatomical Sciences, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Negin Azizifar
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Soraya Alimohammadi
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Gisou Mohaddes
- Department of Biomedical Education, California Health Sciences University, College of Osteopathic Medicine, Clovis, CA, USA.
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Shoji H, Maeda Y, Miyakawa T. Chronic corticosterone exposure causes anxiety- and depression-related behaviors with altered gut microbial and brain metabolomic profiles in adult male C57BL/6J mice. Mol Brain 2024; 17:79. [PMID: 39511657 PMCID: PMC11545877 DOI: 10.1186/s13041-024-01146-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2024] [Accepted: 09/26/2024] [Indexed: 11/15/2024] Open
Abstract
Chronic exposure to glucocorticoids in response to long-term stress is thought to be a risk factor for major depression. Depression is associated with disturbances in the gut microbiota composition and peripheral and central energy metabolism. However, the relationship between chronic glucocorticoid exposure, the gut microbiota, and brain metabolism remains largely unknown. In this study, we first investigated the effects of chronic corticosterone exposure on various domains of behavior in adult male C57BL/6J mice treated with the glucocorticoid corticosterone to evaluate them as an animal model of depression. We then examined the gut microbial composition and brain and plasma metabolome in corticosterone-treated mice. Chronic corticosterone treatment resulted in reduced locomotor activity, increased anxiety-like and depression-related behaviors, decreased rotarod latency, reduced acoustic startle response, decreased social behavior, working memory deficits, impaired contextual fear memory, and enhanced cued fear memory. Chronic corticosterone treatment also altered the composition of gut microbiota, which has been reported to be associated with depression, such as increased abundance of Bifidobacterium, Turicibacter, and Corynebacterium and decreased abundance of Barnesiella. Metabolomic data revealed that long-term exposure to corticosterone led to a decrease in brain neurotransmitter metabolites, such as serotonin, 5-hydroxyindoleacetic acid, acetylcholine, and gamma-aminobutyric acid, as well as changes in betaine and methionine metabolism, as indicated by decreased levels of adenosine, dimethylglycine, choline, and methionine in the brain. These results indicate that mice treated with corticosterone have good face and construct validity as an animal model for studying anxiety and depression with altered gut microbial composition and brain metabolism, offering new insights into the neurobiological basis of depression arising from gut-brain axis dysfunction caused by prolonged exposure to excessive glucocorticoids.
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Affiliation(s)
- Hirotaka Shoji
- Division of Systems Medical Science, Center for Medical Science, Fujita Health University, Toyoake, Aichi, 470-1192, Japan
| | - Yasuhiro Maeda
- Open Facility Center, Fujita Health University, Toyoake, Aichi, 470-1192, Japan
| | - Tsuyoshi Miyakawa
- Division of Systems Medical Science, Center for Medical Science, Fujita Health University, Toyoake, Aichi, 470-1192, Japan.
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Azizifar N, Mohaddes G, Keyhanmanesh R, Athari SZ, Alimohammadi S, Farajdokht F. Intranasal AdipoRon Mitigated Anxiety and Depression-Like Behaviors in 6-OHDA-Induced Parkinson 's Disease Rat Model: Going Beyond Motor Symptoms. Neurochem Res 2024; 49:3030-3042. [PMID: 39096412 DOI: 10.1007/s11064-024-04223-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Revised: 07/02/2024] [Accepted: 07/29/2024] [Indexed: 08/05/2024]
Abstract
Depression and anxiety are prevalent neuropsychiatric conditions among patients with Parkinson's disease (PD), which may manifest prior to motor symptoms. As levodopa, a prominent treatment for PD motor symptoms, provides few benefits for mood-related abnormalities, tackling non-motor symptoms is particularly important. AdipoRon (Ad), an adiponectin agonist, has demonstrated neuroprotective effects by suppressing neuroinflammatory responses and activating the AMPK/Sirt-1 signaling pathway. This study looked at the potential advantages and underlying mechanisms of intranasal Ad in a rat model of PD induced by 6-hydroxydopamine (6-OHDA). We found that Ad at doses of 1 and 10 µg for 21 days exhibited anxiolytic- and antidepressant effects in the open field (OF) test, elevated plus maze (EPM), sucrose splash test, and forced swimming test in a PD model caused by a unilateral 6-OHDA injection into the medial forebrain bundle (MFB). The Ad also lowered the levels of corticosterone in the blood, decreased inflammasome components (NLRP3, caspase 1, and IL-1β), and increased Sirt-1 protein levels in the prefrontal cortex (PFC) of PD rats. We conclude that Ad ameliorates anxious and depressive-like behaviors in the PD rat model through stimulating the AMPK/Sirt-1 signaling and blocking the NLRP3 inflammasome pathways in the PFC.
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Affiliation(s)
- Negin Azizifar
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Gisou Mohaddes
- Department of Biomedical Education, College of Osteopathic Medicine, California Health Sciences University, Clovis, CA, USA
| | - Rana Keyhanmanesh
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Seyed Zanyar Athari
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Soraya Alimohammadi
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Fereshteh Farajdokht
- Neurosciences Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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Wilson C, Hannan AJ, Renoir T. Serotonergic agonism and pharmacologically-induced adolescent stress cause operant-based learning deficits in mice. Neuropharmacology 2024; 244:109801. [PMID: 38040286 DOI: 10.1016/j.neuropharm.2023.109801] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Revised: 11/17/2023] [Accepted: 11/26/2023] [Indexed: 12/03/2023]
Abstract
BACKGROUND The interplay between environmental stress and genetic factors is thought to play an important role in the pathogenesis and maintenance of obsessive-compulsive disorder (OCD). However, the relative contribution of these causative antecedents in the manifestation of cognitive inflexibility-a phenotype often seen in obsessive-compulsive (OC)- spectrum disorders-is not fully understood. METHOD In this study, we treated mice with 50 mg/L corticosterone (CORT, a glucocorticoid stress hormone) in their drinking water during adolescence. In adulthood, we assessed anxiety-like behaviour and locomotor activity; along with operant-based discrimination and reversal learning. RU-24969, a selective serotonin receptor 5-HT1A/1B receptor agonist, was used as an acute pharmacological model of OC-like behaviour. RU-24969 (5 mg/kg) was administered prior to each reversal learning testing session. RESULTS We found that acute treatment with 5 mg/kg RU-24969 induced stereotyped hyperlocomotion in vehicle- and CORT-treated mice. Furthermore, pre-treatment with CORT in adolescence produced subtle anxiety-like behaviour in adult mice, and also resulted in an impairment to late-stage discrimination learning and alterations to reversal learning. Finally, acute treatment with 5 mg/kg RU-24969 caused an impairment to early-stage reversal learning. CONCLUSION Whilst we revealed dissociable detrimental effects of adolescent CORT treatment and acute 5-HT1A/1B receptor agonism on discrimination and reversal learning, respectively, we did not find evidence of additive deleterious effects of these two treatments. We therefore suggest that while disrupted serotonergic signalling is likely to be involved in the cognitive phenotype of OC-spectrum disorders, distinct neuropathological pathways may be at play in mediating the role of stress as an antecedent in OCD and related illnesses.
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Affiliation(s)
- Carey Wilson
- Florey Institute of Neuroscience and Mental Health, Melbourne Brain Centre, University of Melbourne, Parkville, Australia; Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Australia
| | - Anthony J Hannan
- Florey Institute of Neuroscience and Mental Health, Melbourne Brain Centre, University of Melbourne, Parkville, Australia; Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Australia
| | - Thibault Renoir
- Florey Institute of Neuroscience and Mental Health, Melbourne Brain Centre, University of Melbourne, Parkville, Australia; Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Australia.
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Dudakovic A, Limberg AK, Bothun CE, Dilger OB, Bayram B, Bettencourt JW, Salmons HI, Thaler R, Karczewski DC, Owen AR, Iyer VG, Payne AN, Carstens MF, van Wijnen AJ, Berry DJ, Sanchez-Sotelo J, Morrey ME, Abdel MP. AdipoRon reduces TGFβ1-mediated collagen deposition in vitro and alleviates knee stiffness in vivo. J Cell Physiol 2024; 239:e31168. [PMID: 38149794 PMCID: PMC10922972 DOI: 10.1002/jcp.31168] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Revised: 11/10/2023] [Accepted: 11/28/2023] [Indexed: 12/28/2023]
Abstract
Arthrofibrosis, which causes joint motion restrictions, is a common complication following total knee arthroplasty (TKA). Key features associated with arthrofibrosis include myofibroblast activation, knee stiffness, and excessive scar tissue formation. We previously demonstrated that adiponectin levels are suppressed within the knee tissues of patients affected by arthrofibrosis and showed that AdipoRon, an adiponectin receptor agonist, exhibited anti-fibrotic properties in human mesenchymal stem cells. In this study, the therapeutic potential of AdipoRon was evaluated on TGFβ1-mediated myofibroblast differentiation of primary human knee fibroblasts and in a mouse model of knee stiffness. Picrosirius red staining revealed that AdipoRon reduced TGFβ1-induced collagen deposition in primary knee fibroblasts derived from patients undergoing primary TKA and revision TKA for arthrofibrosis. AdipoRon also reduced mRNA and protein levels of ACTA2, a key myofibroblast marker. RNA-seq analysis corroborated the anti-myofibrogenic effects of AdipoRon. In our knee stiffness mouse model, 6 weeks of knee immobilization, to induce a knee contracture, in conjunction with daily vehicle (DMSO) or AdipoRon (1, 5, and 25 mg/kg) via intraperitoneal injections were well tolerated based on animal behavior and weight measurements. Biomechanical testing demonstrated that passive extension angles (PEAs) of experimental knees were similar between vehicle and AdipoRon treatment groups in mice evaluated immediately following immobilization. Interestingly, relative to vehicle-treated mice, 5 mg/kg AdipoRon therapy improved the PEA of the experimental knees in mice that underwent 4 weeks of knee remobilization following the immobilization and therapy. Together, these studies revealed that AdipoRon may be an effective therapeutic modality for arthrofibrosis.
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Affiliation(s)
- Amel Dudakovic
- Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA
| | - Afton K. Limberg
- Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA
| | - Cole E. Bothun
- Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA
| | - Oliver B. Dilger
- Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA
| | - Banu Bayram
- Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA
| | | | | | - Roman Thaler
- Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA
| | | | - Aaron R. Owen
- Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA
| | - Varun G. Iyer
- Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA
| | - Ashley N. Payne
- Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA
| | | | - Andre J. van Wijnen
- Department of Biochemistry, University of Vermont College of Medicine, Burlington, VT, USA
| | - Daniel J. Berry
- Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA
| | | | - Mark E. Morrey
- Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA
| | - Matthew P. Abdel
- Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA
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Chen M, Cui Y, Chen X, Shang R, Zhang X. C-F bond activation enables synthesis of aryl difluoromethyl bicyclopentanes as benzophenone-type bioisosteres. Nat Commun 2024; 15:419. [PMID: 38199996 PMCID: PMC10781780 DOI: 10.1038/s41467-023-44653-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2023] [Accepted: 12/22/2023] [Indexed: 01/12/2024] Open
Abstract
Bioisosteric design has become an essential approach in the development of drug molecules. Recent advancements in synthetic methodologies have enabled the rapid adoption of this strategy into drug discovery programs. Consequently, conceptionally innovative practices would be appreciated by the medicinal chemistry community. Here we report an expeditous synthetic method for synthesizing aryl difluoromethyl bicyclopentane (ADB) as a bioisostere of the benzophenone core. This approach involves the merger of light-driven C-F bond activation and strain-release chemistry under the catalysis of a newly designed N-anionic-based organic photocatalyst. This defluorinative coupling methodology enables the direct conversion of a wide variety of commercially available trifluoromethylaromatic C-F bonds (more than 70 examples) into the corresponding difluoromethyl bicyclo[1.1.1]pentanes (BCP) arenes/difluoromethyl BCP boronates in a single step. The strategy can also be applied to [3.1.1]and [4.1.1]propellane systems, providing access to analogues with different geometries. Moreover, we have successfully used this protocol to rapidly prepare ADB-substituted analogues of the bioactive molecule Adiporon. Biological testing has shown that the ADB scaffold has the potential to enhance the pharmacological properties of benzophenone-type drug candidates.
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Affiliation(s)
- Mingshuo Chen
- School of Chemistry and Materials Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, 1 Sub-lane Xiangshan, 310024, Hangzhou, People's Republic of China
| | - Yuang Cui
- School of Chemistry and Materials Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, 1 Sub-lane Xiangshan, 310024, Hangzhou, People's Republic of China
| | - Xiaoping Chen
- School of Chemistry and Materials Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, 1 Sub-lane Xiangshan, 310024, Hangzhou, People's Republic of China
| | - Rui Shang
- Department of Chemistry, The University of Tokyo, Tokyo, 113-0033, Japan
| | - Xiaheng Zhang
- School of Chemistry and Materials Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, 1 Sub-lane Xiangshan, 310024, Hangzhou, People's Republic of China.
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El Safadi D, Lebeau G, Turpin J, Lefebvre d’Hellencourt C, Diotel N, Viranaicken W, Krejbich-Trotot P. The Antiviral Potential of AdipoRon, an Adiponectin Receptor Agonist, Reveals the Ability of Zika Virus to Deregulate Adiponectin Receptor Expression. Viruses 2023; 16:24. [PMID: 38257725 PMCID: PMC10820441 DOI: 10.3390/v16010024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Revised: 12/11/2023] [Accepted: 12/20/2023] [Indexed: 01/24/2024] Open
Abstract
Zika virus (ZIKV) is a pathogenic member of the flavivirus family, with several unique characteristics. Unlike any other arbovirus, ZIKV can be transmitted sexually and maternally, and thus produce congenital syndromes (CZS) due to its neurotropism. This challenges the search for safe active molecules that can protect pregnant women and their fetuses. In this context, and in the absence of any existing treatment, it seemed worthwhile to test whether the known cytoprotective properties of adiponectin and its pharmacological analog, AdipoRon, could influence the outcome of ZIKV infection. We showed that both AdipoRon and adiponectin could significantly reduce the in vitro infection of A549 epithelial cells, a well-known cell model for flavivirus infection studies. This effect was particularly observed when a pre-treatment was carried out. Conversely, ZIKV revealed an ability to downregulate adiponectin receptor expression and thereby limit adiponectin signaling.
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Affiliation(s)
- Daed El Safadi
- Unité Mixte Processus Infectieux en Milieu Insulaire Tropical, Plateforme Technologique CYROI, Université de la Réunion, INSERM U1187, CNRS UMR 9192, IRD UMR 249, 94791 Sainte Clotilde, La Réunion, France; (D.E.S.); (G.L.); (J.T.)
| | - Grégorie Lebeau
- Unité Mixte Processus Infectieux en Milieu Insulaire Tropical, Plateforme Technologique CYROI, Université de la Réunion, INSERM U1187, CNRS UMR 9192, IRD UMR 249, 94791 Sainte Clotilde, La Réunion, France; (D.E.S.); (G.L.); (J.T.)
| | - Jonathan Turpin
- Unité Mixte Processus Infectieux en Milieu Insulaire Tropical, Plateforme Technologique CYROI, Université de la Réunion, INSERM U1187, CNRS UMR 9192, IRD UMR 249, 94791 Sainte Clotilde, La Réunion, France; (D.E.S.); (G.L.); (J.T.)
