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González-Rodríguez L, González LM, García-Herráiz A, Mota-Zamorano S, Flores I, Gervasini G. Association of genetic variation in the leptin-melanocortin system with drive for thinness in patients with eating disorders: A pilot study. Gene 2025; 949:149364. [PMID: 40015467 DOI: 10.1016/j.gene.2025.149364] [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: 10/25/2024] [Revised: 02/03/2025] [Accepted: 02/24/2025] [Indexed: 03/01/2025]
Abstract
We aimed to investigate whether genetic variants in the leptin-melanocortin system involved in anorexigenic signaling influence personality dimensions and psychopathological symptoms in eating disorders (ED) patients. The population consisted of 309 ED patients [221 with anorexia nervosa (AN) and 88 with bulimia nervosa (BN)] and 396 healthy controls. Patients underwent psychometric assessment using the Eating Disorders Inventory Test-2 (EDI-2) and the Symptom Checklist 90 Revised (SCL-90R) questionnaires. Fourteen tag-SNPs in the LEP, POMC, and MC4R genes, were determined. Drive for thinness (DT) was significantly affected by genetic variability. After correction for multiple testing, regression models showed that AN patients carrying the LEP rs11761556 CC variant genotype scored higher in this scale than AA/CA carriers did [mean difference = 4.43 (2.18-6.68), p < 0.001], although the significance was restrained to the restrictive subtype [4.92 (2.00-7.83), p = 0.001]. BN patients with the LEP rs10954173 AA genotype displayed lower scores [-8.7 (-12.31--3.91); p < 0.001]. Finally, gene-gene interaction analyses revealed two SNP pairs associated with body-mass index in AN patients (LEPrs3828942-POMCrs1009388, p < 0.001 and LEP rs11763517-POMCrs1009388, p = 0.002). Regarding DT scores, the POMCrs6545975-LEP11763517 SNP pair showed the strongest effect (p < 0.001) in AN. Genetic variants in the leptin-melanocortin system, may interact to influence personality dimensions in ED patients, which highlights the importance of considering genetic factors in the pathophysiology of these disorders.
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Affiliation(s)
- Laura González-Rodríguez
- Department of Medical & Surgical Therapeutics, Medical School, University of Extremadura, Badajoz, Spain
| | - Luz María González
- Department of Medical & Surgical Therapeutics, Medical School, University of Extremadura, Badajoz, Spain
| | | | - Sonia Mota-Zamorano
- Department of Medical & Surgical Therapeutics, Medical School, University of Extremadura, Badajoz, Spain; Institute of Molecular Pathology Biomarkers, University of Extremadura, Badajoz, Spain
| | - Isalud Flores
- Eating Disorders Unit, Health Service of Extremadura, Badajoz, Spain
| | - Guillermo Gervasini
- Department of Medical & Surgical Therapeutics, Medical School, University of Extremadura, Badajoz, Spain; Institute of Molecular Pathology Biomarkers, University of Extremadura, Badajoz, Spain.
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Mutwalli H, Keeler JL, Chung R, Dalton B, Patsalos O, Hodsoll J, Schmidt U, Breen G, Treasure J, Himmerich H. Metabolic Signalling Peptides and Their Relation to Clinical and Demographic Characteristics in Acute and Recovered Females with Anorexia Nervosa. Nutrients 2025; 17:1341. [PMID: 40284205 PMCID: PMC12030328 DOI: 10.3390/nu17081341] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2025] [Revised: 04/08/2025] [Accepted: 04/09/2025] [Indexed: 04/29/2025] Open
Abstract
Background/Objectives: Recent research has established that metabolic factors may increase the vulnerability to develop anorexia nervosa (AN). The aim of this study was to explore the serum concentrations of leptin, insulin-like growth factor-1 (IGF-1), insulin and insulin receptor substrate (IRS-1) as possible state or trait biomarkers for AN in the acute and recovery (recAN) phases. Our secondary aim was to test associations between the tested markers and demographic and clinical characteristics. Methods: This cross-sectional study included data from 56 participants with AN, 24 recAN participants and 51 healthy controls (HCs). Enzyme-linked immunosorbent assays (ELISAs) were used to quantify serum concentrations of leptin, IGF-1, insulin and IRS-1. An analysis of covariance (ANCOVA) and linear regression models were utilised to test our results. Results: There were significant differences with a large effect size between the groups for serum leptin (p < 0.001; d = 0.80), whereby people with AN had lower leptin than those with recAN (p = 0.023; d = 0.35) and HCs (p < 0.001; d = 0.74). The between-group comparison of IGF-1 did not reach significance, although the effect size was moderate (d = 0.6) and was driven by lower levels of IGF-1 in people with acute AN compared to HCs (p = 0.036; d = 0.53). Serum insulin and IRS-1 did not differ between groups. Conclusions: Low leptin levels seen in individuals with AN may be due to starvation leading to fatty tissue depletion. Understanding the regulation of IGF-1 and insulin signalling over the course of the disorder requires further investigation.
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Affiliation(s)
- Hiba Mutwalli
- Centre for Research in Eating and Weight Disorders (CREW), Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London SE5 8AF, UK (O.P.); (H.H.)
- Department of Clinical Nutrition, College of Applied Medical Sciences, Imam Abdulrahman Bin Faisal University, Dammam 34221, Saudi Arabia
| | - Johanna L. Keeler
- Centre for Research in Eating and Weight Disorders (CREW), Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London SE5 8AF, UK (O.P.); (H.H.)
| | - Raymond Chung
- NIHR BioResource Centre Maudsley, London WC2R 2LS, UK
- NIHR Maudsley Biomedical Research Centre (BRC), South London and Maudsley NHS Foundation Trust (SLaM), London SE5 8AF, UK
- Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London SE5 8AB, UK
| | - Bethan Dalton
- Centre for Research in Eating and Weight Disorders (CREW), Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London SE5 8AF, UK (O.P.); (H.H.)
| | - Olivia Patsalos
- Centre for Research in Eating and Weight Disorders (CREW), Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London SE5 8AF, UK (O.P.); (H.H.)
| | - John Hodsoll
- Biostatistics & Health Informatics, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London SE5 8AF, UK
| | - Ulrike Schmidt
- Centre for Research in Eating and Weight Disorders (CREW), Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London SE5 8AF, UK (O.P.); (H.H.)
- Adult Eating Disorders Service, South London and Maudsley NHS Foundation Trust (SLaM), London SE6 4RU, UK
| | - Gerome Breen
- Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London SE5 8AF, UK
| | - Janet Treasure
- Centre for Research in Eating and Weight Disorders (CREW), Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London SE5 8AF, UK (O.P.); (H.H.)
- Adult Eating Disorders Service, South London and Maudsley NHS Foundation Trust (SLaM), London SE6 4RU, UK
| | - Hubertus Himmerich
- Centre for Research in Eating and Weight Disorders (CREW), Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London SE5 8AF, UK (O.P.); (H.H.)
- Adult Eating Disorders Service, South London and Maudsley NHS Foundation Trust (SLaM), London SE6 4RU, UK
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3
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Mancini M, Hikima T, Witkovsky P, Patel JC, Stone DW, Affinati AH, Rice ME. Leptin activates dopamine and GABA neurons in the substantia nigra via a local pars compacta-pars reticulata circuit. J Neurosci 2025; 45:e1539242025. [PMID: 40127936 PMCID: PMC12096038 DOI: 10.1523/jneurosci.1539-24.2025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2024] [Revised: 02/28/2025] [Accepted: 03/16/2025] [Indexed: 03/26/2025] Open
Abstract
Adipose-derived leptin contributes to energy homeostasis by balancing food intake and motor output, but how leptin acts in brain motor centers remains poorly understood. We investigated the influence of leptin on neuronal activity in two basal ganglia nuclei involved in motor control: the substantia nigra pars compacta (SNc) and pars reticulata (SNr). Using a mouse reporter line to identify cells expressing leptin receptors (LepRs), we found that in both sexes, a majority of SNc dopamine neurons express a high level of LepR. Whole-cell recording in ex vivo midbrain slices from male wild-type mice showed that leptin activates SNc dopamine neurons directly and increases somatodendritic dopamine release. Although LepR expression in SNr GABA output neurons was low, leptin also activated these cells. Additional experiments showed that the influence of leptin on SNr neurons is indirect and involves D1 dopamine receptors and TRPC3 channels. Administration of leptin to male mice increased locomotor activity, consistent with activation of dopamine neurons in the SNc coupled to previously reported amplification of axonal dopamine release by leptin in striatal slices. These findings indicate that in addition to managing energy homeostasis through its actions as a satiety hormone, leptin also promotes axonal and somatodendritic dopamine release that can influence motor output.Significance statement Dopamine neurons regulate motivated behaviors, but how they are influenced by metabolic hormones, like leptin, is incompletely understood. We show here that leptin increases the activity of substantia nigra (SN) pars compacta dopamine neurons directly, and that this enhances somatodendritic dopamine release. Leptin also increases the activity of GABAergic neurons in the SN pars reticulata, but does so indirectly via D1 dopamine receptors activated by locally released dopamine. Consistent with increased nigral dopamine neuron activity and previous evidence showing that leptin amplifies striatal dopamine release, systemic leptin increases locomotor behavior. This increase in motor activity complements the well-established inhibitory effect of leptin on food intake and adds an additional dimension to the regulation of energy balance by this hormone.