- UMR 1188 Diabète Athérothombose Réunion Océan Indien (DéTROI), Campus Santé Université de la Réunion, Université de La Réunion, INSERM, 77 Avenue du Docteur Jean-Marie Dambreville, 97410 Saint-Pierre, La Réunion, France; (C.L.d.); (N.D.)
| | - Christian Lefebvre d’Hellencourt
- UMR 1188 Diabète Athérothombose Réunion Océan Indien (DéTROI), Campus Santé Université de la Réunion, Université de La Réunion, INSERM, 77 Avenue du Docteur Jean-Marie Dambreville, 97410 Saint-Pierre, La Réunion, France; (C.L.d.); (N.D.)
| | - Nicolas Diotel
- UMR 1188 Diabète Athérothombose Réunion Océan Indien (DéTROI), Campus Santé Université de la Réunion, Université de La Réunion, INSERM, 77 Avenue du Docteur Jean-Marie Dambreville, 97410 Saint-Pierre, La Réunion, France; (C.L.d.); (N.D.)
| | - Wildriss Viranaicken
- Unité Mixte Processus Infectieux en Milieu Insulaire Tropical, Plateforme Technologique CYROI, Université de la Réunion, INSERM U1187, CNRS UMR 9192, IRD UMR 249, 94791 Sainte Clotilde, La Réunion, France; (D.E.S.); (G.L.); (J.T.)
- UMR 1188 Diabète Athérothombose Réunion Océan Indien (DéTROI), Campus Santé Université de la Réunion, Université de La Réunion, INSERM, 77 Avenue du Docteur Jean-Marie Dambreville, 97410 Saint-Pierre, La Réunion, France; (C.L.d.); (N.D.)
| | - Pascale Krejbich-Trotot
- Unité Mixte Processus Infectieux en Milieu Insulaire Tropical, Plateforme Technologique CYROI, Université de la Réunion, INSERM U1187, CNRS UMR 9192, IRD UMR 249, 94791 Sainte Clotilde, La Réunion, France; (D.E.S.); (G.L.); (J.T.)
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Wu SK, Chen WJ, Chang JPC, Guu TW, Hsin MC, Huang CK, Mischoulon D, Capuron L, Su KP. Personalized Medicine of Omega-3 Fatty Acids in Depression Treatment in Obese and Metabolically Dysregulated Patients. J Pers Med 2023; 13:1003. [PMID: 37373992 DOI: 10.3390/jpm13061003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2023] [Revised: 06/07/2023] [Accepted: 06/12/2023] [Indexed: 06/29/2023] Open
Abstract
The co-occurrence of depression and obesity has become a significant public health concern worldwide. Recent studies have shown that metabolic dysfunction, which is commonly observed in obese individuals and is characterized by inflammation, insulin resistance, leptin resistance, and hypertension, is a critical risk factor for depression. This dysfunction may induce structural and functional changes in the brain, ultimately contributing to depression's development. Given that obesity and depression mutually increase each other's risk of development by 50-60%, there is a need for effective interventions that address both conditions. The comorbidity of depression with obesity and metabolic dysregulation is thought to be related to chronic low-grade inflammation, characterized by increased circulating levels of pro-inflammatory cytokines and C-reactive protein (CRP). As pharmacotherapy fails in at least 30-40% of cases to adequately treat major depressive disorder, a nutritional approach is emerging as a promising alternative. Omega-3 polyunsaturated fatty acids (n-3 PUFAs) are a promising dietary intervention that can reduce inflammatory biomarkers, particularly in patients with high levels of inflammation, including pregnant women with gestational diabetes, patients with type 2 diabetes mellitus, and overweight individuals with major depressive disorder. Further efforts directed at implementing these strategies in clinical practice could contribute to improved outcomes in patients with depression, comorbid obesity, and/or metabolic dysregulation.
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Grants
- MOST 109-2320-B-038-057-MY3, 110-2321-B-006-004, 110-2811-B-039-507, 110-2320-B-039-048-MY2,110-2320-B-039-047-MY3, 110-2813-C-039-327-B, 110-2314-B-039-029-MY3, 111-2321-B-006-008, and NSTC 111-2314-B-039-041-MY3 Ministry of Science and Technology, Taiwan
- ANHRF 109-31, 109-40, 110-13, 110-26, 110-44, 110-45, 111-27, 111-28, 111-47, 111-48, and 111-52 An-Nan Hospital, China Medical University, Tainan, Taiwan
- CMRC-CMA-2 Ministry of Education (MOE), Taiwan
- CMU 110-AWARD-02, 110-N-17, 1110-SR-73 China Medical University, Taichung, Taiwan
- DMR-106-101, 106-227, 109-102, 109-244, 110-124, 111-245, 112-097, 112-086, 112-109, 112-232 and DMR-HHC-109-11, HHC-109-12, HHC-110-10, and HHC-111-8 China Medical University Hospital, Taichung, Taiwan
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Affiliation(s)
- Suet-Kei Wu
- Graduate Institute of Nutrition, China Medical University, Taichung 404, Taiwan
- Mind-Body Interface Research Center (MBI-Lab), China Medical University Hospital, Taichung 404, Taiwan
| | - Wei-Jen Chen
- An-Nan Hospital, China Medical University, Tainan 709, Taiwan
| | - Jane Pei-Chen Chang
- Mind-Body Interface Research Center (MBI-Lab), China Medical University Hospital, Taichung 404, Taiwan
- Department of Psychiatry, China Medical University Hospital, Taichung 404, Taiwan
- College of Medicine, China Medical University, Taichung 404, Taiwan
| | - Ta-Wei Guu
- Mind-Body Interface Research Center (MBI-Lab), China Medical University Hospital, Taichung 404, Taiwan
- Division of Psychiatry, Department of Internal Medicine, China Medical University Beigang Hospital, Yunlin 651, Taiwan
| | - Ming-Che Hsin
- Body Science & Metabolic Disorders International Medical Centre (BMIMC), China Medical University & Hospital, Taichung 404, Taiwan
| | - Chih-Kun Huang
- Body Science & Metabolic Disorders International Medical Centre (BMIMC), China Medical University & Hospital, Taichung 404, Taiwan
| | - David Mischoulon
- Depression Clinical and Research Program, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Lucile Capuron
- NutriNeuro, University of Bordeaux, INRAE, Bordeaux INP, UMR 1286, F-33076 Bordeaux, France
| | - Kuan-Pin Su
- Mind-Body Interface Research Center (MBI-Lab), China Medical University Hospital, Taichung 404, Taiwan
- An-Nan Hospital, China Medical University, Tainan 709, Taiwan
- Department of Psychiatry, China Medical University Hospital, Taichung 404, Taiwan
- College of Medicine, China Medical University, Taichung 404, Taiwan
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11
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Arjunan A, Song J. Pharmacological and physiological roles of adipokines and myokines in metabolic-related dementia. Biomed Pharmacother 2023; 163:114847. [PMID: 37150030 DOI: 10.1016/j.biopha.2023.114847] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Revised: 04/27/2023] [Accepted: 05/04/2023] [Indexed: 05/09/2023] Open
Abstract
Dementia is a detrimental neuropathologic condition with considerable physical, mental, social, and financial impact on patients and society. Patients with metabolic syndrome (MetS), a group of diseases that occur in tandem and increase the risk of neurologic diseases, have a higher risk of dementia. The ratio between muscle and adipose tissue is crucial in MetS, as these contain many hormones, including myokines and adipokines, which are involved in crosstalk and local paracrine/autocrine interactions. Evidence suggests that abnormal adipokine and myokine synthesis and release may be implicated in various MetS, such as atherosclerosis, diabetic mellitus (DM), and dyslipidemia, but their precise role is unclear. Here we review the literature on adipokine and myokine involvement in MetS-induced dementia via glucose and insulin homeostasis regulation, neuroinflammation, vascular dysfunction, emotional changes, and cognitive function.
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Affiliation(s)
- Archana Arjunan
- Department of Anatomy, Chonnam National University Medical School, Seoyangro 264, Hwasun 58128, Republic of Korea
| | - Juhyun Song
- Department of Anatomy, Chonnam National University Medical School, Seoyangro 264, Hwasun 58128, Republic of Korea.
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12
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Salmons HI, Gow C, Limberg AK, Bettencourt JW, Carstens MF, Payne AN, Morrey ME, Sanchez-Sotelo J, Berry DJ, Dudakovic A, Abdel MP. The Safety of Adiponectin Receptor Agonist AdipoRon in a Rabbit Model of Arthrofibrosis. Tissue Eng Part C Methods 2023; 29:154-159. [PMID: 36924279 PMCID: PMC10122264 DOI: 10.1089/ten.tec.2023.0008] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Accepted: 03/09/2023] [Indexed: 03/18/2023] Open
Abstract
AdipoRon is an adiponectin receptor 1, 2 (ADIPOR1 and ADIPOR2) agonist with numerous reported physiological benefits in murine models of human disease, including a proposed reduction in fibrosis. However, AdipoRon has never been investigated in rabbits, which provide a robust model for orthopedic conditions. We examined the safety of intravenous (IV) AdipoRon in New Zealand White (NZW) female rabbits surgically stressed by a procedure that mimics human arthrofibrosis. Fifteen female NZW rabbits were prospectively studied using increasing AdipoRon doses based on established literature. AdipoRon was dissolved in dimethyl sulfoxide (DMSO), diluted in normal saline, and administered IV preoperatively and for 5 subsequent days postoperatively. The primary outcome was overall toxicity to rabbits, whereas secondary outcomes were change in rabbit weights and hemodynamics and defining acid-base characteristics of the drug formulation. Two rabbits expired during preoperative drug administration at 25 mg/kg. Remaining rabbits received preoperative doses of DMSO (vehicle), 2.5, 5, or 10 mg/kg of AdipoRon without complications. On postoperative day 1, one rabbit sustained a tonic-clonic seizure after their second dose of 10 mg/kg AdipoRon. The remaining 12 rabbits (4 in each group) received six serial doses of vehicle, 2.5, or 5 mg/kg of AdipoRon without adverse effects. All formulations of AdipoRon were within safe physiological pH ranges (4-5). We are the first to report the use of IV AdipoRon in a surgically stressed rabbit model of orthopedic disease. AdipoRon doses of 5 mg/kg or less appear to be well-tolerated in female NZW rabbits. Impact statement We provided the first in vivo toxicity assessment and dose optimization of a new antifibrotic experimental medication, AdipoRon, in a surgically stressed rabbit model of knee arthrofibrosis.
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Affiliation(s)
- Harold I. Salmons
- Department of Orthopedic Surgery and Mayo Clinic, Rochester, Minnesota, USA
| | - Christopher Gow
- Department of Comparative Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Afton K. Limberg
- Department of Orthopedic Surgery and Mayo Clinic, Rochester, Minnesota, USA
| | | | - Mason F. Carstens
- Department of Orthopedic Surgery and Mayo Clinic, Rochester, Minnesota, USA
| | - Ashley N. Payne
- Department of Orthopedic Surgery and Mayo Clinic, Rochester, Minnesota, USA
| | - Mark E. Morrey
- Department of Orthopedic Surgery and Mayo Clinic, Rochester, Minnesota, USA
| | | | - Daniel J. Berry
- Department of Orthopedic Surgery and Mayo Clinic, Rochester, Minnesota, USA
| | - Amel Dudakovic
- Department of Orthopedic Surgery and Mayo Clinic, Rochester, Minnesota, USA
| | - Matthew P. Abdel
- Department of Orthopedic Surgery and Mayo Clinic, Rochester, Minnesota, USA
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13
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Increasing Adiponectin Signaling by Sub-Chronic AdipoRon Treatment Elicits Antidepressant- and Anxiolytic-Like Effects Independent of Changes in Hippocampal Plasticity. Biomedicines 2023; 11:biomedicines11020249. [PMID: 36830788 PMCID: PMC9953351 DOI: 10.3390/biomedicines11020249] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Revised: 01/16/2023] [Accepted: 01/16/2023] [Indexed: 01/20/2023] Open
Abstract
(1) Background: Adiponectin is an adipocyte-secreted hormone that has antidepressant- and anxiolytic-like effects in preclinical studies. Here, we investigated the antidepressant- and anxiolytic-like effects of sub-chronic treatment with AdipoRon, an adiponectin receptor agonist, and its potential linkage to changes in hippocampal adult neurogenesis and synaptic plasticity. (2) Methods: Different cohorts of wild-type C57BL/6J and CamKIIα-Cre male mice were treated with sub-chronic (7 days) AdipoRon, followed by behavioral, molecular, and electrophysiological experiments. (3) Results: 7-day AdipoRon treatment elicited antidepressant- and anxiolytic-like effects but did not affect hippocampal neurogenesis. AdipoRon treatment reduced hippocampal brain-derived neurotrophic factor (BDNF) levels, neuronal activation in the ventral dentate gyrus, and long-term potentiation of the perforant path. The knockdown of N-methyl-D-aspartate (NMDA) receptor subunits GluN2A and GluN2B in the ventral hippocampus did not affect the antidepressant- and anxiolytic-like effects of AdipoRon. (4) Conclusions: Increasing adiponectin signaling through sub-chronic AdipoRon treatment results in antidepressant- and anxiolytic-like effects independent of changes in hippocampal structural and synaptic function.
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14
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Nehme R, Diab-Assaf M, Decombat C, Delort L, Caldefie-Chezet F. Targeting Adiponectin in Breast Cancer. Biomedicines 2022; 10:2958. [PMID: 36428526 PMCID: PMC9687473 DOI: 10.3390/biomedicines10112958] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Revised: 11/10/2022] [Accepted: 11/14/2022] [Indexed: 11/19/2022] Open
Abstract
Obesity and breast cancer are two major health issues that could be categorized as sincere threats to human health. In the last few decades, the relationship between obesity and cancer has been well established and extensively investigated. There is strong evidence that overweight and obesity increase the risk of postmenopausal breast cancer, and adipokines are the central players in this relationship. Produced and secreted predominantly by white adipose tissue, adiponectin is a bioactive molecule that exhibits numerous protective effects and is considered the guardian angel of adipokine. In the obesity-cancer relationship, more and more evidence shows that adiponectin may prevent and protect individuals from developing breast cancer. Recently, several updates have been published on the implication of adiponectin in regulating tumor development, progression, and metastases. In this review, we provide an updated overview of the metabolic signaling linking adiponectin and breast cancer in all its stages. On the other hand, we critically summarize all the available promising candidates that may reactivate these pathways mainly by targeting adiponectin receptors. These molecules could be synthetic small molecules or plant-based proteins. Interestingly, the advances in genomics have made it possible to create peptide sequences that could specifically replace human adiponectin, activate its receptor, and mimic its function. Thus, the obvious anti-cancer activity of adiponectin on breast cancer should be better exploited, and adiponectin must be regarded as a serious biomarker that should be targeted in order to confront this threatening disease.
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Affiliation(s)
- Rawan Nehme
- Université Clermont-Auvergne, INRAE, UNH Unité de Nutrition Humaine, CRNH-Auvergne, 63000 Clermont-Ferrand, France
| | - Mona Diab-Assaf
- Equipe Tumorigénèse Moléculaire et Pharmacologie Anticancéreuse, Faculté des Sciences II, Université Libanaise Fanar, Beyrouth 1500, Lebanon
| | - Caroline Decombat
- Université Clermont-Auvergne, INRAE, UNH Unité de Nutrition Humaine, CRNH-Auvergne, 63000 Clermont-Ferrand, France
| | - Laetitia Delort
- Université Clermont-Auvergne, INRAE, UNH Unité de Nutrition Humaine, CRNH-Auvergne, 63000 Clermont-Ferrand, France
| | - Florence Caldefie-Chezet
- Université Clermont-Auvergne, INRAE, UNH Unité de Nutrition Humaine, CRNH-Auvergne, 63000 Clermont-Ferrand, France
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15
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AdipoRon induces AMPK activation and ameliorates Alzheimer's like pathologies and associated cognitive impairment in APP/PS1 mice. Neurobiol Dis 2022; 174:105876. [PMID: 36162737 DOI: 10.1016/j.nbd.2022.105876] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Revised: 09/12/2022] [Accepted: 09/21/2022] [Indexed: 11/24/2022] Open
Abstract
Alzheimer's disease (AD) is a progressive devastating neurodegenerative disorder characterized by extracellular amyloid beta (Aβ42) plaque formation, hyperphosphorylation of tau protein leading to intracellular neurofibrillary tangle formation. Recently discovered hallmark features responsible for AD pathogenesis are neuronal insulin resistance, dysregulation in adiponectin and AMPK signaling. The presence of adiponectin and its receptor in the brain with its unique anti-diabetic effects and association with neurodegenerative diseases has raised our interest in exploring orally active small molecule adiponectin receptor agonist, AdipoRon. To date, all the available drugs for the treatment of AD provides symptomatic relief and do not stall the progression of the disease. Indeed, it is becoming increasingly apparent to find appropriate targets. Here, we attempt to shed lights on adiponectin receptor agonist, AdipoRon and its downstream molecular targets in reducing disease pathogenesis and insulin resistance. In brain, AdipoRon induced AMPK activation, increased insulin sensitivity, reduced amyloid beta plaque deposition and improved cognitive impairment. Levels of BACE were also downregulated while LDLR, APOE and neprilysin were upregulated promoting amyloid beta clearance from brain. AdipoRon further reduced the chronic inflammatory marker, GFAP and improved synaptic markers PSD-95 and synaptophysin in APP/PS1 mice. Our in-vitro studies further confirmed the potential role of AdipoRon in improving insulin sensitivity by increasing GLUT 4 translocation, glucose uptake and insulin signaling under hyperinsulinemic condition. Our findings suggest that AdipoRon could be a promising lead in the future treatment strategies in the development of effective AD treatment.
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16
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Bai S, Bai H, Li D, Zhong Q, Xie J, Chen JJ. Gut Microbiota-Related Inflammation Factors as a Potential Biomarker for Diagnosing Major Depressive Disorder. Front Cell Infect Microbiol 2022; 12:831186. [PMID: 35372107 PMCID: PMC8965553 DOI: 10.3389/fcimb.2022.831186] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Accepted: 01/12/2022] [Indexed: 12/15/2022] Open
Abstract
Objective Although many works have been done, the objectively measured diagnostic biomarkers are not available. Thus, we conducted this study to identify potential biomarkers for objectively diagnosing depression and explore the role of gut microbiota in the onset of depression. Methods Major depressive disorder (MDD) patients (n=56) and demographic data-matched healthy controls (HCs) (n=56) were included in this study. The gut microbiota in fecal samples and inflammation-related factors in serum were measured. Both univariate and multivariate statistical analyses were performed to identify the differential gut microbiota and inflammation-related factors. Results Finally, 46 differential operational taxonomic units (OTUs) (60.9% OTUs belonging to Firmicutes) and ten differential inflammation-related factors were identified. Correlation analysis showed that there were significant correlations between 14 differential OTUs (9 OTUs belonging to Firmicutes and 5 OTUs belonging to family Lachnospiraceae under Firmicutes) and seven differential inflammation-related factors. Meanwhile, 14 differential OTUs (9 OTUs belonging to Firmicutes and 5 OTUs belonging to family Lachnospiraceae under Firmicutes) and five differential inflammation-related factors (adiponectin, apolipoprotein A1, alpha 1-antitrypsin, neutrophilicgranulocyte count/white blood cell count and basophil count) were significantly correlated to depression severity. A panel consisting of these five differential inflammation-related factors could effectively diagnose MDD patients from HCs. Conclusions Our results suggested that Firmicutes, especially family Lachnospiraceae, might play a role in the onset of depression via affecting the inflammation levels of host, and these five differential inflammation-related factors could be potential biomarkers for objectively diagnosing MDD.
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Affiliation(s)
- Shunjie Bai
- Department of Laboratory Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Huili Bai
- The Center for Clinical Molecular Medical Detection, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Detao Li
- Department of Laboratory Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Qi Zhong
- Institute of Life Sciences, Chongqing Medical University, Chongqing, China
| | - Jing Xie
- Chongqing Emergency Medical Center, Department of Endocrinology, The Fourth People’s Hospital of Chongqing, Central Hospital of Chongqing University, Chongqing, China
| | - Jian-jun Chen
- Institute of Life Sciences, Chongqing Medical University, Chongqing, China
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17
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Zhang Z, Du J, Shi H, Wang S, Yan Y, Xu Q, Zhou S, Zhao Z, Mu Y, Qian C, Zhao AZ, Cao S, Li F. Adiponectin suppresses tumor growth of nasopharyngeal carcinoma through activating AMPK signaling pathway. J Transl Med 2022; 20:89. [PMID: 35164782 PMCID: PMC8843017 DOI: 10.1186/s12967-022-03283-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Accepted: 01/28/2022] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND Adiponectin is an adipocyte-secreted cytokine that enhances insulin sensitivity and attenuates inflammation. Although circulating adiponectin level is often inversely associated with several malignancies, its role in the development of nasopharyngeal carcinoma (NPC) remains unclear. Here, we investigated the clinical association between circulating adiponectin level and NPC, and examined the impact of adiponectin, as well as the underlying mechanisms, on NPC growth both in vitro and in vivo. METHODS The association between circulating adiponectin level and the risk of developing NPC was assessed in two different cohorts, including a hospital-based case-control study with 152 cases and 132 controls, and a nested case-control study with 71 cases and 142 controls within a community-based NPC screening cohort. Tumor xenograft model, cell proliferation and cycle assays were applied to confirm the effects of adiponectin on NPC growth in cultured cells and in xenograft models. We also investigated the underlying signaling mechanisms with various specific pharmacological inhibitors and biochemistry analysis. RESULTS High adiponectin levels were associated with a monotonic decreased trend of NPC risk among males in both the hospital-based case-control study and a nested case-control study. In vitro, recombinant human full-length adiponectin significantly inhibited NPC cell growth and arrested cell cycle, which were dependent on AMPK signaling pathway. The growth of xenograft of NPC tumor was sharply accelerated in the nude mice carrying genetic adiponectin deficiency. An adiponectin receptor agonist, AdipoRon, displayed strong anti-tumor activity in human xenograft models. CONCLUSIONS These findings demonstrated for the first time that circulating adiponectin is not only inversely associated with NPC, but also controls the development of NPC via AMPK signaling pathway. Stimulation of adiponectin function may become a novel therapeutic modality for NPC.
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Affiliation(s)
- Zongmeng Zhang
- The School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, No.100 Waihuanxi Road, Guangzhou Higher Education Mega Center, Guangzhou, 510006, China
| | - Jinlin Du
- Department of Epidemiology and Health Statistics, School of Public Health, Guangdong Medical University, Dongguan, 523808, China
| | - Hui Shi
- Department of Pathology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China
| | - Shuai Wang
- The School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, No.100 Waihuanxi Road, Guangzhou Higher Education Mega Center, Guangzhou, 510006, China
| | - Yunjing Yan
- The School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, No.100 Waihuanxi Road, Guangzhou Higher Education Mega Center, Guangzhou, 510006, China
| | - Qihua Xu
- The School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, No.100 Waihuanxi Road, Guangzhou Higher Education Mega Center, Guangzhou, 510006, China
| | - Sujin Zhou
- The School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, No.100 Waihuanxi Road, Guangzhou Higher Education Mega Center, Guangzhou, 510006, China
| | - Zhenggang Zhao
- The School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, No.100 Waihuanxi Road, Guangzhou Higher Education Mega Center, Guangzhou, 510006, China
| | - Yunping Mu
- The School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, No.100 Waihuanxi Road, Guangzhou Higher Education Mega Center, Guangzhou, 510006, China
| | - Chaonan Qian
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, China
| | - Allan Zijian Zhao
- The School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, No.100 Waihuanxi Road, Guangzhou Higher Education Mega Center, Guangzhou, 510006, China.
| | - Sumei Cao
- Department of Cancer Prevention Research, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, China.
| | - Fanghong Li
- The School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, No.100 Waihuanxi Road, Guangzhou Higher Education Mega Center, Guangzhou, 510006, China.
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18
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Anti-depressive-like behaviors of APN KO mice involve Trkb/BDNF signaling related neuroinflammatory changes. Mol Psychiatry 2022; 27:1047-1058. [PMID: 34642455 DOI: 10.1038/s41380-021-01327-3] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 09/08/2021] [Accepted: 09/27/2021] [Indexed: 12/26/2022]
Abstract
Major depression disorder is a severe mental illness often linked with metabolic disorders. Adiponectin is an adipocyte-secreted circulatory hormone with antidiabetic and glucose/lipid modulation capacities. Studies have demonstrated the pathophysiological roles of adiponectin involved in various neurological disorders, including depression. However, the underlying mechanisms are poorly understood. Here we showed that adiponectin deprivation enhanced antidepressive-like behaviors in the LPS-induced model of depression. APN KO mice displayed increased cytokines (both pro and anti-inflammatory), accompanied by an impaired expression of adiponectin receptors (mRNA/protein level) and decreasing IBA-1 level in the cortex and primary microglia of LPS treated APN KO mice. Further, LPS-treatment significantly reduced p-NFκB expression in the microglia of APN KO mice. However, the Bay11-7082 treatment recovered p-NFκB expression in the cortex of APN KO mice in the presence of LPS. Interestingly, the antidepressant potentials of APN KO mice were abolished by TrkB antagonist K252a, IKK inhibitor Bay11-7082, and AdipoRon suggesting crosstalk between TrkB/BDNF signaling and NFκB in depression. Furthermore, the effects of Bay11-7082 were abolished by a TrkB/BDNF activator (7,8-DHF), indicating a critical role of TrkB/BDNF signaling. Taken together, these findings showed that dysregulated neuroinflammatory status and BDNF signaling might underlie the antidepressive-like behaviors of APN KO mice. NFκB elicited BDNF changes may be accountable for the pathogenesis of LPS induced depression, where APN might present an alternative therapeutic target for depressive disorders.
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19
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de Oliveira LRS, Machado FSM, Rocha-Dias I, E Magalhães COD, De Sousa RAL, Cassilhas RC. An overview of the molecular and physiological antidepressant mechanisms of physical exercise in animal models of depression. Mol Biol Rep 2022; 49:4965-4975. [PMID: 35092564 DOI: 10.1007/s11033-022-07156-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Accepted: 01/17/2022] [Indexed: 02/07/2023]
Abstract
BACKGROUND Depression is a global disease that affects the physical and mental health of people of all ages. Non-pharmacological and unconventional methods of treatment, such as regular physical exercise, have been recommended to treat depression. METHODS Here, we briefly review the literature about the physiological and molecular mechanisms of exercise antidepressants in depressive-like behavior in animal models of depression. RESULTS The main hysiological and molecular mechanisms of physical exercise in depression include blood flow changes in several areas of the brain, increase in brain serotonin synthesis, increase in antioxidant enzymes, increase in serum and brain brain-derived neuro factor (BDNF) levels, decrease in cortisol levels and reduced inflammation in peripheral and brain tissues. Physical exercise also leads to increased activation of the phosphatidylinositol-3-kinase (PI3K), PGC-1α/FNDC5/Irisin pathway, BDNF concentrations (serum and cerebral), extracellular signal-regulated kinase and cAMP-response element binding protein (mainly in neurons of the hippocampus and prefrontal cortex), which together contribute to fight or inhibit the development of depression symptoms. These molecular and physiological mechanisms work in synchrony, further enhancing their effects. CONCLUSION Physical exercise can be used as a safe and effective non-pharmacological treatment in depression.
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Affiliation(s)
- Lucas Renan Sena de Oliveira
- Department of Physical Education, Federal University of the Valleys of Jequitinhonha and Mucuri (UFVJM), Rodovia MGT 367 - Km 583, nº 5000, Bairro Alto da Jacuba, Diamantina, MG, CEP 39100-000, Brazil.,Neuroscience and Exercise Study Group (Grupo de Estudos em Neurociências e Exercício - GENE), UFVJM, Diamantina, MG, Brazil.,Multicenter Post Graduation Program in Physiological Sciences (PMPGCF), UFVJM, Brazilian Society of Physiology, Diamantina, MG, Brazil
| | | | - Isabella Rocha-Dias
- Neuroscience and Exercise Study Group (Grupo de Estudos em Neurociências e Exercício - GENE), UFVJM, Diamantina, MG, Brazil.,Multicenter Post Graduation Program in Physiological Sciences (PMPGCF), UFVJM, Brazilian Society of Physiology, Diamantina, MG, Brazil
| | - Caíque Olegário Diniz E Magalhães
- Neuroscience and Exercise Study Group (Grupo de Estudos em Neurociências e Exercício - GENE), UFVJM, Diamantina, MG, Brazil.,Multicenter Post Graduation Program in Physiological Sciences (PMPGCF), UFVJM, Brazilian Society of Physiology, Diamantina, MG, Brazil
| | - Ricardo Augusto Leoni De Sousa
- Neuroscience and Exercise Study Group (Grupo de Estudos em Neurociências e Exercício - GENE), UFVJM, Diamantina, MG, Brazil.,Multicenter Post Graduation Program in Physiological Sciences (PMPGCF), UFVJM, Brazilian Society of Physiology, Diamantina, MG, Brazil
| | - Ricardo Cardoso Cassilhas
- Department of Physical Education, Federal University of the Valleys of Jequitinhonha and Mucuri (UFVJM), Rodovia MGT 367 - Km 583, nº 5000, Bairro Alto da Jacuba, Diamantina, MG, CEP 39100-000, Brazil. .,Neuroscience and Exercise Study Group (Grupo de Estudos em Neurociências e Exercício - GENE), UFVJM, Diamantina, MG, Brazil. .,Multicenter Post Graduation Program in Physiological Sciences (PMPGCF), UFVJM, Brazilian Society of Physiology, Diamantina, MG, Brazil. .,Post Graduation Program in Health Science (PPGCS), UFVJM, Diamantina, MG, Brasil.
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Benedetti F, Branchi I, Poletti S, Lorenzi C, Bigai G, Colombo C, Zanardi R. Adiponectin predicts poor response to antidepressant drugs in major depressive disorder. Hum Psychopharmacol 2021; 36:e2793. [PMID: 33945186 DOI: 10.1002/hup.2793] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Accepted: 04/26/2021] [Indexed: 12/23/2022]
Abstract
OBJECTIVE Produced by adipocytes, adiponectin crosses the blood-brain barrier to bind with specific receptors in the hypothalamus, brainstem, hippocampus, and cortex. In patients with major depressive disorder (MDD), circulating levels of adiponectin inversely related with antidepressant response to ketamine, and predicted a better response to multi-target drug combinations than to escitalopram. We investigated the effect of adiponectin on response to antidepressants in a naturalistic setting. METHODS We assessed baseline plasma levels of adiponectin in 121 MDD inpatients, treated with antidepressant drug monotherapy based on clinical need (selective serotonin reuptake inhibitors, venlafaxine, duloxetine) in a specialized hospital setting. Severity of depression was weekly assessed with Hamilton scale ratings. RESULTS Adiponectin plasma levels were higher in patients with MDD compared with healthy controls, and negatively influenced the pattern of antidepressant response (higher baseline levels, worse response) independent of the drug class and of the baseline severity of depression, and of age, sex, and body mass index. CONCLUSIONS The identification of adiponectin as a predictor of antidepressant response to drugs of different mechanism of action, such as ketamine, SSRIs, and SNRIs, and both in experimental and in clinical settings, warrants interest for further study of its pathways to search for novel biomarkers and therapeutic targets.