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Affiliation(s)
- Maria Mancini
- Department of Neuroscience and Physiology, NYU School of Medicine, New York, NY, USA
- Neuroscience Institute, NYU School of Medicine, New York, NY, USA
| | - Takuya Hikima
- Department of Neurosurgery, NYU School of Medicine, New York, NY, USA
| | - Paul Witkovsky
- Department of Neurosurgery, NYU School of Medicine, New York, NY, USA
| | - Jyoti C Patel
- Neuroscience Institute, NYU School of Medicine, New York, NY, USA
- Department of Neurosurgery, NYU School of Medicine, New York, NY, USA
| | - Dominic W Stone
- Department of Neurosurgery, NYU School of Medicine, New York, NY, USA
| | - Alison H Affinati
- Division of Metabolism, Endocrinology, and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Margaret E Rice
- Department of Neuroscience and Physiology, NYU School of Medicine, New York, NY, USA
- Neuroscience Institute, NYU School of Medicine, New York, NY, USA
- Department of Neurosurgery, NYU School of Medicine, New York, NY, USA
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Gill A, Gill M, Mittal R, Hirani K, Sharma A. Leptin-dopamine interactions: unveiling the common link between type-2 diabetes and neuropsychiatric comorbidities. Behav Pharmacol 2025:00008877-990000000-00124. [PMID: 40079260 DOI: 10.1097/fbp.0000000000000820] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/15/2025]
Abstract
Clinical evidence highlights the central nervous system as a key target in type-2 diabetes-related complications, yet the mechanisms underlying the increased prevalence of mood disorder issues, mainly depression, in patients with diabetes remain poorly understood. Leptin, an adiposity hormone known for its role in energy homeostasis, has been shown to improve insulin sensitivity and regulate blood glucose levels in diabetic populations. Beyond its metabolic effects, leptin also has the potential to mitigate psychiatric complications such as depression and anxiety. Notably, leptin receptors are predominantly expressed on dopamine (DA) neurons in the brain, hinting that leptin may orchestrate DA activity by serving as its endogenous modulator. This review examines the role of leptin as a potential common link between type-2 diabetes and mood disorders, particularly through its effects on DA function. This article proposes defective leptin signaling as a vital mechanism contributing to psychiatric complications and compromised DA functions in type-2 diabetes, highlighting leptin as a promising therapeutic target for addressing metabolic and psychiatric comorbidities.
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Affiliation(s)
- Allyson Gill
- Department of Pharmacy Practice, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Science Center, Lubbock, Texas
| | - Madison Gill
- Department of Pharmacy Practice, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Science Center, Lubbock, Texas
| | - Rahul Mittal
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Khemraj Hirani
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Ajay Sharma
- Department of Pharmacy Practice, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Science Center, Lubbock, Texas
- Department of Pharmacology and Toxicology, Wright State University, Boonshoft School of Medicine, Dayton, Ohio
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5
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Asgari R, Caceres-Valdiviezo M, Wu S, Hamel L, Humber BE, Agarwal SM, Fletcher PJ, Fulton S, Hahn MK, Pereira S. Regulation of energy balance by leptin as an adiposity signal and modulator of the reward system. Mol Metab 2025; 91:102078. [PMID: 39615837 PMCID: PMC11696864 DOI: 10.1016/j.molmet.2024.102078] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Revised: 11/02/2024] [Accepted: 11/26/2024] [Indexed: 12/08/2024] Open
Abstract
BACKGROUND Leptin is an adipose tissue-derived hormone that plays a crucial role in body weight, appetite, and behaviour regulation. Leptin controls energy balance as an indicator of adiposity levels and as a modulator of the reward system, which is associated with liking palatable foods. Obesity is characterized by expanded adipose tissue mass and consequently, elevated concentrations of leptin in blood. Leptin's therapeutic potential for most forms of obesity is hampered by leptin resistance and a narrow dose-response window. SCOPE OF REVIEW This review describes the current knowledge of the brain regions and intracellular pathways through which leptin promotes negative energy balance and restrains neural circuits affecting food reward. We also describe mechanisms that hinder these biological responses in obesity and highlight potential therapeutic interventions. MAJOR CONCLUSIONS Additional research is necessary to understand how pathways engaged by leptin in different brain regions are interconnected in the control of energy balance.
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Affiliation(s)
| | - Maria Caceres-Valdiviezo
- Centre for Addiction and Mental Health, Toronto, ON, Canada; Laboratory of Omic Sciences, School of Medicine, Universidad de Especialidades Espíritu Santo, Samborondón, Ecuador
| | - Sally Wu
- Centre for Addiction and Mental Health, Toronto, ON, Canada
| | - Laurie Hamel
- Centre for Addiction and Mental Health, Toronto, ON, Canada
| | | | - Sri Mahavir Agarwal
- Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada; Banting & Best Diabetes Centre, University of Toronto, Toronto, ON, Canada
| | - Paul J Fletcher
- Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada; Department of Psychology, University of Toronto, Toronto, ON, Canada
| | - Stephanie Fulton
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal Diabetes Research Center, Montréal, QC, Canada; Department of Nutrition, Université de Montréal, QC, Canada
| | - Margaret K Hahn
- Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada; Banting & Best Diabetes Centre, University of Toronto, Toronto, ON, Canada; Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada; Department of Pharmacology, University of Toronto, Toronto, ON, Canada.
| | - Sandra Pereira
- Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Physiology, University of Toronto, Toronto, ON, Canada.
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6
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Borruto AM, Calpe-López C, Spanagel R, Bernardi RE. Conditional deletion of the AMPA-GluA1 and NMDA-GluN1 receptor subunit genes in midbrain D1 neurons does not alter cocaine reward in mice. Neuropharmacology 2024; 258:110081. [PMID: 39002853 DOI: 10.1016/j.neuropharm.2024.110081] [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: 04/29/2024] [Revised: 06/11/2024] [Accepted: 07/10/2024] [Indexed: 07/15/2024]
Abstract
Synaptic plasticity in the mesolimbic dopamine (DA) system contributes to the neural adaptations underlying addictive behaviors and relapse. However, the specific behavioral relevance of glutamatergic excitatory drive onto dopamine D1 receptor (D1R)-expressing neurons in mediating the reinforcing effect of cocaine remains unclear. Here, we investigated how midbrain AMPAR and NMDAR function modulate cocaine reward-related behavior using mutant mouse lines lacking the glutamate receptor genes Gria1 or Grin1 in D1R-expressing neurons (GluA1D1CreERT2 or GluN1D1CreERT2, respectively). We found that conditional genetic deletion of either GluA1 or GluN1 within this neuronal sub-population did not impact the ability of acute cocaine injection to increase intracranial self-stimulation (ICSS) ratio or reduced brain reward threshold compared to littermate controls. Additionally, our data demonstrate that deletion of GluA1 and GluN1 receptor subunits within D1R-expressing neurons did not affect cocaine reinforcement in an operant self-administration paradigm, as mutant mice showed comparable cocaine responses and intake to controls. Given the pivotal role of glutamate receptors in mediating relapse behavior, we further explored the impact of genetic deletion of AMPAR and NMDAR onto D1R-expressing neurons on cue-induced reinstatement following extinction. Surprisingly, deletion of AMPAR and NMDAR onto these neurons did not impair cue-induced reinstatement of cocaine-seeking behavior. These findings suggest that glutamatergic activity via NMDAR and AMPAR in D1R-expressing neurons may not exclusively mediate the reinforcing effects of cocaine and cue-induced reinstatement.
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MESH Headings
- Animals
- Cocaine/pharmacology
- Cocaine/administration & dosage
- Receptors, N-Methyl-D-Aspartate/genetics
- Receptors, N-Methyl-D-Aspartate/metabolism
- Reward
- Receptors, AMPA/genetics
- Receptors, AMPA/metabolism
- Receptors, Dopamine D1/genetics
- Receptors, Dopamine D1/metabolism
- Mice
- Self Administration
- Male
- Mesencephalon/metabolism
- Mesencephalon/drug effects
- Conditioning, Operant/drug effects
- Conditioning, Operant/physiology
- Neurons/metabolism
- Neurons/drug effects
- Mice, Knockout
- Dopamine Uptake Inhibitors/pharmacology
- Mice, Inbred C57BL
- Reinforcement, Psychology
- Nerve Tissue Proteins
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Affiliation(s)
- Anna Maria Borruto
- Institute of Psychopharmacology, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
| | - Claudia Calpe-López
- Institute of Psychopharmacology, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Rainer Spanagel
- Institute of Psychopharmacology, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany; German Center for Mental Health (DZPG), Partner Site Mannheim, Heidelberg, Ulm, Germany
| | - Rick E Bernardi
- Institute of Psychopharmacology, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
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7
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Clarke GS, Page AJ, Eldeghaidy S. The gut-brain axis in appetite, satiety, food intake, and eating behavior: Insights from animal models and human studies. Pharmacol Res Perspect 2024; 12:e70027. [PMID: 39417406 PMCID: PMC11483575 DOI: 10.1002/prp2.70027] [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: 01/16/2024] [Revised: 09/02/2024] [Accepted: 09/24/2024] [Indexed: 10/19/2024] Open
Abstract
The gut-brain axis plays a pivotal role in the finely tuned orchestration of food intake, where both homeostatic and hedonic processes collaboratively control our dietary decisions. This interplay involves the transmission of mechanical and chemical signals from the gastrointestinal tract to the appetite centers in the brain, conveying information on meal arrival, quantity, and chemical composition. These signals are processed in the brain eventually leading to the sensation of satiety and the termination of a meal. However, the regulation of food intake and appetite extends beyond the realms of pure physiological need. Hedonic mechanisms, including sensory perception (i.e., through sight, smell, and taste), habitual behaviors, and psychological factors, exert profound influences on food intake. Drawing from studies in animal models and human research, this comprehensive review summarizes the physiological mechanisms that underlie the gut-brain axis and its interplay with the reward network in the regulation of appetite and satiety. The recent advancements in neuroimaging techniques, with a focus on human studies that enable investigation of the neural mechanisms underpinning appetite regulation are discussed. Furthermore, this review explores therapeutic/pharmacological strategies that hold the potential for controlling food intake.