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Affiliation(s)
- Francesco Benedetti
- Psychiatry & Clinical Psychobiology, Division of Neuroscience, IRCCS Scientific Institute Ospedale San Raffaele, Milano, Italy.,Vita-Salute San Raffaele University, Milano, Italy
| | - Igor Branchi
- Center for Behavioral Sciences and Mental Health, Istituto Superiore di Sanità, Roma, Italy
| | - Sara Poletti
- Psychiatry & Clinical Psychobiology, Division of Neuroscience, IRCCS Scientific Institute Ospedale San Raffaele, Milano, Italy.,Vita-Salute San Raffaele University, Milano, Italy
| | - Cristina Lorenzi
- Psychiatry & Clinical Psychobiology, Division of Neuroscience, IRCCS Scientific Institute Ospedale San Raffaele, Milano, Italy
| | | | - Cristina Colombo
- Vita-Salute San Raffaele University, Milano, Italy.,Mood Disorders Unit, IRCCS Scientific Institute Ospedale San Raffaele, Milano, Italy
| | - Raffaella Zanardi
- Vita-Salute San Raffaele University, Milano, Italy.,Mood Disorders Unit, IRCCS Scientific Institute Ospedale San Raffaele, Milano, Italy
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21
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Miao W, Jiang L, Xu F, Lyu J, Jiang X, He M, Liu Y, Yang T, Leak RK, Stetler RA, Chen J, Hu X. Adiponectin ameliorates hypoperfusive cognitive deficits by boosting a neuroprotective microglial response. Prog Neurobiol 2021; 205:102125. [PMID: 34333040 DOI: 10.1016/j.pneurobio.2021.102125] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2021] [Revised: 06/20/2021] [Accepted: 07/27/2021] [Indexed: 12/27/2022]
Abstract
Vascular cognitive impairment and dementia (VaD) is the second most common type of dementia caused by chronic vascular hypoperfusion. Adiponectin, one of the cytokines produced by adipocytes (adipocytokine), plays a role in CNS pathologies, but its specific function in VaD is unknown. Here, transcriptomic analyses on human brain tissues showed downregulation of adipocytokine/PPAR signaling in VaD patients, with prominent upregulation of pro-inflammatory responses. Using the murine asymmetric common carotid artery stenosis (ACAS) model, we discovered that the adiponectin/PPARγ axis is essential in reducing chronic hypoperfusion-induced cognitive deficits via modulation of microglial function. Adiponectin levels in the plasma increased early after VaD induction, but decreased in the cerebrospinal fluid in the late phase of VaD. Adiponectin deficiency worsened hippocampus-dependent cognitive deficits, exacerbated neuroinflammation and microglia/macrophage activation, and amplified neuronal loss, but these behavioral and histological outcomes were rescued by adipoRon, a small molecule agonist of the adiponectin receptors. AdipoRon boosted PPARγ expression and inhibited pro-inflammatory microglial responses in vitro, thereby protecting ischemic neurons in primary microglia-neuron cocultures. Microglia/macrophage-specific knockout of PPARγ abolished the neuroprotective effects of adipoRon. Collectively, these data confirm the importance of adiponectin/PPARγ signaling in maintaining cognitive functions in chronic hypoperfusion-induced dementia, and thus provide novel therapeutic targets for VaD.
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Affiliation(s)
- Wanying Miao
- Pittsburgh Institute of Brain Disorders & Recovery and Department of Neurology, University of Pittsburgh, Pittsburgh, PA, 15213, USA
| | - Liyuan Jiang
- Pittsburgh Institute of Brain Disorders & Recovery and Department of Neurology, University of Pittsburgh, Pittsburgh, PA, 15213, USA
| | - Fei Xu
- Pittsburgh Institute of Brain Disorders & Recovery and Department of Neurology, University of Pittsburgh, Pittsburgh, PA, 15213, USA; Geriatric Research, Education and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA, 15261, USA
| | - Junxuan Lyu
- Pittsburgh Institute of Brain Disorders & Recovery and Department of Neurology, University of Pittsburgh, Pittsburgh, PA, 15213, USA
| | - Xiaoyan Jiang
- Pittsburgh Institute of Brain Disorders & Recovery and Department of Neurology, University of Pittsburgh, Pittsburgh, PA, 15213, USA; Geriatric Research, Education and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA, 15261, USA
| | - Maxine He
- Pittsburgh Institute of Brain Disorders & Recovery and Department of Neurology, University of Pittsburgh, Pittsburgh, PA, 15213, USA
| | - Yaan Liu
- Pittsburgh Institute of Brain Disorders & Recovery and Department of Neurology, University of Pittsburgh, Pittsburgh, PA, 15213, USA
| | - Tuo Yang
- Pittsburgh Institute of Brain Disorders & Recovery and Department of Neurology, University of Pittsburgh, Pittsburgh, PA, 15213, USA; Geriatric Research, Education and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA, 15261, USA
| | - Rehana K Leak
- Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA, 15282, USA
| | - R Anne Stetler
- Pittsburgh Institute of Brain Disorders & Recovery and Department of Neurology, University of Pittsburgh, Pittsburgh, PA, 15213, USA; Geriatric Research, Education and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA, 15261, USA
| | - Jun Chen
- Pittsburgh Institute of Brain Disorders & Recovery and Department of Neurology, University of Pittsburgh, Pittsburgh, PA, 15213, USA; Geriatric Research, Education and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA, 15261, USA.
| | - Xiaoming Hu
- Pittsburgh Institute of Brain Disorders & Recovery and Department of Neurology, University of Pittsburgh, Pittsburgh, PA, 15213, USA; Geriatric Research, Education and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA, 15261, USA.
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22
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Ng RCL, Jian M, Ma OKF, Bunting M, Kwan JSC, Zhou GJ, Senthilkumar K, Iyaswamy A, Chan PK, Li M, Leung KMY, Kumar Durairajan SS, Lam KSL, Chu LW, Festenstein R, Chung SK, Chan KH. Chronic oral administration of adipoRon reverses cognitive impairments and ameliorates neuropathology in an Alzheimer's disease mouse model. Mol Psychiatry 2021; 26:5669-5689. [PMID: 32132650 DOI: 10.1038/s41380-020-0701-0] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Revised: 02/18/2020] [Accepted: 02/21/2020] [Indexed: 01/01/2023]
Abstract
Circulating adiponectin (APN) levels decrease with age and obesity. On the other hand, a reduction in APN levels is associated with neurodegeneration and neuroinflammation. We previously showed that aged adiponectin knockout (APN-/-) mice developed Alzheimer's like pathologies, cerebral insulin resistance, and cognitive impairments. More recently, we also demonstrated that APN deficiency increased Aβ-induced microglia activation and neuroinflammatory responses in 5xFAD mice. There is compelling evidence that deregulated insulin activities or cerebral insulin resistance contributes to neuroinflammation and Alzheimer's disease (AD) pathogenesis. Here, we demonstrated that APN levels were reduced in the brain of AD patients and 5xFAD mice. We crossbred 5xFAD mice with APN-/- mice to generate APN-deficient 5xFAD (5xFAD;APN-/-). APN deficiency in 5xFAD mice accelerated amyloid loading, increased cerebral amyloid angiopathy, and reduced insulin-signaling activities. Pharmacokinetics study demonstrated adipoRon (APN receptor agonist) was a blood-brain barrier penetrant. AdipoRon improved neuronal insulin-signaling activities and insulin sensitivity in vitro and in vivo. Chronic adipoRon treatment improved spatial memory functions and significantly rescued neuronal and synaptic loss in 5xFAD and 5xFAD;APN-/- mice. AdipoRon lowered plaque and Aβ levels in AD mice. AdipoRon also exerted anti-inflammatory effects by reducing microglial and astrocytes activation as well as suppressing cerebral cytokines levels. The microglial phagocytic activity toward Aβ was restored after adipoRon treatment. Our results indicated that adipoRon exerts multiple beneficial effects providing important therapeutic implications. We propose chronic adipoRon administration as a potential treatment for AD.
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Affiliation(s)
- Roy Chun-Laam Ng
- Department of Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
- Neuroimmunology and Neuroinflammation Research Laboratory, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Min Jian
- Department of Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
- Neuroimmunology and Neuroinflammation Research Laboratory, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Oscar Ka-Fai Ma
- Department of Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
- Neuroimmunology and Neuroinflammation Research Laboratory, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Myriam Bunting
- Department of Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
- Neuroimmunology and Neuroinflammation Research Laboratory, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Jason Shing-Cheong Kwan
- Department of Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
- Neuroimmunology and Neuroinflammation Research Laboratory, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Guang-Jie Zhou
- The Swire Institute of Marine Science and School of Biological Sciences, The University of Hong Kong, Pokfulam, Hong Kong, China
| | - Krishnamoorthi Senthilkumar
- Mr & Mrs Ko Chi-Ming Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
| | - Ashok Iyaswamy
- Mr & Mrs Ko Chi-Ming Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
| | - Ping-Kei Chan
- Gene Control Mechanisms and Disease Group, Department of Brain Sciences, Faculty of Medicine, MRC London Institute of Medical Sciences, Imperial College London, London, W120NN, UK
| | - Min Li
- Mr & Mrs Ko Chi-Ming Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
| | - Kenneth Mei-Yee Leung
- The Swire Institute of Marine Science and School of Biological Sciences, The University of Hong Kong, Pokfulam, Hong Kong, China
| | - Siva-Sundara Kumar Durairajan
- Mr & Mrs Ko Chi-Ming Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
- Division of Myobiology and Neurodegenerative Disease Research, Department of Microbiology, School of Life Sciences, Central University of Tamil Nadu, Tiruvarur, India
| | - Karen Siu-Ling Lam
- Department of Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
- Research Center of Heart, Brain, Hormone and Healthy Aging, The University of Hong Kong, Pokfulam, Hong Kong, China
| | - Leung-Wing Chu
- Department of Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Richard Festenstein
- Gene Control Mechanisms and Disease Group, Department of Brain Sciences, Faculty of Medicine, MRC London Institute of Medical Sciences, Imperial College London, London, W120NN, UK
| | - Sookja Kim Chung
- Research Center of Heart, Brain, Hormone and Healthy Aging, The University of Hong Kong, Pokfulam, Hong Kong, China
- School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
- Faculty of Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macau
| | - Koon-Ho Chan
- Department of Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
- Neuroimmunology and Neuroinflammation Research Laboratory, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
- Research Center of Heart, Brain, Hormone and Healthy Aging, The University of Hong Kong, Pokfulam, Hong Kong, China.
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23
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Lindfors S, Polianskyte-Prause Z, Bouslama R, Lehtonen E, Mannerla M, Nisen H, Tienari J, Salmenkari H, Forsgård R, Mirtti T, Lehto M, Groop PH, Lehtonen S. Adiponectin receptor agonist AdipoRon ameliorates renal inflammation in diet-induced obese mice and endotoxin-treated human glomeruli ex vivo. Diabetologia 2021; 64:1866-1879. [PMID: 33987714 PMCID: PMC8245393 DOI: 10.1007/s00125-021-05473-9] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Accepted: 03/01/2021] [Indexed: 11/10/2022]
Abstract
AIMS/HYPOTHESIS Chronic low-grade inflammation with local upregulation of proinflammatory molecules plays a role in the progression of obesity-related renal injury. Reduced serum concentration of anti-inflammatory adiponectin may promote chronic inflammation. Here, we investigated the potential anti-inflammatory and renoprotective effects and mechanisms of action of AdipoRon, an adiponectin receptor agonist. METHODS Wild-type DBA/2J mice were fed with high-fat diet (HFD) supplemented or not with AdipoRon to model obesity-induced metabolic endotoxaemia and chronic low-grade inflammation and we assessed changes in the glomerular morphology and expression of proinflammatory markers. We also treated human glomeruli ex vivo and human podocytes in vitro with AdipoRon and bacterial lipopolysaccharide (LPS), an endotoxin upregulated in obesity and diabetes, and analysed the secretion of inflammatory cytokines, activation of inflammatory signal transduction pathways, apoptosis and migration. RESULTS In HFD-fed mice, AdipoRon attenuated renal inflammation, as demonstrated by reduced expression of glomerular activated NF-κB p65 subunit (NF-κB-p65) (70%, p < 0.001), TNFα (48%, p < 0.01), IL-1β (51%, p < 0.001) and TGFβ (46%, p < 0.001), renal IL-6 and IL-4 (21% and 20%, p < 0.05), and lowered glomerular F4/80-positive macrophage infiltration (31%, p < 0.001). In addition, AdipoRon ameliorated HFD-induced glomerular hypertrophy (12%, p < 0.001), fibronectin accumulation (50%, p < 0.01) and podocyte loss (12%, p < 0.001), and reduced podocyte foot process effacement (15%, p < 0.001) and thickening of the glomerular basement membrane (18%, p < 0.001). In cultured podocytes, AdipoRon attenuated the LPS-induced activation of the central inflammatory signalling pathways NF-κB-p65, c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38-MAPK) (30%, 36% and 22%, respectively, p < 0.001), reduced the secretion of TNFα (32%, p < 0.01), and protected against podocyte apoptosis and migration. In human glomeruli ex vivo, AdipoRon reduced the LPS-induced secretion of inflammatory cytokines IL-1β, IL-18, IL-6 and IL-10. CONCLUSIONS/INTERPRETATION AdipoRon attenuated the renal expression of proinflammatory cytokines in HFD-fed mice and LPS-stimulated human glomeruli, which apparently contributed to the amelioration of glomerular inflammation and injury. Mechanistically, based on assays on cultured podocytes, AdipoRon reduced LPS-induced activation of the NF-κB-p65, JNK and p38-MAPK pathways, thereby impelling the decrease in apoptosis, migration and secretion of TNFα. We conclude that the activation of the adiponectin receptor by AdipoRon is a potent strategy to attenuate endotoxaemia-associated renal inflammation.
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Affiliation(s)
- Sonja Lindfors
- Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Zydrune Polianskyte-Prause
- Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Rim Bouslama
- Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Eero Lehtonen
- Department of Pathology, University of Helsinki, Helsinki, Finland
| | - Miia Mannerla
- Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland
- Abdominal Center, Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Harry Nisen
- Abdominal Center, Urology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Jukka Tienari
- Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Hanne Salmenkari
- Pharmacology, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Richard Forsgård
- Pharmacology, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Tuomas Mirtti
- Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Research Program in Systems Oncology, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Markku Lehto
- Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland
- Abdominal Center, Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Per-Henrik Groop
- Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland
- Abdominal Center, Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Department of Diabetes, Central Clinical School, Monash University, Melbourne, VIC, Australia
| | - Sanna Lehtonen
- Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
- Department of Pathology, University of Helsinki, Helsinki, Finland.
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24
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PEGylated AdipoRon derivatives improve glucose and lipid metabolism under insulinopenic and high-fat diet conditions. J Lipid Res 2021; 62:100095. [PMID: 34214600 PMCID: PMC8327158 DOI: 10.1016/j.jlr.2021.100095] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Accepted: 06/17/2021] [Indexed: 12/19/2022] Open
Abstract
The pleiotropic actions of adiponectin in improving cell survival and metabolism have motivated the development of small-molecule therapeutic agents for treating diabetes and lipotoxicity. AdipoRon is a synthetic agonist of the adiponectin receptors, yet is limited by its poor solubility and bioavailability. In this work, we expand on the protective effects of AdipoRon in pancreatic β-cells and examine how structural modifications could affect the activity, pharmacokinetics, and bioavailability of this small molecule. We describe a series of AdipoRon analogs containing amphiphilic ethylene glycol (PEG) chains. Among these, AdipoRonPEG5 induced pleiotropic effects in mice under insulinopenic and high-fat diet (HFD) conditions. While both AdipoRon and AdipoRonPEG5 substantially attenuate palmitate-induced lipotoxicity in INS-1 cells, only AdipoRonPEG5 treatment is accompanied by a significant reduction in cytotoxic ceramides. In vivo, AdipoRonPEG5 can substantially reduce pancreatic, hepatic, and serum ceramide species, with a concomitant increase in the corresponding sphingoid bases and improves insulin sensitivity of mice under HFD feeding conditions. Furthermore, hyperglycemia in streptozotocin (STZ)-induced insulinopenic adiponectin-null mice is also attenuated upon AdipoRonPEG5 treatment. Our results suggest that AdipoRonPEG5 is more effective in reducing ceramides and dihydroceramides in the liver of HFD-fed mice than AdipoRon, consistent with its potent activity in activating ceramidase in vitro in INS-1 cells. Additionally, these results indicate that the beneficial effects of AdipoRonPEG5 can be partially attributed to improved pharmacokinetics as compared with AdipoRon, thus suggesting that further derivatization may improve affinity and tissue-specific targeting.
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25
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Lee TH, Christie BR, Lin K, Siu PMF, Zhang L, Yuan TF, Komal P, Xu A, So KF, Yau SY. Chronic AdipoRon Treatment Mimics the Effects of Physical Exercise on Restoring Hippocampal Neuroplasticity in Diabetic Mice. Mol Neurobiol 2021; 58:4666-4681. [PMID: 34164760 PMCID: PMC8487422 DOI: 10.1007/s12035-021-02441-7] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Accepted: 05/25/2021] [Indexed: 02/07/2023]
Abstract
Administration of exercise mimetic drugs could be a novel therapeutic approach to combat comorbid neurodegeneration and metabolic syndromes. Adiponectin is an adipocyte-secreted hormone. In addition to its antidiabetic effect, adiponectin mediates the antidepressant effect of physical exercise associated with adult hippocampal neurogenesis. The antidiabetic effect of the adiponectin receptor agonist AdipoRon has been demonstrated, but its potential pro-cognitive and neurotrophic effects in the hippocampus under diabetic condition are still unclear. This study reported that chronic AdipoRon treatment for 2 weeks improved hippocampal-dependent spatial recognition memory in streptozotocin-induced diabetic mice. Besides, AdipoRon treatment increased progenitor cell proliferation and neuronal differentiation in the hippocampal dentate gyrus (DG) of diabetic mice. Furthermore, AdipoRon treatment significantly increased dendritic complexity, spine density, and N-methyl-D-aspartate receptor-dependent long-term potentiation (LTP) in the dentate region, and increased BDNF levels in the DG of diabetic mice. AdipoRon treatment activated AMPK/PGC-1α signalling in the DG, whereas increases in cell proliferation and LTP were not observed when PGC-1α signalling was pharmacologically inhibited. In sum, chronic AdipoRon treatment partially mimics the benefits of physical exercise for learning and memory and hippocampal neuroplasticity in the diabetic brain. The results suggested that AdipoRon could be a potential physical exercise mimetic to improve hippocampal plasticity and hence rescue learning and memory impairment typically associated with diabetes.
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Affiliation(s)
- Thomas H Lee
- Department of Rehabilitation Sciences, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University, 11 Yuk Choi Road, Hung Hom, Hong Kong SAR
| | - Brian R Christie
- Division of Medical Sciences, University of Victoria, Victoria, British Columbia, Canada
| | - Kangguang Lin
- Department of Affective Disorder, Guangzhou Brain Hospital, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou, China
| | - Parco Ming-Fai Siu
- School of Public Health, LKS Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR
| | - Li Zhang
- Key Laboratory of CNS Regeneration (Ministry of Education), Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China
| | - Ti-Fei Yuan
- Shanghai Mental Health Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Pragya Komal
- Department of Biological Sciences, Birla Institute of Technology and Sciences (BITS-Pilani Hyderabad), Hyderabad, India
| | - Aimin Xu
- Department of Pharmacology and Pharmacy, LKS Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR
- State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Pokfulam, Hong Kong SAR
| | - Kwok-Fai So
- Key Laboratory of CNS Regeneration (Ministry of Education), Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China
- State Key Laboratory of Brain and Cognitive Science, The University of Hong Kong, Pokfulam, Hong Kong SAR
| | - Suk-Yu Yau
- Department of Rehabilitation Sciences, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University, 11 Yuk Choi Road, Hung Hom, Hong Kong SAR.
- University Research Facility in Behavioral and Systems Neuroscience, The Hong Kong Polytechnic University, Hung Hom, Hong Kong SAR.
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26
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Sowka A, Dobrzyn P. Role of Perivascular Adipose Tissue-Derived Adiponectin in Vascular Homeostasis. Cells 2021; 10:cells10061485. [PMID: 34204799 PMCID: PMC8231548 DOI: 10.3390/cells10061485] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Revised: 06/04/2021] [Accepted: 06/08/2021] [Indexed: 12/27/2022] Open
Abstract
Studies of adipose tissue biology have demonstrated that adipose tissue should be considered as both passive, energy-storing tissue and an endocrine organ because of the secretion of adipose-specific factors, called adipokines. Adiponectin is a well-described homeostatic adipokine with metabolic properties. It regulates whole-body energy status through the induction of fatty acid oxidation and glucose uptake. Adiponectin also has anti-inflammatory and antidiabetic properties, making it an interesting subject of biomedical studies. Perivascular adipose tissue (PVAT) is a fat depot that is conterminous to the vascular wall and acts on it in a paracrine manner through adipokine secretion. PVAT-derived adiponectin can act on the vascular wall through endothelial cells and vascular smooth muscle cells. The present review describes adiponectin's structure, receptors, and main signaling pathways. We further discuss recent studies of the extent and nature of crosstalk between PVAT-derived adiponectin and endothelial cells, vascular smooth muscle cells, and atherosclerotic plaques. Furthermore, we argue whether adiponectin and its receptors may be considered putative therapeutic targets.
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27
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Bhat IA, Kabeer SW, Reza MI, Mir RH, Dar MO. AdipoRon: A Novel Insulin Sensitizer in Various Complications and the Underlying Mechanisms: A Review. Curr Mol Pharmacol 2021; 13:94-107. [PMID: 31642417 DOI: 10.2174/1874467212666191022102800] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Revised: 09/26/2019] [Accepted: 10/03/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND AdipoRon is the first synthetic analog of endogenous adiponectin, an adipose tissue-derived hormone. AdipoRon possesses pharmacological properties similar to adiponectin and its ability to bind and activate the adipoR1 and adipoR2 receptors makes it a suitable candidate for the treatment of a multitude of disorders. OBJECTIVE In the present review, an attempt was made to compile and discuss the efficacy of adipoRon against various disorders. RESULTS AdipoRon is a drug that acts not only in metabolic diseases but in other conditions unrelated to energy metabolism. It is well- reported that adipoRon exhibits strong anti-obesity, anti-diabetic, anticancer, anti-depressant, anti-ischemic, anti-hypertrophic properties and also improves conditions like post-traumatic stress disorder, anxiety, and systemic sclerosis. CONCLUSION A lot is known about its effects in experimental systems, but the translation of this knowledge to the clinic requires studies which, for many of the potential target conditions, have yet to be carried out. The beneficial effects of AdipoRon in novel clinical conditions will suggest an underlying pathophysiological role of adiponectin and its receptors in previously unsuspected settings.
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Affiliation(s)
- Ishfaq Ahmad Bhat
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar (Mohali), Punjab-160062, India
| | - Shaheen Wasil Kabeer
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar (Mohali), Punjab-160062, India
| | - Mohammad Irshad Reza
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar (Mohali), Punjab-160062, India
| | - Reyaz Hassan Mir
- Department of Pharmaceutical Sciences, Faculty of Applied Sciences and Technology, University of Kashmir, Hazratbal, Srinagar-190006, J&K, India
| | - Muhammad Ovais Dar
- Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, Mohali, Punjab, 160062, India
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28
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Lee TH, Christie BR, van Praag H, Lin K, Siu PMF, Xu A, So KF, Yau SY. AdipoRon Treatment Induces a Dose-Dependent Response in Adult Hippocampal Neurogenesis. Int J Mol Sci 2021; 22:2068. [PMID: 33669795 PMCID: PMC7922380 DOI: 10.3390/ijms22042068] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 02/01/2021] [Accepted: 02/05/2021] [Indexed: 12/28/2022] Open
Abstract
AdipoRon, an adiponectin receptor agonist, elicits similar antidiabetic, anti-atherogenic, and anti-inflammatory effects on mouse models as adiponectin does. Since AdipoRon can cross the blood-brain barrier, its chronic effects on regulating hippocampal function are yet to be examined. This study investigated whether AdipoRon treatment promotes hippocampal neurogenesis and spatial recognition memory in a dose-dependent manner. Adolescent male C57BL/6J mice received continuous treatment of either 20 mg/kg (low dose) or 50 mg/kg (high dose) AdipoRon or vehicle intraperitoneally for 14 days, followed by the open field test to examine anxiety and locomotor activity, and the Y maze test to examine hippocampal-dependent spatial recognition memory. Immunopositive cell markers of neural progenitor cells, immature neurons, and newborn cells in the hippocampal dentate gyrus were quantified. Immunosorbent assays were used to measure the serum levels of factors that can regulate hippocampal neurogenesis, including adiponectin, brain-derived neurotrophic factor (BDNF), and corticosterone. Our results showed that 20 mg/kg AdipoRon treatment significantly promoted hippocampal cell proliferation and increased serum levels of adiponectin and BDNF, though there were no effects on spatial recognition memory and locomotor activity. On the contrary, 50 mg/kg AdipoRon treatment impaired spatial recognition memory, suppressed cell proliferation, neuronal differentiation, and cell survival associated with reduced serum levels of BDNF and adiponectin. The results suggest that a low-dose AdipoRon treatment promotes hippocampal cell proliferation, while a high-dose AdipoRon treatment is detrimental to the hippocampus function.
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Affiliation(s)
- Thomas H. Lee
- Department of Rehabilitation Sciences, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University, Hong Kong;
| | - Brian R. Christie
- Division of Biomedical Sciences, University of Victoria, Victoria, BC V8P 5C2, Canada;
| | - Henriette van Praag
- FAU Brain Institute and Charles E. Schmidt College of Medicine, Florida Atlantic University, Jupiter, FL 33431, USA;
| | - Kangguang Lin
- Department of Affective Disorder, Guangzhou Brain Hospital, The Brain Affiliated Hospital of Guangzhou Medical University, Guangzhou 510370, China;
| | - Parco Ming-Fai Siu
- Division of Kinesiology, School of Public Health, The University of Hong Kong, Hong Kong;
| | - Aimin Xu
- Department of Medicine, The University of Hong Kong, Hong Kong;
- Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong
- The State Key Laboratory of Pharmacology, The University of Hong Kong, Hong Kong
| | - Kwok-Fai So
- Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou 510632, China;
- State Key Laboratory of Brain and Cognitive Sciences, The University of Hong Kong, Hong Kong
- Department of Ophthalmology, The University of Hong Kong, Hong Kong
| | - Suk-yu Yau
- Department of Rehabilitation Sciences, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University, Hong Kong;
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Subba R, Sandhir R, Singh SP, Mallick BN, Mondal AC. Pathophysiology linking depression and type 2 diabetes: Psychotherapy, physical exercise, and fecal microbiome transplantation as damage control. Eur J Neurosci 2021; 53:2870-2900. [PMID: 33529409 DOI: 10.1111/ejn.15136] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 01/10/2021] [Accepted: 01/28/2021] [Indexed: 02/06/2023]
Abstract
Diabetes increases the likelihood of developing depression and vice versa. Research on this bidirectional association has somewhat managed to delineate the interplay among implicated physiological processes. Still, further exploration is required in this context. This review addresses the comorbidity by investigating suspected common pathophysiological mechanisms. One such factor is psychological stress which disturbs the hypothalamic-pituitary-adrenal axis causing hormonal imbalance. This includes elevated cortisol levels, a common biomarker of both depression and diabetes. Disrupted insulin signaling drives the hampered neurotransmission of serotonin, dopamine, and norepinephrine. Also, adipokine hormones such as adiponectin, leptin, and resistin and the orexigenic hormone, ghrelin, are involved in both depression and T2DM. This disarray further interferes with physiological processes encompassing sleep, the gut-brain axis, metabolism, and mood stability. Behavioral coping mechanisms, such as unhealthy eating, mediate disturbed glucose homeostasis, and neuroinflammation. This is intricately linked to oxidative stress, redox imbalance, and mitochondrial dysfunction. However, interventions such as psychotherapy, physical exercise, fecal microbiota transplantation, and insulin-sensitizing agents can help to manage the distressing condition. The possibility of glucagon-like peptide 1 possessing a therapeutic role has also been discussed. Nonetheless, there stands an urgent need for unraveling new correlating targets and biological markers for efficient treatment.