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Affiliation(s)
- Georgia S. Clarke
- School of BiomedicineThe University of AdelaideAdelaideSouth AustraliaAustralia
- Robinson Research InstituteThe University of AdelaideAdelaideSouth AustraliaAustralia
- Nutrition, Diabetes and Gut Health, Lifelong Health ThemeSouth Australian Health and Medical Research Institute, SAHMRIAdelaideSouth AustraliaAustralia
| | - Amanda J. Page
- School of BiomedicineThe University of AdelaideAdelaideSouth AustraliaAustralia
- Nutrition, Diabetes and Gut Health, Lifelong Health ThemeSouth Australian Health and Medical Research Institute, SAHMRIAdelaideSouth AustraliaAustralia
| | - Sally Eldeghaidy
- Division of Food, Nutrition and DieteticsSchool of Biosciences, University of NottinghamNottinghamUK
- Sir Peter Mansfield Imaging CentreSchool of Physics and Astronomy, University of NottinghamNottinghamUK
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8
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Salazar J, Duran P, Garrido B, Parra H, Hernández M, Cano C, Añez R, García-Pacheco H, Cubillos G, Vasquez N, Chacin M, Bermúdez V. Weight Regain after Metabolic Surgery: Beyond the Surgical Failure. J Clin Med 2024; 13:1143. [PMID: 38398456 PMCID: PMC10888585 DOI: 10.3390/jcm13041143] [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: 12/11/2023] [Revised: 01/20/2024] [Accepted: 02/02/2024] [Indexed: 02/25/2024] Open
Abstract
Patients undergoing metabolic surgery have factors ranging from anatomo-surgical, endocrine metabolic, eating patterns and physical activity, mental health and psychological factors. Some of the latter can explain the possible pathophysiological neuroendocrine, metabolic, and adaptive mechanisms that cause the high prevalence of weight regain in postbariatric patients. Even metabolic surgery has proven to be effective in reducing excess weight in patients with obesity; some of them regain weight after this intervention. In this vein, several studies have been conducted to search factors and mechanisms involved in weight regain, to stablish strategies to manage this complication by combining metabolic surgery with either lifestyle changes, behavioral therapies, pharmacotherapy, endoscopic interventions, or finally, surgical revision. The aim of this revision is to describe certain aspects and mechanisms behind weight regain after metabolic surgery, along with preventive and therapeutic strategies for this complication.
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Affiliation(s)
- Juan Salazar
- Endocrine and Metabolic Diseases Research Center, School of Medicine, University of Zulia, Maracaibo 4004, Venezuela
| | - Pablo Duran
- Endocrine and Metabolic Diseases Research Center, School of Medicine, University of Zulia, Maracaibo 4004, Venezuela
| | - Bermary Garrido
- Endocrine and Metabolic Diseases Research Center, School of Medicine, University of Zulia, Maracaibo 4004, Venezuela
| | - Heliana Parra
- Endocrine and Metabolic Diseases Research Center, School of Medicine, University of Zulia, Maracaibo 4004, Venezuela
| | - Marlon Hernández
- Endocrine and Metabolic Diseases Research Center, School of Medicine, University of Zulia, Maracaibo 4004, Venezuela
| | - Clímaco Cano
- Endocrine and Metabolic Diseases Research Center, School of Medicine, University of Zulia, Maracaibo 4004, Venezuela
| | - Roberto Añez
- Departamento de Endocrinología y Nutrición, Hospital Quirónsalud, 28009 Madrid, Spain
| | - Henry García-Pacheco
- Facultad de Medicina, Departamento de Cirugía, Universidad del Zulia, Hospital General del Sur, Dr. Pedro Iturbe, Maracaibo 4004, Venezuela
- Unidad de Cirugía para Obesidad y Metabolismo (UCOM), Maracaibo 4004, Venezuela
| | | | | | - Maricarmen Chacin
- Facultad de Ciencias de la Salud, Universidad Simón Bolívar, Barranquilla 080001, Colombia
- Centro de Investigaciones en Ciencias de la Vida, Universidad Simón Bolívar, Barranquilla 080001, Colombia
| | - Valmore Bermúdez
- Facultad de Ciencias de la Salud, Universidad Simón Bolívar, Barranquilla 080001, Colombia
- Centro de Investigaciones en Ciencias de la Vida, Universidad Simón Bolívar, Barranquilla 080001, Colombia
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9
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Liu Z, Xiao T, Liu H. Leptin signaling and its central role in energy homeostasis. Front Neurosci 2023; 17:1238528. [PMID: 38027481 PMCID: PMC10644276 DOI: 10.3389/fnins.2023.1238528] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2023] [Accepted: 10/17/2023] [Indexed: 12/01/2023] Open
Abstract
Leptin plays a critical role in regulating appetite, energy expenditure and body weight, making it a key factor in maintaining a healthy balance. Despite numerous efforts to develop therapeutic interventions targeting leptin signaling, their effectiveness has been limited, underscoring the importance of gaining a better understanding of the mechanisms through which leptin exerts its functions. While the hypothalamus is widely recognized as the primary site responsible for the appetite-suppressing and weight-reducing effects of leptin, other brain regions have also been increasingly investigated for their involvement in mediating leptin's action. In this review, we summarize leptin signaling pathways and the neural networks that mediate the effects of leptin, with a specific emphasis on energy homeostasis.
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Affiliation(s)
- Zhaoxun Liu
- Nursing Department, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
- Department of Emergency, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Tao Xiao
- Nursing Department, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Hailan Liu
- USDA/ARS Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, United States
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10
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von Schnurbein J, Remy M, Brandt S, Manzoor J, Kohlsdorf K, Mahmood S, Hebebrand J, Wabitsch M. Positive effect of leptin substitution on mood and behaviour in patients with congenital leptin deficiency. Pediatr Obes 2023; 18:e13057. [PMID: 37226403 DOI: 10.1111/ijpo.13057] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 04/24/2023] [Accepted: 04/27/2023] [Indexed: 05/26/2023]
Abstract
BACKGROUND States of starvation are characterized by reduced physical activity and social withdrawal. This has been suggested to be mediated at least in part via reduced leptin concentrations. OBJECTIVE We therefore aimed to ascertain if leptin substitution in patients with congenital leptin deficiency (CLD) can improve physical activity and mood. METHODS Seven patients with CLD were filmed prior to and after short- and long-term substitution (2-21 days; 3-4 months) in a play situation. Six independent, blinded investigators ranked each video according to specifically developed scales concerning motor activity, social interaction, emotionality, and mood with higher scores representing improvements. RESULTS Short term metreleptin substitution significantly increased mean total score from 17.7 ± 4.1 to 22.6 ± 6.6 (p = 0.039), and mean scores for motor activity (4.1 ± 1.1 to 5.1 ± 1.5, p = 0.023) and social interaction (4.6 ± 1.1 to 6.2 ± 1.7, p = 0.016). After long term substitution means of all four single scales and of total score were even higher than at short-term follow-up. During a treatment pause of 3 months in two children, all four scale scores fell below substitution levels and rose again after restart. CONCLUSIONS Metreleptin substitution improved indices of physical activity and psychological wellbeing in patients with CLD. This suggests that reduced leptin concentrations might be in part responsible for emotional and behavioural changes seen during starvation.
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Affiliation(s)
- Julia von Schnurbein
- Department for Paediatrics and Adolescent Medicine, Division of Paediatric Endocrinology and Diabetes, University Ulm Medical Centre, Ulm, Germany
| | - Miriam Remy
- Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Essen, Essen, Germany
| | - Stephanie Brandt
- Department for Paediatrics and Adolescent Medicine, Division of Paediatric Endocrinology and Diabetes, University Ulm Medical Centre, Ulm, Germany
| | - Jaida Manzoor
- The Children's Hospital, University of Child Health Sciences, Lahore, Pakistan
| | - Katja Kohlsdorf
- Department for Paediatrics and Adolescent Medicine, Division of Paediatric Endocrinology and Diabetes, University Ulm Medical Centre, Ulm, Germany
| | - Saqib Mahmood
- Human Genetics & Molecular Biology, University of Health Sciences, Lahore, Pakistan
| | - Johannes Hebebrand
- Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Essen, Essen, Germany
| | - Martin Wabitsch
- Department for Paediatrics and Adolescent Medicine, Division of Paediatric Endocrinology and Diabetes, University Ulm Medical Centre, Ulm, Germany
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11
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Donka RM, Hsu T, Roitman MF, Roitman JD. Chronic water restriction reduces sensitivity to brain stimulation reward in male and female rats. Physiol Behav 2023; 263:114110. [PMID: 36740136 PMCID: PMC10064935 DOI: 10.1016/j.physbeh.2023.114110] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Revised: 01/25/2023] [Accepted: 02/01/2023] [Indexed: 02/05/2023]
Abstract
States of physiological need motivate individuals to seek and consume stimuli that restore homeostatic balance. This goal-directed behavior is driven, in part, by pathways that process reward and are sensitive to changes in physiological state, including the mesolimbic dopamine system. The effects of hunger and its physiological markers have been more widely studied for their role in modulating reward signaling pathways. However, fluid need produces robust goal-directed behavior and has also been shown to affect neural substrates of reward processing. To test how acute and chronic states of thirst might alter reward sensitivity, we used the intracranial self-stimulation (ICSS) rate-frequency paradigm (Carlezon & Chartoff, 2007) with male and female Long Evans rats. We hypothesized that sensitivity to ICSS would increase under an acute need state for water and would decrease under chronic deprivation. We found that acute water deprivation for 22-hours prior to the ICSS session did not alter any parameters of reward sensitivity. To elicit motivated behavior toward water in the absence of physiological need, we chemogenetically activated glutamatergic neurons of the subfornical organ (SFO). Despite eliciting more water consumption than acute deprivation, acute chemogenetic activation of SFO neurons also did not alter reward sensitivity. Finally, subjects underwent a five-day chronic water restriction protocol with daily ICSS sessions to determine the effects of sustained physiological need. Chronic water restriction resulted in reduced sensitivity to ICSS. Together, these results indicate that persistent changes in physiological state alter the responsiveness of reward circuitry that could potentially exacerbate maladaptive reward-seeking behaviors.
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Affiliation(s)
- Rachel M Donka
- Department of Psychology, University of Illinois at Chicago, 1007 West Harrison Street, Chicago, IL 60607, United States
| | - Ted Hsu
- Department of Psychology, University of Illinois at Chicago, 1007 West Harrison Street, Chicago, IL 60607, United States
| | - Mitchell F Roitman
- Department of Psychology, University of Illinois at Chicago, 1007 West Harrison Street, Chicago, IL 60607, United States
| | - Jamie D Roitman
- Department of Psychology, University of Illinois at Chicago, 1007 West Harrison Street, Chicago, IL 60607, United States.
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12
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Gruber J, Hanssen R, Qubad M, Bouzouina A, Schack V, Sochor H, Schiweck C, Aichholzer M, Matura S, Slattery DA, Zopf Y, Borgland SL, Reif A, Thanarajah SE. Impact of insulin and insulin resistance on brain dopamine signalling and reward processing- an underexplored mechanism in the pathophysiology of depression? Neurosci Biobehav Rev 2023; 149:105179. [PMID: 37059404 DOI: 10.1016/j.neubiorev.2023.105179] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 04/04/2023] [Accepted: 04/11/2023] [Indexed: 04/16/2023]
Abstract
Type 2 diabetes and major depressive disorder (MDD) are the leading causes of disability worldwide and have a high comorbidity rate with fatal outcomes. Despite the long-established association between these conditions, the underlying molecular mechanisms remain unknown. Since the discovery of insulin receptors in the brain and the brain's reward system, evidence has accumulated indicating that insulin modulates dopaminergic (DA) signalling and reward behaviour. Here, we review the evidence from rodent and human studies, that insulin resistance directly alters central DA pathways, which may result in motivational deficits and depressive symptoms. Specifically, we first elaborate on the differential effects of insulin on DA signalling in the ventral tegmental area (VTA) - the primary DA source region in the midbrain - and the striatum as well as its effects on behaviour. We then focus on the alterations induced by insulin deficiency and resistance. Finally, we review the impact of insulin resistance in DA pathways in promoting depressive symptoms and anhedonia on a molecular and epidemiological level and discuss its relevance for stratified treatment strategies.
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Affiliation(s)
- Judith Gruber
- Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt, Germany
| | - Ruth Hanssen
- University of Cologne, Faculty of Medicine and University Hospital Cologne, Policlinic for Endocrinology, Diabetology and Prevention Medicine, Germany
| | - Mishal Qubad
- Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt, Germany
| | - Aicha Bouzouina
- Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt, Germany
| | - Vivi Schack
- Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt, Germany
| | - Hannah Sochor
- Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt, Germany
| | - Carmen Schiweck
- Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt, Germany
| | - Mareike Aichholzer
- Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt, Germany
| | - Silke Matura
- Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt, Germany
| | - David A Slattery
- Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt, Germany
| | - Yurdaguel Zopf
- Hector-Center for Nutrition, Exercise and Sports, Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Stephanie L Borgland
- Department of Physiology and Pharmacology, Hotchkiss Brain Institute, The University of Calgary, Calgary, Canada
| | - Andreas Reif
- Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt, Germany
| | - Sharmili Edwin Thanarajah
- Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt, Germany.
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13
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Chamorro R, Jouffe C, Oster H, Uhlenhaut NH, Meyhöfer SM. When should I eat: A circadian view on food intake and metabolic regulation. Acta Physiol (Oxf) 2023; 237:e13936. [PMID: 36645134 DOI: 10.1111/apha.13936] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 12/19/2022] [Accepted: 01/11/2023] [Indexed: 01/17/2023]
Abstract
The circadian clock is a hierarchical timing system regulating most physiological and behavioral functions with a period of approximately 24 h in humans and other mammalian species. The circadian clock drives daily eating rhythms that, in turn, reinforce the circadian clock network itself to anticipate and orchestrate metabolic responses to food intake. Eating is tightly interconnected with the circadian clock and recent evidence shows that the timing of meals is crucial for the control of appetite and metabolic regulation. Obesity results from combined long-term dysregulation in food intake (homeostatic and hedonic circuits), energy expenditure, and energy storage. Increasing evidence supports that the loss of synchrony of daily rhythms significantly impairs metabolic homeostasis and is associated with obesity. This review presents an overview of mechanisms regulating food intake (homeostatic/hedonic) and focuses on the crucial role of the circadian clock on the metabolic response to eating, thus providing a fundamental research axis to maintain a healthy eating behavior.
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Affiliation(s)
- Rodrigo Chamorro
- Institute for Endocrinology and Diabetes, University of Lübeck, Lübeck, Germany.,Department of Nutrition, Faculty of Medicine, University of Chile, Santiago, Chile
| | - Céline Jouffe
- Institute for Diabetes and Endocrinology, Helmholtz Diabetes Center, Helmholtz Zentrum München, Neuherberg, Germany.,Institute for Diabetes and Cancer, Helmholtz Diabetes Center, Helmholtz Zentrum München, Neuherberg, Germany
| | - Henrik Oster
- Center of Brain, Behavior and Metabolism (CBBM), University of Lübeck, Lübeck, Germany.,Institute of Neurobiology, University of Lübeck, Lübeck, Germany
| | - N Henriette Uhlenhaut
- Institute for Diabetes and Endocrinology, Helmholtz Diabetes Center, Helmholtz Zentrum München, Neuherberg, Germany.,Chair for Metabolic Programming, TUM School of Life Sciences Weihenstephan, & ZIEL-Institute for Food & Health, Freising, Germany
| | - Sebastian M Meyhöfer
- Institute for Endocrinology and Diabetes, University of Lübeck, Lübeck, Germany.,Center of Brain, Behavior and Metabolism (CBBM), University of Lübeck, Lübeck, Germany.,German Center for Diabetes Research (DZD), München-Neuherberg, Germany
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14
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Hoffmann S, Gerhardt S, Koopmann A, Bach P, Sommer WH, Kiefer F, Mazza M, Lenz B. Body mass index interacts with sex to predict readmission in in-patients with alcohol use disorder. Addict Biol 2023; 28:e13239. [PMID: 36577723 DOI: 10.1111/adb.13239] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 08/19/2022] [Accepted: 09/22/2022] [Indexed: 12/23/2022]
Abstract
A previous highly controlled pilot study revealed that body mass index (BMI) predicts outcome of in-patients with alcohol use disorder (AUD) in a sex-specific manner. We here provide translational evidence from a daily clinical routine setting and investigated whether BMI and sex interact to predict 24-month readmission risk in four naturalistic cohorts of a specialized addiction clinic (i.e., all patients admitted to the clinic from 2016 to 2020): (i) in-patients (443 males and 197 females) and (ii) day clinic patients (241 males and 103 females) with a primary diagnosis of AUD; (iii) in-patients (175 males and 98 females) and (iv) day clinic patients (174 males and 64 females) with a primary substance use disorder (SUD) other than alcohol. In the in-patients with AUD, BMI interacted with sex to predict the 24-month readmission risks (p = 0.008; after adjustment for age and liver enzyme activities: p = 0.012); with higher BMI, the risk increases significantly in males, whereas for females, the risk tends to decrease. In the group of overweight in-patients, we found higher readmission rates in males relative to females with an odds ratio of 1.8 (p = 0.038). No such significant effects were found in the other cohorts. This study's findings support previous results, suggesting that the easily accessible BMI may serve as a predictive and sex-sensitive biomarker for outcome in in-patients with AUD. Future studies are necessary to elucidate the underlying aetiopathological mechanisms.