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Affiliation(s)
- Rhea Subba
- School of Life Sciences, Jawaharlal Nehru University, New Delhi, India
| | - Rajat Sandhir
- Dept. of Biochemistry, Panjab University, Chandigarh, Punjab, India
| | - Surya Pratap Singh
- Dept. of Biochemistry, Banaras Hindu University, Varanasi, Uttar Pradesh, India
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Wang XQ, Tang YH, Zeng GR, Wu LF, Zhou YJ, Cheng ZN, Jiang DJ. Carnosic acid alleviates depression-like behaviors on chronic mild stressed mice via PPAR-γ-dependent regulation of ADPN/FGF9 pathway. Psychopharmacology (Berl) 2021; 238:501-516. [PMID: 33161473 DOI: 10.1007/s00213-020-05699-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Accepted: 10/30/2020] [Indexed: 01/12/2023]
Abstract
RATIONALE The pathway of adiponectin (ADPN)/fibroblast growth factor 9 (FGF9) was recently thought as a key role in the development of depression. ADPN is crucially regulated by peroxisome proliferator-activated receptor-gamma (PPAR-γ). Natural material carnosic acid (CA) has been applied for therapeutics of mental disorders. OBJECTIVES To evaluate the antidepressive effect of CA in stress-treated mice and define whether its effects is involved in the regulation of ADPN/FGF9 pathway. METHODS In vivo study, the levels of ADPN and FGF9 in both serum and hippocampus tissues, the expressions of ADPN receptor 2 (AdipoR2) in hippocampus and PPAR-γ in abdominal adipose, as well as the pathological changes of hippocampus were determined in 28-day period of chronic unpredictable mild stress (CUMS)-induced depression model of male ICR (Institute of Cancer Research) mice or adipo-/- mice. In vitro study, the level of ADPN and the mRNA expressions of both ADPN and PPAR-γ were determined in mouse 3T3-L1 preadipocytes. RESULTS In vivo study, treatment with CA (50 or 100 mg/kg per day) for 21 days markedly suppressed depressive-like behaviors, the elevating levels of FGF9 and decreasing levels of ADPN in both serum and hippocampus tissues, the downregulating protein and mRNA expressions of AdipoR2 in hippocampus and PPAR-γ in abdominal adipose, as well as the pathological injury of hippocampus induced by CUMS in male ICR mice. The antidepressive effects of CA were markedly attenuated in male CUMS-treated adipo-/- mice. In vitro study, incubation with CA (3-30 μmol/L) for 24 h could concentration-dependently upregulate the mRNA expressions of both PPAR-γ and ADPN as well as increase the level of ADPN. The experiments using PPAR-γ-specific inhibitor GW9662 and transient transfection with mutated PPAR-γ-binding site promotor constructs showed that the activation of PPAR-γ mediated CA-induced ADPN expression in adipocytes. CONCLUSIONS CA could significantly improve stress-induced depressive disorder, which may be related to regulating the dysfunction of ADPN-FGF9 pathway via activating PPAR-γ in adipocytes.
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Affiliation(s)
- Xiao-Qing Wang
- XiangYa Pharmacy School, Central South University, Changsha, 410083, China.,Hunan Center for Safety Evaluation and Research of Drugs & Hunan Key Laboratory for Pharmacodynamics and Safety Evaluation of New Drugs, Changsha, 410013, China
| | - Ya-Hui Tang
- Hunan Center for Safety Evaluation and Research of Drugs & Hunan Key Laboratory for Pharmacodynamics and Safety Evaluation of New Drugs, Changsha, 410013, China
| | - Gui-Rong Zeng
- Hunan Center for Safety Evaluation and Research of Drugs & Hunan Key Laboratory for Pharmacodynamics and Safety Evaluation of New Drugs, Changsha, 410013, China
| | - Li-Feng Wu
- Hunan Center for Safety Evaluation and Research of Drugs & Hunan Key Laboratory for Pharmacodynamics and Safety Evaluation of New Drugs, Changsha, 410013, China
| | - Ying-Jun Zhou
- XiangYa Pharmacy School, Central South University, Changsha, 410083, China
| | - Ze-Neng Cheng
- XiangYa Pharmacy School, Central South University, Changsha, 410083, China.
| | - De-Jian Jiang
- Hunan Center for Safety Evaluation and Research of Drugs & Hunan Key Laboratory for Pharmacodynamics and Safety Evaluation of New Drugs, Changsha, 410013, China.
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Theilade S, Christensen MB, Vilsbøll T, Knop FK. An overview of obesity mechanisms in humans: Endocrine regulation of food intake, eating behaviour and common determinants of body weight. Diabetes Obes Metab 2021; 23 Suppl 1:17-35. [PMID: 33621414 DOI: 10.1111/dom.14270] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Revised: 11/21/2020] [Accepted: 11/23/2020] [Indexed: 12/13/2022]
Abstract
Obesity is one of the biggest health challenges of the 21st century, already affecting close to 700 million people worldwide, debilitating and shortening lives and costing billions of pounds in healthcare costs and loss of workability. Body weight homeostasis relies on complex biological mechanisms and the development of obesity occurs on a background of genetic susceptibility and an environment promoting increased caloric intake and reduced physical activity. The pathophysiology of common obesity links neuro-endocrine and metabolic disturbances with behavioural changes, genetics, epigenetics and cultural habits. Also, specific causes of obesity exist, including monogenetic diseases and iatrogenic causes. In this review, we provide an overview of obesity mechanisms in humans with a focus on energy homeostasis, endocrine regulation of food intake and eating behavior, as well as the most common specific causes of obesity.
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Affiliation(s)
- Simone Theilade
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Medicine, Herlev-Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Mikkel B Christensen
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Pharmacology, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark
- Copenhagen Center for Translational Research, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Tina Vilsbøll
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Steno Diabetes Center Copenhagen, Gentofte, Denmark
| | - Filip K Knop
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Medicine, Herlev-Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark
- Steno Diabetes Center Copenhagen, Gentofte, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Uddin MS, Rahman MM, Sufian MA, Jeandet P, Ashraf GM, Bin-Jumah MN, Mousa SA, Abdel-Daim MM, Akhtar MF, Saleem A, Amran MS. Exploring the New Horizon of AdipoQ in Obesity-Related Alzheimer's Dementia. Front Physiol 2021; 11:567678. [PMID: 33584324 PMCID: PMC7873563 DOI: 10.3389/fphys.2020.567678] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2020] [Accepted: 12/21/2020] [Indexed: 12/15/2022] Open
Abstract
Alzheimer's disease (AD) is the most common form of dementia, which causes abnormalities in learning, thinking, memory, as well as behavior. Generally, symptoms of AD develop gradually and aggravate over time, and consequently severely interfere with daily activities. Furthermore, obesity is one of the common risk factors for dementia. Dysregulation of adipokine and adipocyte dysfunction are assumed to be accountable for the high risk of obesity in people that develop many related disorders such as AD. Moreover, it has been observed that the dysfunction of adipose is connected with changes in brain metabolism, brain atrophy, cognitive decline, impaired mood, neuroinflammation, impaired insulin signaling, and neuronal dysfunction in people with obesity. Conversely, the pathological mechanisms, as well as the molecular players which are involved in this association, have been unclear until now. In this article, we discuss the impact of adiponectin (AdipoQ) on obesity-related Alzheimer's dementia.
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Affiliation(s)
- Md. Sahab Uddin
- Department of Pharmacy, Southeast University, Dhaka, Bangladesh
- Pharmakon Neuroscience Research Network, Dhaka, Bangladesh
| | - Md. Motiar Rahman
- Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology (SIAT), Chinese Academy of Sciences (CAS), Shenzhen, China
| | - Mohammad Abu Sufian
- Department of Pharmacy, Southeast University, Dhaka, Bangladesh
- Pharmakon Neuroscience Research Network, Dhaka, Bangladesh
| | - Philippe Jeandet
- Research Unit, Induced Resistance and Plant Bioprotection, EA 4707, SFR Condorcet FR CNRS 3417, Faculty of Sciences, University of Reims Champagne-Ardenne, Reims Cedex, France
| | - Ghulam Md. Ashraf
- Pre-clinical Research Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
| | - May N. Bin-Jumah
- Department of Biology, College of Science, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia
| | - Shaker A. Mousa
- Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, New York, NY, United States
| | - Mohamed M. Abdel-Daim
- Department of Zoology, College of Science, King Saud University, Riyadh, Saudi Arabia
- Pharmacology Department, Faculty of Veterinary Medicine, Suez Canal University, Ismailia, Egypt
| | - Muhammad Furqan Akhtar
- Riphah Institute of Pharmaceutical Sciences, Riphah International University, Lahore, Pakistan
| | - Ammara Saleem
- Department of Pharmacology, Faculty of Pharmaceutical Sciences, Government College University Faisalabad, Faisalabad, Pakistan
| | - Md. Shah Amran
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Dhaka, Dhaka, Bangladesh
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Francischetti EA, Dezonne RS, Pereira CM, de Moraes Martins CJ, Celoria BMJ, de Oliveira PAC, de Abreu VG. Insights Into the Controversial Aspects of Adiponectin in Cardiometabolic Disorders. Horm Metab Res 2020; 52:695-707. [PMID: 32927496 DOI: 10.1055/a-1239-4349] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
In 2016, the World Health Organization estimated that more than 1.9 billion adults were overweight or obese. This impressive number shows that weight excess is pandemic. Overweight and obesity are closely associated with a high risk of comorbidities, such as insulin resistance and its most important outcomes, including metabolic syndrome, type 2 diabetes mellitus, and cardiovascular disease. Adiponectin has emerged as a salutary adipocytokine, with insulin-sensitizing, anti-inflammatory, and cardiovascular protective properties. However, under metabolically unfavorable conditions, visceral adipose tissue-derived inflammatory cytokines might reduce the transcription of the adiponectin gene and consequently its circulating levels. Low circulating levels of adiponectin are negatively associated with various conditions, such as insulin resistance, type 2 diabetes mellitus, metabolic syndrome, and cardiovascular disease. In contrast, several recent clinical trials and meta-analyses have reported high circulating adiponectin levels positively associated with cardiovascular mortality and all-cause mortality. These results are biologically intriguing and counterintuitive, and came to be termed "the adiponectin paradox". Adiponectin paradox is frequently associated with adiponectin resistance, a concept related with the downregulation of adiponectin receptors in insulin-resistant states. We review this contradiction between the apparent role of adiponectin as a health promoter and the recent evidence from Mendelian randomization studies indicating that circulating adiponectin levels are an unexpected predictor of increased morbidity and mortality rates in several clinical conditions. We also critically review the therapeutic perspective of synthetic peptide adiponectin receptors agonist that has been postulated as a promising alternative for the treatment of metabolic syndrome and type 2 diabetes mellitus.
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Affiliation(s)
- Emilio Antonio Francischetti
- Laboratory of Clinical and Experimental Pathophysiology, Rio de Janeiro State University, Rio de Janeiro, Brazil
| | - Rômulo Sperduto Dezonne
- Postgraduate Program in Translational Biomedicine, Grande Rio University, Duque de Caxias, Brazil
| | - Cláudia Maria Pereira
- Postgraduate Program in Translational Biomedicine, Grande Rio University, Duque de Caxias, Brazil
| | - Cyro José de Moraes Martins
- Laboratory of Clinical and Experimental Pathophysiology, Rio de Janeiro State University, Rio de Janeiro, Brazil
| | | | | | - Virgínia Genelhu de Abreu
- Laboratory of Clinical and Experimental Pathophysiology, Rio de Janeiro State University, Rio de Janeiro, Brazil
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Kim JY, Barua S, Jeong YJ, Lee JE. Adiponectin: The Potential Regulator and Therapeutic Target of Obesity and Alzheimer's Disease. Int J Mol Sci 2020; 21:6419. [PMID: 32899357 PMCID: PMC7504582 DOI: 10.3390/ijms21176419] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Revised: 08/28/2020] [Accepted: 08/28/2020] [Indexed: 02/08/2023] Open
Abstract
Animal and human mechanistic studies have consistently shown an association between obesity and Alzheimer's disease (AD). AD, a degenerative brain disease, is the most common cause of dementia and is characterized by the presence of extracellular amyloid beta (Aβ) plaques and intracellular neurofibrillary tangles disposition. Some studies have recently demonstrated that Aβ and tau cannot fully explain the pathophysiological development of AD and that metabolic disease factors, such as insulin, adiponectin, and antioxidants, are important for the sporadic onset of nongenetic AD. Obesity prevention and treatment can be an efficacious and safe approach to AD prevention. Adiponectin is a benign adipokine that sensitizes the insulin receptor signaling pathway and suppresses inflammation. It has been shown to be inversely correlated with adipose tissue dysfunction and may enhance the risk of AD because a range of neuroprotection adiponectin mechanisms is related to AD pathology alleviation. In this study, we summarize the recent progress that addresses the beneficial effects and potential mechanisms of adiponectin in AD. Furthermore, we review recent studies on the diverse medications of adiponectin that could possibly be related to AD treatment, with a focus on their association with adiponectin. A better understanding of the neuroprotection roles of adiponectin will help clarify the precise underlying mechanism of AD development and progression.
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Affiliation(s)
- Jong Youl Kim
- Department of Anatomy, Yonsei University College of Medicine, Seoul 120-752, Korea; (J.Y.K.); (S.B.); (Y.J.J.)
| | - Sumit Barua
- Department of Anatomy, Yonsei University College of Medicine, Seoul 120-752, Korea; (J.Y.K.); (S.B.); (Y.J.J.)
| | - Ye Jun Jeong
- Department of Anatomy, Yonsei University College of Medicine, Seoul 120-752, Korea; (J.Y.K.); (S.B.); (Y.J.J.)
| | - Jong Eun Lee
- Department of Anatomy, Yonsei University College of Medicine, Seoul 120-752, Korea; (J.Y.K.); (S.B.); (Y.J.J.)
- BK21 Plus Project for Medical Sciences, and Brain Research Institute, Yonsei University College of Medicine, Seoul 120-752, Korea
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Abstract
Adiponectin is a hormone secreted by adipose tissue, exerting many positive effects in the human body. Its action has been widely studied, placing it into the metabolic health beneficial products of the adipose tissue. Nevertheless, adiponectin has been shown to exert some extra beneficial non metabolic actions, as well. Adiponectin levels can be related to reduced incidence of cancer in obese patients. Moreover, adiponectin has been shown to be implicated in the positive fertility outcomes of women. Some new studies have also indicated that adiponectin has a potential effect in the control of appetite, which raises a question, whether adiponectin could be accredited to be useful in the endocrine evaluation of obesity. Could these additional non-metabolic actions prove its helpfulness?
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Pathak MP, Das A, Patowary P, Chattopadhyay P. Contentious role of 'Good Adiponectin' in pulmonary and cardiovascular diseases: Is adiponectin directed therapy a boon or a bane? Biochimie 2020; 175:106-119. [PMID: 32473183 DOI: 10.1016/j.biochi.2020.05.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Revised: 04/27/2020] [Accepted: 05/12/2020] [Indexed: 11/24/2022]
Abstract
After two decades of its discovery, numerous facts of adiponectin (APN) biology has been uncovered, yet, APN remains an elusive adipokine. Findings from clinical studies and animal models established APN's ameliorative role in cardiovascular disease (CVD) and pulmonary disease (PD) but the same condition is prognostic for mortality in the same set of patients which cornered APN towards a dubious state. A repertoire of mechanisms associated with the positive association of APN in both lean/cachectic or obese CVD and PD patients from past publications are evaluated. Newer pharmacological agent may be explored to regulate elevated blood APN concentration in COPD or CHF patients whereas administration of recombinant APN as well as growth hormone may augment blood APN concentration in obese subjects associated with low blood and intracellular APN concentration. However, some APN directed therapy in clinical as well as in pre-clinical setup has pronounced some contentious effects. After reviewing the mechanisms of the contentious role of APN functioning in pathologic conditions of CVD and PD in both lean and obese conditions, the authors came to conclusion that APN directed therapy may be utilized with caution keeping in mind the different age group, sex and the different CVD as well as pulmonary diseases they are suffering from.
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Affiliation(s)
- Manash Pratim Pathak
- Division of Pharmaceutical Technology, Defence Research Laboratory, Tezpur, India; Department of Pharmaceutical Sciences, Dibrugarh University, Dibrugarh, India
| | - Aparoop Das
- Department of Pharmaceutical Sciences, Dibrugarh University, Dibrugarh, India
| | - Pompy Patowary
- Division of Pharmaceutical Technology, Defence Research Laboratory, Tezpur, India; Department of Pharmaceutical Sciences, Dibrugarh University, Dibrugarh, India
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Liu B, Liu J, Wang JG, Liu CL, Yan HJ. AdipoRon improves cognitive dysfunction of Alzheimer’s disease and rescues impaired neural stem cell proliferation through AdipoR1/AMPK pathway. Exp Neurol 2020; 327:113249. [DOI: 10.1016/j.expneurol.2020.113249] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Revised: 02/03/2020] [Accepted: 02/14/2020] [Indexed: 12/16/2022]
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Abou-Samra M, Selvais CM, Dubuisson N, Brichard SM. Adiponectin and Its Mimics on Skeletal Muscle: Insulin Sensitizers, Fat Burners, Exercise Mimickers, Muscling Pills … or Everything Together? Int J Mol Sci 2020; 21:ijms21072620. [PMID: 32283840 PMCID: PMC7178193 DOI: 10.3390/ijms21072620] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Revised: 04/01/2020] [Accepted: 04/03/2020] [Indexed: 02/07/2023] Open
Abstract
Adiponectin (ApN) is a hormone abundantly secreted by adipocytes and it is known to be tightly linked to the metabolic syndrome. It promotes insulin-sensitizing, fat-burning, and anti-atherosclerotic actions, thereby effectively counteracting several metabolic disorders, including type 2 diabetes, obesity, and cardiovascular diseases. ApN is also known today to possess powerful anti-inflammatory/oxidative and pro-myogenic effects on skeletal muscles exposed to acute or chronic inflammation and injury, mainly through AdipoR1 (ApN specific muscle receptor) and AMP-activated protein kinase (AMPK) pathway, but also via T-cadherin. In this review, we will report all the beneficial and protective properties that ApN can exert, specifically on the skeletal muscle as a target tissue. We will highlight its effects and mechanisms of action, first in healthy skeletal muscle including exercised muscle, and second in diseased muscle from a variety of pathological conditions. In the end, we will go over some of AdipoRs agonists that can be easily produced and administered, and which can greatly mimic ApN. These interesting and newly identified molecules could pave the way towards future therapeutic approaches to potentially prevent or combat not only skeletal muscle disorders but also a plethora of other diseases with sterile inflammation or metabolic dysfunction.
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Abou-Samra M, Selvais CM, Boursereau R, Lecompte S, Noel L, Brichard SM. AdipoRon, a new therapeutic prospect for Duchenne muscular dystrophy. J Cachexia Sarcopenia Muscle 2020; 11:518-533. [PMID: 31965757 PMCID: PMC7113498 DOI: 10.1002/jcsm.12531] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2019] [Revised: 10/23/2019] [Accepted: 11/14/2019] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Adiponectin (ApN) is a hormone known to exhibit insulin-sensitizing, fat-burning, and anti-inflammatory properties in several tissues, including the skeletal muscle. Duchenne muscular dystrophy (DMD) is a devastating disease characterized by dystrophin deficiency with subsequent chronic inflammation, myofiber necrosis, and impaired regeneration. Previously, we showed that transgenic up-regulation of ApN could significantly attenuate the dystrophic phenotype in mdx mice (model of DMD). Recently, an orally active ApN receptor agonist, AdipoRon, has been identified. This synthetic small molecule has the advantage of being more easily produced and administrable than ApN. The aim of this study was to investigate the potential effects of AdipoRon on the dystrophic muscle. METHODS Four-week-old mdx mice (n = 6-9 per group) were orally treated with AdipoRon (mdx-AR) for 8 weeks and compared with untreated (mdx) mice and to control (wild-type) mice. In vivo functional tests were carried out to measure the global force and endurance of mice. Ex vivo biochemical and molecular analyses were performed to evaluate the pathophysiology of the skeletal muscle. Finally, in vitro tests were conducted on primary cultures of healthy and DMD human myotubes. RESULTS AdipoRon treatment mitigated oxidative stress (-30% to 45% for 4-hydroxy-2-nonenal and peroxiredoxin 3, P < 0.0001) as well as inflammation in muscles of mdx mice (-35% to 65% for interleukin 1 beta, tumour necrosis factor alpha, and cluster of differentiation 68, a macrophage maker, P < 0.0001) while increasing the anti-inflammatory cytokine, interleukin 10 (~5-fold, P < 0.0001). AdipoRon also improved the myogenic programme as assessed by a ~2-fold rise in markers of muscle proliferation and differentiation (P < 0.01 or less vs. untreated mdx). Plasma lactate dehydrogenase and creatine kinase were reduced by 30-40% in mdx-AR mice, reflecting less sarcolemmal damage (P < 0.0001). When compared with untreated mdx mice, mdx-AR mice exhibited enhanced physical performance with an increase in both muscle force and endurance and a striking restoration of the running capacity during eccentric exercise. AdipoRon mainly acted through ApN receptor 1 by increasing AMP-activated protein kinase signalling, which led to repression of nuclear factor-kappa B, up-regulation of utrophin (a dystrophin analogue), and a switch towards an oxidative and more resistant fibre phenotype. The effects of AdipoRon were then recapitulated in human DMD myotubes. CONCLUSIONS These results demonstrate that AdipoRon exerts several beneficial effects on the dystrophic muscle. This molecule could offer promising therapeutic prospect for managing DMD or other muscle and inflammatory disorders.
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Affiliation(s)
- Michel Abou-Samra
- Endocrinology, Diabetes and Nutrition Unit, Institute of Experimental and Clinical Research, Medical Sector, Université Catholique de Louvain, Brussels, Belgium
| | - Camille M Selvais
- Endocrinology, Diabetes and Nutrition Unit, Institute of Experimental and Clinical Research, Medical Sector, Université Catholique de Louvain, Brussels, Belgium
| | - Raphael Boursereau
- Endocrinology, Diabetes and Nutrition Unit, Institute of Experimental and Clinical Research, Medical Sector, Université Catholique de Louvain, Brussels, Belgium
| | - Sophie Lecompte
- Endocrinology, Diabetes and Nutrition Unit, Institute of Experimental and Clinical Research, Medical Sector, Université Catholique de Louvain, Brussels, Belgium
| | - Laurence Noel
- Endocrinology, Diabetes and Nutrition Unit, Institute of Experimental and Clinical Research, Medical Sector, Université Catholique de Louvain, Brussels, Belgium
| | - Sonia M Brichard
- Endocrinology, Diabetes and Nutrition Unit, Institute of Experimental and Clinical Research, Medical Sector, Université Catholique de Louvain, Brussels, Belgium
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Sun LN, Liu XL. Functions of adiponectin signaling in regulating neural plasticity and its application as the therapeutic target to neurological and psychiatric diseases. Rev Neurosci 2020; 30:485-495. [PMID: 30864396 DOI: 10.1515/revneuro-2018-0062] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2018] [Accepted: 10/06/2018] [Indexed: 12/15/2022]
Abstract
Convergent lines of evidence indicate the critical roles of adiponectin in regulating neural functions on different levels. Because of the importance in maintaining neural plasticity including adult neurogenesis and synaptic plasticity, adiponectin has the potential to serve as the treatment targets in therapies of neurological and psychiatric disorders. Hence, systematic review is needed to summarize how adiponectin works in the brain, and how the adiponectin pathway is employed as the treatment method needs to be determined. Moreover, the benefits of adiponectin as the regulator for neural plasticity such as synaptic plasticity and neurogenesis have been supported by many literatures. In the current article, we reviewed the functions of adiponectin in different types of neural plasticity. We also demonstrated the potential value of adiponectin as the treatment target for different types of neurodegenerative and psychiatric disorders. Taken together, this review offers a new insight about adiponectin as the ideal target to develop the new treatment methods against neurodegeneration or psychiatric diseases.
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Affiliation(s)
- Li-Na Sun
- School of PE and Sport, Beijing Normal University, Beijing 100875, China
| | - Xiao-Li Liu
- School of PE and Sport, Beijing Normal University, Beijing 100875, China
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Nicolas S, Rochet N, Gautier N, Chabry J, Pisani DF. The adiponectin receptor agonist AdipoRon normalizes glucose metabolism and prevents obesity but not growth retardation induced by glucocorticoids in young mice. Metabolism 2020; 103:154027. [PMID: 31778708 DOI: 10.1016/j.metabol.2019.154027] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Revised: 11/08/2019] [Accepted: 11/22/2019] [Indexed: 12/21/2022]
Abstract
OBJECTIVE Glucocorticoids (GCs) are highly effective anti-inflammatory and immunosuppressive drugs. However, prolonged GC therapy may cause numerous adverse effects leading to diabetes and obesity, as well as bone disorders such as osteoporosis in adults and growth retardation in children and adolescents. Prevention and care of the GC-induced adverse effects remain challenging. We have previously demonstrated the efficacy of a treatment with a non-peptidic agonist of adiponectin receptors, AdipoRon, to reverse behaviour disorders and fat mass gain induced by long-term GC treatment. In this work, we have established a relevant model of GC-induced growth and metabolic disorders and determined that AdipoRon is a potential therapeutic tool to reverse these metabolic disturbances. METHODS 5-Week-old mice were treated continuously with or without corticosterone (35 mg/L) in drinking water for seven consecutive weeks. Taking advantage of this mouse model displaying various growth and metabolic disorders, we assayed whether AdipoRon (daily intraperitoneal injection of 1 mg/kg/day for the last 20 days) might prevent the GC-induced adverse effects. The control group was treated with vehicle only. Nutritional behaviors and metabolic parameters were followed-up throughout the treatment. Serum insulin and leptin levels were measured by ELISA. Computed tomography and histological analysis of adipose tissue were assessed at the end of the experimental procedure. RESULTS We found that GC treatment in young mice resulted in continuously increased body weight gain associated with a food intake increase. Compared to vehicle-, GC-treated mice displayed early major hyperleptinemia (up to 6-fold more) and hyperinsulinemia (up to 20-fold more) maintained throughout the treatment. At the end of the experimental procedure, GC-treated mice displayed bone growth retardation (e.g. femur length 15.1 versus 14.0 mm, P < 0.01), higher abdominal adipose tissue volume (4.1 versus 2.3, P < 0.01) and altered glucose metabolism compared to control mice. Interestingly, AdipoRon prevented GC-induced effects on energy metabolism such as abdominal adiposity, insulinemia and leptinemia. However, AdipoRon failed to counteract bone growth retardation. CONCLUSION We characterized the very early pathological steps induced by long-term GC in young mice in a relevant model, including growth retardation, fat mass gain and glucose homeostasis dysregulation. The adiponectin system stimulation enabled normalization of the adipose tissue and metabolic features of GC-treated mice. Adiponectin receptor agonists such as AdipoRon might constitute a novel way to counteract some GC-induced adverse effects.
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Affiliation(s)
- Sarah Nicolas
- Université Côte d'Azur, CNRS, Institut de Pharmacologie Moléculaire et Cellulaire UMR 7275, 660 route des lucioles, Sophia Antipolis, 06560 Valbonne, France
| | - Nathalie Rochet
- Université Côte d'Azur, CNRS, Inserm, Institut de Biologie Valrose UMR 7277, 28 avenue de Valombrose, 06107 Nice, France
| | - Nadine Gautier
- Université Côte d'Azur, CNRS, Inserm, Institut de Biologie Valrose UMR 7277, 28 avenue de Valombrose, 06107 Nice, France
| | - Joëlle Chabry
- Université Côte d'Azur, CNRS, Institut de Pharmacologie Moléculaire et Cellulaire UMR 7275, 660 route des lucioles, Sophia Antipolis, 06560 Valbonne, France.
| | - Didier F Pisani
- Université Côte d'Azur, CNRS, Laboratoire de PhysioMédecine Moléculaire UMR7370, 28 avenue de Valombrose, 06107 Nice, France.
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Sapio L, Nigro E, Ragone A, Salzillo A, Illiano M, Spina A, Polito R, Daniele A, Naviglio S. AdipoRon Affects Cell Cycle Progression and Inhibits Proliferation in Human Osteosarcoma Cells. JOURNAL OF ONCOLOGY 2020; 2020:7262479. [PMID: 32411241 PMCID: PMC7204133 DOI: 10.1155/2020/7262479] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Accepted: 12/07/2019] [Indexed: 12/15/2022]
Abstract
AdipoRon (AdipoR) is the first synthetic molecule acting as a selective and potent adiponectin receptor agonist. Recently, the possible pharmacological use of AdipoR in different pathological conditions has been addressed. Interestingly, initial evidence suggests that AdipoR may have anticancer properties in different preclinical models, such as pancreatic and ovarian cancer. To our knowledge, so far no research has been directed at determining the impact of AdipoR on osteosarcoma, the most aggressive and metastatic bone malignancy occurring in childhood and adolescence age. Here, we investigate the possible antitumor effects of AdipoR in osteosarcoma cell lines. MTT and cell growth curve assays clearly indicate that AdipoR inhibits, at different extents, proliferation in both U2OS and Saos-2 osteosarcoma cell lines, the latter being more sensitive. Moreover, flow cytometry-based assays point out a significant G0/G1 phase accumulation and a contemporary S phase decrease in response to AdipoR. Consistent with the different sensitivity, a strong subG1 appearance in Saos-2 after 48 and 72 hours of treatment is also observed. The investigation of the molecular mechanisms highlights a common and initial ERK1/2 activation in response to AdipoR in both Saos-2 and U2OS cells. Interestingly, a simultaneous and dramatic downregulation of p70S6K phosphorylation, one of the main targets of mTORC1 pathway, has also been observed in AdipoR-treated Saos-2, but not in U2OS cells. Importantly, a strengthening of AdipoR-induced effects was reported upon everolimus-mediated mTORC1 perturbation in U2OS cells. In conclusion, our findings provide initial evidence of AdipoR as an anticancer molecule differently affecting various signaling pathways involved in cell cycle and cell death in osteosarcoma cells and encourage the design of future studies to further understand its pattern of activities.