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Affiliation(s)
- Sabine Hoffmann
- Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health (CIMH), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.,Department of Biostatistics, Central Institute of Mental Health (CIMH), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Sarah Gerhardt
- Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health (CIMH), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Anne Koopmann
- Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health (CIMH), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Patrick Bach
- Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health (CIMH), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Wolfgang H Sommer
- Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health (CIMH), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.,Department of Psychopharmacology, Central Institute of Mental Health (CIMH), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.,Bethanian Hospital for Psychiatry, Psychosomatics and Psychotherapy, Greifswald, Germany
| | - Falk Kiefer
- Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health (CIMH), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Massimiliano Mazza
- Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health (CIMH), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Bernd Lenz
- Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health (CIMH), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
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15
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Verdier A, Dominique N, Groussard D, Aldanondo A, Bathellier B, Bagur S. Enhanced perceptual task performance without deprivation in mice using medial forebrain bundle stimulation. CELL REPORTS METHODS 2022; 2:100355. [PMID: 36590697 PMCID: PMC9795331 DOI: 10.1016/j.crmeth.2022.100355] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 10/04/2022] [Accepted: 11/09/2022] [Indexed: 05/11/2023]
Abstract
Perceptual decision-making tasks are essential to many fields of neuroscience. Current protocols generally reward deprived animals with water. However, balancing animals' deprivation level with their well-being is challenging, and trial number is limited by satiation. Here, we present electrical stimulation of the medial forebrain bundle (MFB) as an alternative that avoids deprivation while yielding stable motivation for thousands of trials. Using licking or lever press as a report, MFB animals learnt auditory discrimination tasks at similar speed to water-deprived mice. Moreover, they more reliably reached higher accuracy in harder tasks, performing up to 4,500 trials per session without loss of motivation. MFB stimulation did not impact the underlying sensory behavior since psychometric parameters and response times are preserved. MFB mice lacked signs of metabolic or behavioral stress compared with water-deprived mice. Overall, MFB stimulation is a highly promising tool for task learning because it enhances task performance while avoiding deprivation.
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Affiliation(s)
- Antonin Verdier
- Institut de l’Audition, Institut Pasteur, Université de Paris, INSERM, 75012 Paris, France
| | - Noémi Dominique
- Institut Pasteur, Université Paris Cité, DT, Animalerie Centrale, 75724 Paris, France
| | - Déborah Groussard
- Institut Pasteur, Université Paris Cité, DT, Animalerie Centrale, 75724 Paris, France
| | - Anna Aldanondo
- Institut de l’Audition, Institut Pasteur, Université de Paris, INSERM, 75012 Paris, France
| | - Brice Bathellier
- Institut de l’Audition, Institut Pasteur, Université de Paris, INSERM, 75012 Paris, France
| | - Sophie Bagur
- Institut de l’Audition, Institut Pasteur, Université de Paris, INSERM, 75012 Paris, France
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16
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Calcaterra V, Rossi V, Mari A, Casini F, Bergamaschi F, Zuccotti GV, Fabiano V. Medical treatment of weight loss in children and adolescents with obesity. Pharmacol Res 2022; 185:106471. [PMID: 36174963 DOI: 10.1016/j.phrs.2022.106471] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 09/16/2022] [Accepted: 09/23/2022] [Indexed: 12/01/2022]
Abstract
Obesity remains one of the biggest health problems both in adults and children. Lifestyle modification, including diet and exercise, continues to be the mainstay of obesity prevention and treatment. Unfortunately, lifestyle modifications are often unsuccessful. Pharmacological treatment of obesity in pediatric patients can be applied in selected cases, and not before evidence of failure of the multidisciplinary lifestyle intervention. In this narrative review, we revised the most up-to-date evidence on medical treatment of weight loss in children and adolescents with obesity, including FDA- or EMA-approved and -experimented, not approved, drugs for pediatric population. Multidisciplinary treatment of childhood obesity, regulation of appetite control, energy balance and body weight were also discussed, in order to clarify the indications and mechanism action of drugs. Despite a substantial number of medications used for the treatment of obesity in adults, a limited number of drugs are approved by the drug regulatory agencies for pediatric population. Further research is needed to evaluate the efficacy and safety of novel pharmacological approaches for treatment of pediatric obesity in order to optimize weight management for children and adolescents and limit the development obesity-related comorbidities.
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Affiliation(s)
- Valeria Calcaterra
- Department of Pediatrics, Vittore Buzzi Children's Hospital, 20154 Milan, Italy; Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy
| | - Virginia Rossi
- Department of Pediatrics, Vittore Buzzi Children's Hospital, 20154 Milan, Italy
| | - Alessandra Mari
- Department of Pediatrics, Vittore Buzzi Children's Hospital, 20154 Milan, Italy
| | - Francesca Casini
- Department of Pediatrics, Vittore Buzzi Children's Hospital, 20154 Milan, Italy
| | | | - Gian Vincenzo Zuccotti
- Department of Pediatrics, Vittore Buzzi Children's Hospital, 20154 Milan, Italy; Department of Biomedical and Clinical Sciences, Università di Milano, 20122 Milan, Italy
| | - Valentina Fabiano
- Department of Pediatrics, Vittore Buzzi Children's Hospital, 20154 Milan, Italy; Department of Biomedical and Clinical Sciences, Università di Milano, 20122 Milan, Italy.
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17
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Hebebrand J, Hildebrandt T, Schlögl H, Seitz J, Denecke S, Vieira D, Gradl-Dietsch G, Peters T, Antel J, Lau D, Fulton S. The role of hypoleptinemia in the psychological and behavioral adaptation to starvation: implications for anorexia nervosa. Neurosci Biobehav Rev 2022; 141:104807. [PMID: 35931221 DOI: 10.1016/j.neubiorev.2022.104807] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 06/11/2022] [Accepted: 07/31/2022] [Indexed: 12/17/2022]
Abstract
This narrative review aims to pinpoint mental and behavioral effects of starvation, which may be triggered by hypoleptinemia and as such may be amenable to treatment with leptin receptor agonists. The reduced leptin secretion results from the continuous loss of fat mass, thus initiating a graded triggering of diverse starvation related adaptive functions. In light of leptin receptors located in several peripheral tissues and many brain regions adaptations may extend beyond those of the hypothalamus-pituitary-end organ-axes. We focus on gastrointestinal tract and reward system as relevant examples of peripheral and central effects of leptin. Despite its association with extreme obesity, congenital leptin deficiency with its many parallels to a state of starvation allows the elucidation of mental symptoms amenable to treatment with exogenous leptin in both ob/ob mice and humans with this autosomal recessive disorder. For starvation induced behavioral changes with an intact leptin signaling we particularly focus on rodent models for which proof of concept has been provided for the causative role of hypoleptinemia. For humans, we highlight the major cognitive, emotional and behavioral findings of the Minnesota Starvation Experiment to contrast them with results obtained upon a lesser degree of caloric restriction. Evidence for hypoleptinemia induced mental changes also stems from findings obtained in lipodystrophies. In light of the recently reported beneficial cognitive, emotional and behavioral effects of metreleptin-administration in anorexia nervosa we discuss potential implications for the treatment of this eating disorder. We postulate that leptin has profound psychopharmacological effects in the state of starvation.
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Affiliation(s)
- Johannes Hebebrand
- Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Essen, University of Duisburg-Essen, Wickenburgstr. 21, 45134 Essen, Germany
| | - Tom Hildebrandt
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029 USA
| | - Haiko Schlögl
- Department of Endocrinology, Nephrology, Rheumatology, Division of Endocrinology, University Hospital Leipzig, Liebigstr. 20, 04103 Leipzig, Germany; Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig and University Hospital Leipzig, Philipp-Rosenthal-Str. 27, 04103 Leipzig, Germany
| | - Jochen Seitz
- Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, RWTH University Hospital Aachen, Germany
| | - Saskia Denecke
- Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Essen, University of Duisburg-Essen, Wickenburgstr. 21, 45134 Essen, Germany
| | - Diana Vieira
- Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Essen, University of Duisburg-Essen, Wickenburgstr. 21, 45134 Essen, Germany
| | - Gertraud Gradl-Dietsch
- Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Essen, University of Duisburg-Essen, Wickenburgstr. 21, 45134 Essen, Germany
| | - Triinu Peters
- Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Essen, University of Duisburg-Essen, Wickenburgstr. 21, 45134 Essen, Germany
| | - Jochen Antel
- Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Essen, University of Duisburg-Essen, Wickenburgstr. 21, 45134 Essen, Germany
| | - David Lau
- Department of Nutrition, Neuroscience - University of Montreal & CRCHUM, Montréal QC H3T1J4, Canada
| | - Stephanie Fulton
- Department of Nutrition, Neuroscience - University of Montreal & CRCHUM, Montréal QC H3T1J4, Canada
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18
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Krishna AG, Goyal N, Ram D, Rajan AK, Kshitiz KK. Hunger Hormones in Disruptive Mood Dysregulation Disorder in Adolescents: An Exploratory Study. ADOLESCENT PSYCHIATRY 2022. [DOI: 10.2174/2210676612666220415112851] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Background:
Hunger hormones, including ghrelin and leptin, are associated with appetitive behaviors in various psychiatric disorders. Biochemical and hormonal status in disruptive mood dysregulation disorder (DMDD) in adolescents is largely unexplored.
Objectives:
The study aimed to assess levels of leptin and ghrelin and find their association with lipid profiles in adolescents with DMDD.
Methods:
Twenty adolescents with a DSM 5 diagnosis of DMDD with age and gender-matched 19 healthy controls were recruited, followed by clinical assessment. They were assessed for leptin, ghrelin, and lipid profiles, respectively.
Results:
Adolescents with DMDD were comparable in age, education, family income, domicile status, psychiatric illness in the family, and body mass index (BMI) with matched controls. There was no difference in mean lipid profile and ghrelin in both groups. However, the DMDD group had statistically significant higher mean level of leptin as compared to the control group (t=1.84, p < 0.05). As measured by the Modified Overt Aggression Scale in DMDD, aggression showed a significant positive correlation with measures of lipid profile.
Conclusion:
Adolescents with DMDD have elevated serum leptin levels. Further research is needed to confirm this finding.
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Affiliation(s)
| | - Nishant Goyal
- Associate Professor of Psychiatry, Centre for Child and Adolescent Psychiatry, Central Institute of Psychiatry, Ranchi
| | - Dushad Ram
- Associate Professor of Psychiatry, College of Medicine, Shaqra University, Shaqra
| | | | - K. K. Kshitiz
- Professor of Biochemistry, Central Institute of Psychiatry, Ranchi
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19
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Watts AG, Kanoski SE, Sanchez-Watts G, Langhans W. The physiological control of eating: signals, neurons, and networks. Physiol Rev 2022; 102:689-813. [PMID: 34486393 PMCID: PMC8759974 DOI: 10.1152/physrev.00028.2020] [Citation(s) in RCA: 69] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Accepted: 08/30/2021] [Indexed: 02/07/2023] Open
Abstract
During the past 30 yr, investigating the physiology of eating behaviors has generated a truly vast literature. This is fueled in part by a dramatic increase in obesity and its comorbidities that has coincided with an ever increasing sophistication of genetically based manipulations. These techniques have produced results with a remarkable degree of cell specificity, particularly at the cell signaling level, and have played a lead role in advancing the field. However, putting these findings into a brain-wide context that connects physiological signals and neurons to behavior and somatic physiology requires a thorough consideration of neuronal connections: a field that has also seen an extraordinary technological revolution. Our goal is to present a comprehensive and balanced assessment of how physiological signals associated with energy homeostasis interact at many brain levels to control eating behaviors. A major theme is that these signals engage sets of interacting neural networks throughout the brain that are defined by specific neural connections. We begin by discussing some fundamental concepts, including ones that still engender vigorous debate, that provide the necessary frameworks for understanding how the brain controls meal initiation and termination. These include key word definitions, ATP availability as the pivotal regulated variable in energy homeostasis, neuropeptide signaling, homeostatic and hedonic eating, and meal structure. Within this context, we discuss network models of how key regions in the endbrain (or telencephalon), hypothalamus, hindbrain, medulla, vagus nerve, and spinal cord work together with the gastrointestinal tract to enable the complex motor events that permit animals to eat in diverse situations.
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Affiliation(s)
- Alan G Watts
- The Department of Biological Sciences, Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, California
| | - Scott E Kanoski
- The Department of Biological Sciences, Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, California
| | - Graciela Sanchez-Watts
- The Department of Biological Sciences, Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, California
| | - Wolfgang Langhans
- Physiology and Behavior Laboratory, Eidgenössische Technische Hochschule-Zürich, Schwerzenbach, Switzerland
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20
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The Effect of Fasting on Human Metabolism and Psychological Health. DISEASE MARKERS 2022; 2022:5653739. [PMID: 35035610 PMCID: PMC8754590 DOI: 10.1155/2022/5653739] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 11/07/2021] [Accepted: 12/21/2021] [Indexed: 12/26/2022]
Abstract
Fasting is a prevalent approach to weight loss and is a feasible method for treating some diseases, such as type 2 diabetes. Meanwhile, the effects of intermittent fasting on health, aging, and disease process are hot issues and are of concern by researchers of multiple areas, even the public. This article introduces the effects of fasting on human lipid metabolism, glucose metabolism, protein metabolism, and neuroendocrine metabolism; demonstrates the metabolic conversion caused by fasting; and describes the effects of fasting on human psychological health, the relationship between mood regulation and glucose, and the emotional enhancing effect induced by fasting.
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21
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Nomura H, Son C, Aotani D, Shimizu Y, Katsuura G, Noguchi M, Kusakabe T, Tanaka T, Miyazawa T, Hosoda K, Nakao K. Impaired leptin responsiveness in the nucleus accumbens of leptin-overexpressing transgenic mice with dysregulated sucrose and lipid preference independent of obesity. Neurosci Res 2021; 177:94-102. [PMID: 34971637 DOI: 10.1016/j.neures.2021.12.007] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 12/06/2021] [Accepted: 12/26/2021] [Indexed: 11/19/2022]
Abstract
While hypothalamic leptin resistance can occur prior to establishment of obesity, clarification is needed as to whether the impaired response to leptin in the reward-related nuclei occurs independently of obesity. To answer this question, we attempted to dissociate the normally coexisting leptin resistance from obesity. We investigated phenotypes of leptin-overexpressing transgenic mice fed for 1 week with 60 % high-fat diet (HFD) (LepTg-HFD1W mice). After 1 week, we observed that LepTg-HFD1W mice weighed as same as wild type (WT) mice fed standard chow diet (CD) for 1 week (WT-CD1W mice). However, compared to WT-CD1W mice, LepTg-HFD1W mice exhibited attenuated leptin-induced anorexia, decreased leptin-induced c-fos immunostaining in nucleus accumbens (NAc), one of important site of reward system, decreased leptin-stimulated pSTAT3 immunostaining in hypothalamus. Furthermore, neither sucrose nor lipid preference was suppressed by leptin in LepTg-HFD1W mice. On the contrary, leptin significantly suppressed both preferences in WT mice fed HFD (WT-HFD1 W mice). These results indicate that leptin responsiveness decreases in NAc independently of obesity. Additionally, in this situation, suppressive effect of leptin on the hedonic feeding results in impaired regulation. Such findings suggest the impaired leptin responsiveness in NAc partially contributes to dysregulated hedonic feeding behavior independently of obesity.
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Affiliation(s)
- Hidenari Nomura
- Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan; Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Cheol Son
- Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan; Omics Research Center, National Cerebral and Cardiovascular Center, Suita, Japan.
| | - Daisuke Aotani
- Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Yoshiyuki Shimizu
- Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan; Department of Human Health and Science, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Goro Katsuura
- Department of Social and Behavioral Medicine, Division of Psychosomatic Internal Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Michio Noguchi
- Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Toru Kusakabe
- Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Tomohiro Tanaka
- Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Takashi Miyazawa
- Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Kiminori Hosoda
- Department of Human Health and Science, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Kazuwa Nakao
- Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan
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Identification of Novel Neurocircuitry Through Which Leptin Targets Multiple Inputs to the Dopamine System to Reduce Food Reward Seeking. Biol Psychiatry 2021; 90:843-852. [PMID: 33867112 DOI: 10.1016/j.biopsych.2021.02.017] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Revised: 01/27/2021] [Accepted: 02/14/2021] [Indexed: 01/08/2023]
Abstract
BACKGROUND Leptin reduces the motivation to obtain food by modulating activity of the mesolimbic dopamine (DA) system upon presentation of cues that predict a food reward. Although leptin directly reduces the activity of ventral tegmental area (VTA) DA neurons, the majority of leptin receptor (LepR)-expressing DA neurons do not project to the nucleus accumbens, the projection implicated in driving food reward seeking. Therefore, the precise locus of leptin action to modulate motivation for a food reward is unresolved. METHODS We used transgenic mice expressing Cre recombinase under the control of the LepR promoter, anatomical tracing, optogenetics-assisted patch-clamp electrophysiology, in vivo optogenetics with fiber photometric calcium measurements, and chemogenetics to unravel how leptin-targeted neurocircuitry inhibits food reward seeking. RESULTS A large number of DA neurons projecting to the nucleus accumbens are innervated by local VTA LepR-expressing GABA (gamma-aminobutyric acid) neurons. Leptin enhances the activity of these GABA neurons and thereby inhibits nucleus accumbens-projecting DA neurons. In addition, we find that lateral hypothalamic LepR-expressing neurons projecting to the VTA are inhibited by leptin and that these neurons modulate DA neurons indirectly via inhibition of VTA GABA neurons. In accordance with such a disinhibitory function, optogenetically stimulating lateral hypothalamic LepR projections to the VTA potently activates DA neurons in vivo. Moreover, we found that chemogenetic activation of lateral hypothalamic LepR neurons increases the motivation to obtain a food reward only when mice are in a positive energy balance. CONCLUSIONS We identify neurocircuitry through which leptin targets multiple inputs to the DA system to reduce food reward seeking.