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Affiliation(s)
- Luigi Sapio
- Dipartimento di Medicina di Precisione, Università degli Studi della Campania “Luigi Vanvitelli”, Via L. De Crecchio 7, Naples 80138, Italy
| | - Ersilia Nigro
- Dipartimento di Scienze e Tecnologie Ambientali Biologiche Farmaceutiche, Università degli Studi della Campania “Luigi Vanvitelli”, Via G. Vivaldi 42, Caserta 81100, Italy
- CEINGE-Biotecnologie Avanzate Scarl, Via G. Salvatore 486, Naples 80145, Italy
| | - Angela Ragone
- Dipartimento di Medicina di Precisione, Università degli Studi della Campania “Luigi Vanvitelli”, Via L. De Crecchio 7, Naples 80138, Italy
| | - Alessia Salzillo
- Dipartimento di Medicina di Precisione, Università degli Studi della Campania “Luigi Vanvitelli”, Via L. De Crecchio 7, Naples 80138, Italy
| | - Michela Illiano
- Dipartimento di Medicina di Precisione, Università degli Studi della Campania “Luigi Vanvitelli”, Via L. De Crecchio 7, Naples 80138, Italy
| | - Annamaria Spina
- Dipartimento di Medicina di Precisione, Università degli Studi della Campania “Luigi Vanvitelli”, Via L. De Crecchio 7, Naples 80138, Italy
| | - Rita Polito
- Dipartimento di Scienze e Tecnologie Ambientali Biologiche Farmaceutiche, Università degli Studi della Campania “Luigi Vanvitelli”, Via G. Vivaldi 42, Caserta 81100, Italy
- CEINGE-Biotecnologie Avanzate Scarl, Via G. Salvatore 486, Naples 80145, Italy
| | - Aurora Daniele
- Dipartimento di Scienze e Tecnologie Ambientali Biologiche Farmaceutiche, Università degli Studi della Campania “Luigi Vanvitelli”, Via G. Vivaldi 42, Caserta 81100, Italy
- CEINGE-Biotecnologie Avanzate Scarl, Via G. Salvatore 486, Naples 80145, Italy
| | - Silvio Naviglio
- Dipartimento di Medicina di Precisione, Università degli Studi della Campania “Luigi Vanvitelli”, Via L. De Crecchio 7, Naples 80138, Italy
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Vuong E, Nothling J, Lombard C, Jewkes R, Peer N, Abrahams N, Seedat S. Peripheral adiponectin levels in anxiety, mood, trauma- and stressor-related disorders: A systematic review and meta-analysis. J Affect Disord 2020; 260:372-409. [PMID: 31539673 DOI: 10.1016/j.jad.2019.09.050] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2019] [Revised: 07/01/2019] [Accepted: 09/08/2019] [Indexed: 02/08/2023]
Abstract
BACKGROUND Anxiety, mood, trauma- and stressor-related disorders confer increased risk for metabolic disease. Adiponectin, a cytokine released by adipose tissue is associated with these disorders and obesity via inflammatory processes. Available data describing associations with mental disorders remain limited and conflicted. METHODS A systematic search was conducted for English, peer-reviewed articles from inception until February 2019 that assessed for serum or plasma adiponectin levels in adults with an anxiety, mood or trauma-related disorder. Diagnoses were determined by psychiatric interview, based on DSM-IV, DSM-5 or ICD-10 criteria. Analyses were performed using STATA 15 and Standardized mean difference (SMD) with 95% confidence interval was applied to pool the effect size of meta-analysis studies. RESULTS In total 65 eligible studies were included in the systematic review and 30 studies in this meta-analysis. 19,178 participants (11,262 females and 7916 males), comprising healthy adults and adults with anxiety, mood and trauma-related disorders, were included. Overall results indicated an inverse association between adiponectin levels and examined mental disorders. Specifically, patients with an anxiety disorder (SMD = -1.18 µg/mL, 95% CI, -2.34; -0.01, p = 0.047); trauma or stressor-related disorder (SMD = -0.34 µg/mL, 95% CI, -0.52; -0.17, p = 0.0000) or bipolar disorder (SMD = -0.638 µg/mL, 95% CI, -1.16, -0.12, p = 0.017) had significant lower adiponectin levels compared to healthy adults. LIMITATIONS Heterogeneity, potential publication bias, and lack of control for important potential confounders were significant limitations. CONCLUSION Peripheral adiponectin levels appear to be inversely associated with anxiety, mood, trauma- and stressor related disorders and may be a promising biomarker for diagnosis and disease monitoring.
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Affiliation(s)
- E Vuong
- South African Research Chairs Initiative (SARChI), PTSD Program, Department of Psychiatry, Stellenbosch University, South Africa; Department of Psychiatry, Stellenbosch University, Stellenbosch, South Africa.
| | - J Nothling
- South African Research Chairs Initiative (SARChI), PTSD Program, Department of Psychiatry, Stellenbosch University, South Africa; Department of Psychiatry, Stellenbosch University, Stellenbosch, South Africa
| | - C Lombard
- Biostatistics Unit, South Africa Medical Research Council, Cape Town, South Africa
| | - R Jewkes
- Gender and Health Research Unit, South African Medical Research Council, Tygerberg, South Africa
| | - N Peer
- Non-Communicable Diseases Research Unit, South African Medical Research Council, Durban, South Africa
| | - N Abrahams
- Gender and Health Research Unit, South African Medical Research Council, Tygerberg, South Africa
| | - S Seedat
- South African Research Chairs Initiative (SARChI), PTSD Program, Department of Psychiatry, Stellenbosch University, South Africa; Department of Psychiatry, Stellenbosch University, Stellenbosch, South Africa
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Wang XQ, Li WH, Tang YH, Wu LF, Zeng GR, Wang YH, Cheng ZN, Jiang DJ. The correlation between adiponectin and FGF9 in depression disorder. Brain Res 2019; 1729:146596. [PMID: 31836511 DOI: 10.1016/j.brainres.2019.146596] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2019] [Revised: 12/02/2019] [Accepted: 12/07/2019] [Indexed: 02/08/2023]
Abstract
Adiponectin (ADPN) and fibroblast growth factor 9 (FGF9) has been reported as anti-depressive and pro-depressive factor, respectively. However, it is unknown whether there is directly interaction between ADPN and FGF9 in depression. The present study aims to investigate the correlation between ADPN and FGF9 in depression disorder. Firstly, the decreased level of ADPN and the increased level of FGF9 in plasma of depressive patients compared with non-depressive subjects were observed. Furthermore, these is a significant negative correlation between the ratio of ADPN to FGF9 and the total score of Hamilton Depression Scale in total investigated subjects. The similar changes of ADPN and FGF9 were also observed in elder adiponectin gene knockout (Adipo-/-) mice with an increasing trend to depressive-like behaviors. Secondly, the decreasing level of ADPN and increasing level of FGF9 in plasma and hippocampus tissues were observed in chronic unpredictable mild stress (CUMS)-induced depression in ICR mice with significant depressive-like behaviors and hippocampus damage, which attenuated by injection of recombinant ADPN or FGF9 antibody into lateral ventricle. In Adipo-/- mice, injection of FGF9 antibody into lateral ventricle also attenuated CUMS-induced depressivelike behaviors. The protein expression of FGF receptor 3 (FGFR3), the main receptor of FGF9, was significantly down-regulated in hippocampus tissues of CUMS-treated mice, which could be attenuated by treatment with either recombinant ADPN or anti-FGF9. In summary, the present results suggest that ADPN maybe a key negative regulator of FGF9/FGFR3 in depressive disorder and the dysfunction of ADPN-FGF9 pathway plays a key role in stress-induced depression.
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Affiliation(s)
- Xiao-Qing Wang
- XiangYa Pharmacy School, Central South University, Changsha 410083, China; Hunan Center for Safety Evaluation and Research of Drugs & Hunan Key Laboratory for Pharmacodynamics and Safety Evaluation of New Drugs, Changsha 410013, China
| | - Wei-Hui Li
- Department of Psychiatry, The Second XiangYa Hospital of Central South University, Changsha 410011, China
| | - Ya-Hui Tang
- Hunan Center for Safety Evaluation and Research of Drugs & Hunan Key Laboratory for Pharmacodynamics and Safety Evaluation of New Drugs, Changsha 410013, China
| | - Li-Feng Wu
- Hunan Center for Safety Evaluation and Research of Drugs & Hunan Key Laboratory for Pharmacodynamics and Safety Evaluation of New Drugs, Changsha 410013, China
| | - Gui-Rong Zeng
- Hunan Center for Safety Evaluation and Research of Drugs & Hunan Key Laboratory for Pharmacodynamics and Safety Evaluation of New Drugs, Changsha 410013, China
| | - Yu-Hong Wang
- Institute of Innovation and Applied Research in Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410208, China
| | - Ze-Neng Cheng
- XiangYa Pharmacy School, Central South University, Changsha 410083, China.
| | - De-Jian Jiang
- Hunan Center for Safety Evaluation and Research of Drugs & Hunan Key Laboratory for Pharmacodynamics and Safety Evaluation of New Drugs, Changsha 410013, China; Institute of Innovation and Applied Research in Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410208, China.
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Increasing Adiponergic System Activity as a Potential Treatment for Depressive Disorders. Mol Neurobiol 2019; 56:7966-7976. [PMID: 31140056 PMCID: PMC6834732 DOI: 10.1007/s12035-019-01644-3] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Revised: 05/09/2019] [Accepted: 05/10/2019] [Indexed: 12/22/2022]
Abstract
Depression is the most devastating mental disorder and one of the leading contributors to the global medical burden. Current antidepressant prescriptions present drawbacks, including treatment resistance, delayed onset of treatment response, and side effects. The rapid and long-lasting antidepressant effect of ketamine has brought hope to treatment-resistant major depressive disorder patients. However, ketamine has undesirable addictive properties and is a drug of abuse. There is an urgent need, therefore, to develop novel pharmacological interventions that could be as effective as ketamine, but without its side effects. Adiponectin, a pleiotropic adipocyte-secreted hormone, has insulin-sensitizing and neurotrophic properties. It can cross the blood-brain barrier and target multiple brain regions where the adiponectin receptors are detected. Emerging evidence has suggested that adiponectin and the adiponectin receptor agonist, AdipoRon, could promote adult neurogenesis, dendritic and spine remodeling, and synaptic plasticity in the hippocampus, resulting in antidepressant effects in adult mice. By summarizing the most recent clinical and animal studies, this review provides a timely insight on how modulating the adiponergic system in the hippocampus could be a potential therapeutic target for an effective and fast-acting antidepressant response.
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Forny-Germano L, De Felice FG, Vieira MNDN. The Role of Leptin and Adiponectin in Obesity-Associated Cognitive Decline and Alzheimer's Disease. Front Neurosci 2019; 12:1027. [PMID: 30692905 PMCID: PMC6340072 DOI: 10.3389/fnins.2018.01027] [Citation(s) in RCA: 165] [Impact Index Per Article: 27.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Accepted: 12/19/2019] [Indexed: 12/14/2022] Open
Abstract
Cross-talk between adipose tissue and central nervous system (CNS) underlies the increased risk of obese people to develop brain diseases such as cognitive and mood disorders. Detailed mechanisms for how peripheral changes caused by adipose tissue accumulation in obesity impact the CNS to cause brain dysfunction are poorly understood. Adipokines are a large group of substances secreted by the white adipose tissue to regulate a wide range of homeostatic processes including, but not limited to, energy metabolism and immunity. Obesity is characterized by a generalized change in the levels of circulating adipokines due to abnormal accumulation and dysfunction of adipose tissue. Altered adipokine levels underlie complications of obesity as well as the increased risk for the development of obesity-related comorbidities such as type 2 diabetes, cardiovascular and neurodegenerative diseases. Here, we review the literature for the role of adipokines as key mediators of the communication between periphery and CNS in health and disease. We will focus on the actions of leptin and adiponectin, two of the most abundant and well studied adipokines, in the brain, with particular emphasis on how altered signaling of these adipokines in obesity may lead to cognitive dysfunction and augmented risk for Alzheimer's disease. A better understanding of adipokine biology in brain disorders may prove of major relevance to diagnostic, prevention and therapy.
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Affiliation(s)
- Leticia Forny-Germano
- Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Fernanda G. De Felice
- Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
- Centre for Neuroscience Studies, Department of Psychiatry, Queen’s University, Kingston, ON, Canada
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Otvos L. Potential Adiponectin Receptor Response Modifier Therapeutics. Front Endocrinol (Lausanne) 2019; 10:539. [PMID: 31456747 PMCID: PMC6700268 DOI: 10.3389/fendo.2019.00539] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2019] [Accepted: 07/19/2019] [Indexed: 12/13/2022] Open
Abstract
Many human diseases may benefit from adiponectin replacement therapy, but due to pharmacological disadvantages of the intact protein, druggable options focus on peptidic, and small molecule agonists of the adiponectin receptor. Peptide-based adiponectin replacement drug leads are derived from, or resemble, the active site of globular adiponectin. ADP355, the first-in-class such peptide, exhibits low nanomolar cellular activities, and clinically acceptable efficacies in a series of fibrotic and inflammation-derived diseases. The advantage of small molecule therapies, spearheaded by AdipoRon, is oral availability and extension of utility to a series of metabolic conditions. It is exactly the difficulties in the reliability and readout of the in vitro measures and the wealth of in vivo models that make comparison of the various drug classes complicated, if not impossible. While only a fewer number of maladies could take advantage of adiponectin receptor antagonists, the limited number of these available can be very useful tools in target validation studies. Alternative approaches to direct adiponectin signaling control use upstream adiponectin production inducing therapies but currently these offer relatively limited success compared to direct receptor agonists.
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Affiliation(s)
- Laszlo Otvos
- OLPE LLC, Audubon, PA, United States
- Allysta Pharmaceuticals, San Mateo, CA, United States
- Institute of Medical Microbiology, Semmelweis University, Budapest, Hungary
- *Correspondence: Laszlo Otvos Jr.
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Liu Y, Vu V, Sweeney G. Examining the Potential of Developing and Implementing Use of Adiponectin-Targeted Therapeutics for Metabolic and Cardiovascular Diseases. Front Endocrinol (Lausanne) 2019; 10:842. [PMID: 31920962 PMCID: PMC6918867 DOI: 10.3389/fendo.2019.00842] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2019] [Accepted: 11/19/2019] [Indexed: 02/06/2023] Open
Abstract
Cardiometabolic diseases encompass those affecting the heart and vasculature as well as other metabolic problems, such as insulin resistance, diabetes, and non-alcoholic fatty liver disease. These diseases tend to have common risk factors, one of which is impaired adiponectin action. This may be due to reduced bioavailability of the hormone or resistance to its effects on target tissues. A strong negative correlation between adiponectin levels and cardiometabolic diseases has been well-documented and research shown that adiponectin has cardioprotective, insulin sensitizing and direct beneficial metabolic effects. Thus, therapeutic approaches to enhance adiponectin action are widely considered to be desirable. The complexity of adiponectin structure and function has so far made progress in this area less than ideal. In this article we will review the effects and mechanism of action of adiponectin on cardiometabolic tissues, identify scenarios where enhancing adiponectin action would be of clinical value and finally discuss approaches via which this can be achieved.
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Affiliation(s)
- Ying Liu
- Metabolic Disease Research Division, iCarbonX Co. Ltd., Shenzhen, China
- *Correspondence: Ying Liu
| | - Vivian Vu
- Department of Biology, York University, Toronto, ON, Canada
| | - Gary Sweeney
- Department of Biology, York University, Toronto, ON, Canada
- Gary Sweeney
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Wang B, Cheng KKY. Hypothalamic AMPK as a Mediator of Hormonal Regulation of Energy Balance. Int J Mol Sci 2018; 19:ijms19113552. [PMID: 30423881 PMCID: PMC6274700 DOI: 10.3390/ijms19113552] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Revised: 11/06/2018] [Accepted: 11/07/2018] [Indexed: 12/13/2022] Open
Abstract
As a cellular energy sensor and regulator, adenosine monophosphate (AMP)-activated protein kinase (AMPK) plays a pivotal role in the regulation of energy homeostasis in both the central nervous system (CNS) and peripheral organs. Activation of hypothalamic AMPK maintains energy balance by inducing appetite to increase food intake and diminishing adaptive thermogenesis in adipose tissues to reduce energy expenditure in response to food deprivation. Numerous metabolic hormones, such as leptin, adiponectin, ghrelin and insulin, exert their energy regulatory effects through hypothalamic AMPK via integration with the neural circuits. Although activation of AMPK in peripheral tissues is able to promote fatty acid oxidation and insulin sensitivity, its chronic activation in the hypothalamus causes obesity by inducing hyperphagia in both humans and rodents. In this review, we discuss the role of hypothalamic AMPK in mediating hormonal regulation of feeding and adaptive thermogenesis, and summarize the diverse underlying mechanisms by which central AMPK maintains energy homeostasis.
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Affiliation(s)
- Baile Wang
- State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China.
- Department of Medicine, The University of Hong Kong, Hong Kong, China.
| | - Kenneth King-Yip Cheng
- Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong, China.
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