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Luzi L, Gandini S, Massarini S, Bellerba F, Terruzzi I, Senesi P, Macrì C, Ferrulli A. Reduction of impulsivity in patients receiving deep transcranial magnetic stimulation treatment for obesity. Endocrine 2021; 74:559-570. [PMID: 34173157 PMCID: PMC8571225 DOI: 10.1007/s12020-021-02802-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Accepted: 06/13/2021] [Indexed: 12/25/2022]
Abstract
PURPOSE Aims of the present study were to investigate a wide array of psychological symptoms through validated psychometric tests, before and after 5 weeks of deep Transcranial Magnetic Stimulation (dTMS) in individuals with obesity, and to identify possible relationships with neuroendocrine parameters. METHODS Forty-five patients with obesity (33 F, 12 M; age 48.8 ± 9.9 years; body wt 97.6 ± 14.2 Kg; BMI 36.2 ± 4.2) were randomized into two groups: 26 received high frequency (HF) dTMS and 19 Sham stimulation for 5 weeks. At baseline and after the 5-week treatment, all patients underwent the following psychometric evaluations: Food Cravings Questionnaire-Trait (FCQ-T) and its subscales, Barratt Impulsiveness Scale-11 (BIS-11), State and Trait Anxiety Inventory (STAI-y1 and STAI-y2), and Beck Depression Inventory (BDI). Hormonal and neuroendocrine markers were assessed at the first and last dTMS session. RESULTS By adjusting for baseline variables and treatment arms, a significant decrease in body wt and BMI was found in HF group, both with univariate (p = 0.019) and multivariate analyses (p = 0.012). Impulsivity significantly decreased in HF group, both with univariate (p = 0.031) and multivariate analyses (p = 0.011). A positive association between the impulsivity score change and the leptin level variation (p = 0.031) was found. CONCLUSION The decrease of impulsivity together with the BMI reduction in individuals with obesity, treated with real stimulation, suggests that impulsivity may be a risk factor for obesity. Treatment with dTMS revealed to be effective in reducing both BMI and impulsivity by enhancing inhibitory capacity of Pre-Frontal Cortex (PFC), and modulating neuroendocrine system, especially leptin.
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Affiliation(s)
- Livio Luzi
- Department of Biomedical Sciences for Health, University of Milan, Milan, Italy.
- Department of Endocrinology, Nutrition and Metabolic Diseases, IRCCS MultiMedica, Sesto San Giovanni, Milan, Italy.
| | - Sara Gandini
- Department of Experimental Oncology, European Institute of Oncology IRCCS, Milan, Italy
| | - Stefano Massarini
- Department of Endocrinology, Nutrition and Metabolic Diseases, IRCCS MultiMedica, Sesto San Giovanni, Milan, Italy
| | - Federica Bellerba
- Department of Experimental Oncology, European Institute of Oncology IRCCS, Milan, Italy
| | - Ileana Terruzzi
- Department of Biomedical Sciences for Health, University of Milan, Milan, Italy
- Department of Endocrinology, Nutrition and Metabolic Diseases, IRCCS MultiMedica, Sesto San Giovanni, Milan, Italy
| | - Pamela Senesi
- Department of Biomedical Sciences for Health, University of Milan, Milan, Italy
- Department of Endocrinology, Nutrition and Metabolic Diseases, IRCCS MultiMedica, Sesto San Giovanni, Milan, Italy
| | - Concetta Macrì
- Department of Endocrinology, Nutrition and Metabolic Diseases, IRCCS MultiMedica, Sesto San Giovanni, Milan, Italy
| | - Anna Ferrulli
- Department of Biomedical Sciences for Health, University of Milan, Milan, Italy
- Department of Endocrinology, Nutrition and Metabolic Diseases, IRCCS MultiMedica, Sesto San Giovanni, Milan, Italy
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Valentina S, Blasio A, Ferragud A, Quadir SG, Iyer MR, Rice KC, Cottone P. Characterization of a differential reinforcement of low rates of responding task in non-deprived male and female rats: Role of Sigma-1 receptors. Neuropharmacology 2021; 200:108786. [PMID: 34516984 PMCID: PMC9869339 DOI: 10.1016/j.neuropharm.2021.108786] [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: 07/28/2021] [Revised: 08/25/2021] [Accepted: 09/06/2021] [Indexed: 01/26/2023]
Abstract
Impulsive action can be defined as the inability to withhold a response and represents one of the dimensions of the broad construct impulsivity. Here, we characterized a modified differential reinforcement of low rates of responding (DRL) task developed in our laboratory, in which impulsive action is measured in ad libitum fed/watered subjects. Specifically, we first determined the effects of both sex and estrous cycle on impulsive action by systematically comparing male and estrous-synchronized female subjects. In addition, we evaluated the convergent validity of this modified DRL task by testing the effects of the D2R/5HT2AR antagonist, aripiprazole, and the noncompetitive NMDAR antagonist, MK-801. Finally, we tested the effects of the selective antagonist BD-1063 and agonist PRE-084 of Sigma-1 receptor (Sig-1R) on impulsive action using this modified DRL task. We found that female rats showed and increased inability to withhold a response when compared to males, and this effect was driven by the metestrus/diestrus phase of the estrous cycle. In addition, aripiprazole and MK-801 fully retained their capability to reduce and increase impulsive action, respectively. Finally, the selective Sig-1R antagonist, BD-1063 dose-dependently reduced the inability to withhold a response in both sexes, though more potently in female rats. In summary, we show that impulsive action, as measured in a modified DRL task which minimizes energy-homeostatic influences, is a function of both sex and estrous cycle. Furthermore, we validate the convergent validity of the task and provide evidence that Sig-1R antagonism may represent a novel pharmacological strategy to reduce impulsive action.
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Affiliation(s)
- Sabino Valentina
- Laboratory of Addictive Disorders, Departments of Pharmacology and Psychiatry, Boston University School of Medicine, Boston, MA, USA.
| | - Angelo Blasio
- Laboratory of Addictive Disorders, Departments of Pharmacology and Psychiatry, Boston University School of Medicine, Boston, MA, USA
| | - Antonio Ferragud
- Laboratory of Addictive Disorders, Departments of Pharmacology and Psychiatry, Boston University School of Medicine, Boston, MA, USA
| | - Sema G Quadir
- Laboratory of Addictive Disorders, Departments of Pharmacology and Psychiatry, Boston University School of Medicine, Boston, MA, USA
| | - Malliga R Iyer
- Section on Medicinal Chemistry, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USA
| | - Kenner C Rice
- Drug Design and Synthesis, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USA
| | - Pietro Cottone
- Laboratory of Addictive Disorders, Departments of Pharmacology and Psychiatry, Boston University School of Medicine, Boston, MA, USA.
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Kakall ZM, Gopalasingam G, Herzog H, Zhang L. Dynamic regional alterations in mouse brain neuronal activity following short-term changes in energy balance. Obesity (Silver Spring) 2021; 29:1650-1663. [PMID: 34402189 DOI: 10.1002/oby.23253] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Revised: 06/08/2021] [Accepted: 06/10/2021] [Indexed: 11/11/2022]
Abstract
OBJECTIVE Knowledge of the functional contribution to energy homeostatic control by different brain areas is limited. This study employed a systematic approach to identify brain regions specifically influenced by a positive energy balance. METHODS The c-fos expression was mapped throughout the mouse brain after varying durations (24 hours to up to 14 days) of high-fat diet (HFD) exposure or after reversal from a 7-day HFD to a chow diet. In parallel, the metabolic and behavioral impacts of these treatments were examined. RESULTS A HFD elicited rapid and pronounced compensatory responses which were, however, insufficient to overcome the impact of the positive energy balance. Rapid and dynamic responses of c-fos expression throughout the brain were seen over the course of HFD exposure, with some regions showing linear-like responses and some regions exhibiting biphasic responses. The switch from HFD to chow resulted in metabolic compensations mitigating the effects of the negative energy balance and a heightened preference for sweet taste. Interestingly, this diet switch led to a significant c-fos activation in the lateral hypothalamus, an area unresponsive to HFD intervention. CONCLUSIONS Plasticity exists in the extended brain networks facilitating rapid adaptations dependent on energy availability. Knowledge of these critical control points may provide novel antiobesity treatment targets.
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Affiliation(s)
- Zohra Mohtat Kakall
- Neuroscience Division, Garvan Institute of Medical Research, St Vincent's Hospital, Darlinghurst, New South Wales, Australia
| | - Gopana Gopalasingam
- Neuroscience Division, Garvan Institute of Medical Research, St Vincent's Hospital, Darlinghurst, New South Wales, Australia
| | - Herbert Herzog
- Neuroscience Division, Garvan Institute of Medical Research, St Vincent's Hospital, Darlinghurst, New South Wales, Australia
- St Vincent's Clinical School, University of New South Wales Sydney, Sydney, New South Wales, Australia
- Faulty of Medicine, University of New South Wales Sydney, Sydney, New South Wales, Australia
| | - Lei Zhang
- Neuroscience Division, Garvan Institute of Medical Research, St Vincent's Hospital, Darlinghurst, New South Wales, Australia
- St Vincent's Clinical School, University of New South Wales Sydney, Sydney, New South Wales, Australia
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26
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Decoding the Role of Gut-Microbiome in the Food Addiction Paradigm. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2021; 18:ijerph18136825. [PMID: 34202073 PMCID: PMC8297196 DOI: 10.3390/ijerph18136825] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Revised: 06/22/2021] [Accepted: 06/23/2021] [Indexed: 12/12/2022]
Abstract
Eating behaviour is characterised by a solid balance between homeostatic and hedonic regulatory mechanisms at the central level and highly influenced by peripheral signals. Among these signals, those generated by the gut microbiota have achieved relevance in recent years. Despite this complex regulation, under certain circumstances eating behaviour can be deregulated becoming addictive. Although there is still an ongoing debate about the food addiction concept, studies agree that patients with eating addictive behaviour present similar symptoms to those experienced by drug addicts, by affecting central areas involved in the control of motivated behaviour. In this context, this review tries to summarise the main data regarding the role of the gut microbiome in eating behaviour and how a gut dysbiosis can be responsible for a maladaptive behaviour such as “food addiction”.
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27
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Morville T, Madsen KH, Siebner HR, Hulme OJ. Reward signalling in brainstem nuclei under fluctuating blood glucose. PLoS One 2021; 16:e0243899. [PMID: 33826633 PMCID: PMC8026025 DOI: 10.1371/journal.pone.0243899] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Accepted: 12/01/2020] [Indexed: 11/18/2022] Open
Abstract
Phasic dopamine release from mid-brain dopaminergic neurons is thought to signal errors of reward prediction (RPE). If reward maximisation is to maintain homeostasis, then the value of primary rewards should be coupled to the homeostatic errors they remediate. This leads to the prediction that RPE signals should be configured as a function of homeostatic state and thus diminish with the attenuation of homeostatic error. To test this hypothesis, we collected a large volume of functional MRI data from five human volunteers on four separate days. After fasting for 12 hours, subjects consumed preloads that differed in glucose concentration. Participants then underwent a Pavlovian cue-conditioning paradigm in which the colour of a fixation-cross was stochastically associated with the delivery of water or glucose via a gustometer. This design afforded computation of RPE separately for better- and worse-than expected outcomes during ascending and descending trajectories of serum glucose fluctuations. In the parabrachial nuclei, regional activity coding positive RPEs scaled positively with serum glucose for both ascending and descending glucose levels. The ventral tegmental area and substantia nigra became more sensitive to negative RPEs when glucose levels were ascending. Together, the results suggest that RPE signals in key brainstem structures are modulated by homeostatic trajectories of naturally occurring glycaemic flux, revealing a tight interplay between homeostatic state and the neural encoding of primary reward in the human brain.
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Affiliation(s)
- Tobias Morville
- Danish Research Centre for Magnetic Resonance, Centre for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark
| | - Kristoffer H. Madsen
- DTU Compute, Department of Informatics and Mathematical Modelling, Technical University of Denmark, Copenhagen, Denmark
| | - Hartwig R. Siebner
- Danish Research Centre for Magnetic Resonance, Centre for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark
- Department of Neurology, Copenhagen University Hospital Bispebjerg, Copenhagen, Denmark
| | - Oliver J. Hulme
- Danish Research Centre for Magnetic Resonance, Centre for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark
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28
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LSD1-BDNF activity in lateral hypothalamus-medial forebrain bundle area is essential for reward seeking behavior. Prog Neurobiol 2021; 202:102048. [PMID: 33798614 DOI: 10.1016/j.pneurobio.2021.102048] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 03/06/2021] [Accepted: 03/25/2021] [Indexed: 12/24/2022]
Abstract
Reward induces activity-dependant gene expression and synaptic plasticity-related changes. Lysine-specific histone demethylase 1 (LSD1), a key enzyme driving histone modifications, regulates transcription in neural circuits of memory and emotional behavior. Herein, we focus on the role of LSD1 in modulating the expression of brain derived neurotrophic factor (BDNF), the master regulator of synaptic plasticity, in the lateral hypothalamus-medial forebrain bundle (LH-MFB) circuit during positive reinforcement. Rats, trained for intracranial self-stimulation (ICSS) via an electrode-cannula assembly in the LH-MFB area, were assayed for lever press activity, epigenetic parameters and dendritic sprouting. LSD1 expression and markers of synaptic plasticity like BDNF and dendritic arborization in the LH, showed distinct increase in conditioned animals. H3K4me2 levels at Bdnf IV and Bdnf IX promoters were increased in ICSS-conditioned rats, but H3K9me2 was decreased. While intra LH-MFB treatment with pan Lsd1 siRNA inhibited lever press activity, analyses of LH tissue showed reduction in BDNF expression and levels of H3K4me2 and H3K9me2. However, co-administration of BDNF peptide restored lever press activity mitigated by Lsd1 siRNA. BDNF expression in LH, driven by LSD1 via histone demethylation, may play an important role in reshaping the reward pathway and hold the key to decode the molecular basis of addiction.
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29
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Lippert RN, Hess S, Klemm P, Burgeno LM, Jahans-Price T, Walton ME, Kloppenburg P, Brüning JC. Maternal high-fat diet during lactation reprograms the dopaminergic circuitry in mice. J Clin Invest 2021; 130:3761-3776. [PMID: 32510473 DOI: 10.1172/jci134412] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2019] [Accepted: 03/26/2020] [Indexed: 12/31/2022] Open
Abstract
The maternal perinatal environment modulates brain formation, and altered maternal nutrition has been linked to the development of metabolic and psychiatric disorders in the offspring. Here, we showed that maternal high-fat diet (HFD) feeding during lactation in mice elicits long-lasting changes in gene expression in the offspring's dopaminergic circuitry. This translated into silencing of dopaminergic midbrain neurons, reduced connectivity to their downstream targets, and reduced stimulus-evoked dopamine (DA) release in the striatum. Despite the attenuated activity of DA midbrain neurons, offspring from mothers exposed to HFD feeding exhibited a sexually dimorphic expression of DA-related phenotypes, i.e., hyperlocomotion in males and increased intake of palatable food and sucrose in females. These phenotypes arose from concomitantly increased spontaneous activity of D1 medium spiny neurons (MSNs) and profoundly decreased D2 MSN projections. Overall, we have unraveled a fundamental restructuring of dopaminergic circuitries upon time-restricted altered maternal nutrition to induce persistent behavioral changes in the offspring.
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Affiliation(s)
- R N Lippert
- Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Cologne, Germany.,National Center for Diabetes Research (DZD), Neuherberg, Germany
| | - S Hess
- Biocenter, Institute for Zoology, and.,Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
| | - P Klemm
- Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Cologne, Germany
| | - L M Burgeno
- Department of Experimental Psychology, University of Oxford, Oxford, United Kingdom
| | - T Jahans-Price
- Department of Experimental Psychology, University of Oxford, Oxford, United Kingdom
| | - M E Walton
- Department of Experimental Psychology, University of Oxford, Oxford, United Kingdom
| | - P Kloppenburg
- Biocenter, Institute for Zoology, and.,Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
| | - J C Brüning
- Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Cologne, Germany.,National Center for Diabetes Research (DZD), Neuherberg, Germany.,Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.,Center for Endocrinology, Diabetes and Preventive Medicine (CEPD), University Hospital of Cologne, Cologne, Germany
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30
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Li Y, Wu H, Zhang R, Shu G, Wang S, Gao P, Zhu X, Jiang Q, Wang L. Diet containing stearic acid increases food reward-related behaviors in mice compared with oleic acid. Brain Res Bull 2020; 164:45-54. [PMID: 32822805 DOI: 10.1016/j.brainresbull.2020.08.012] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2020] [Revised: 07/30/2020] [Accepted: 08/10/2020] [Indexed: 10/23/2022]
Abstract
Obesity is currently a worldwide phenomenon. The consumption of calorie-rich foods is responsible for most obesity cases, but not all humans exposed to high-calorie diets develop obesity. According to recent studies, exposure to fat-rich diets may be the actual cause of obesity. Dietary long-chain fatty acids affect brain function and are linked to food intake and motivation-related behaviors. Recently, many studies have shown that different types of fatty acids play different roles in animals. In our study, the effects of stearic acid (a saturated fatty acid) and oleic acid (a monounsaturated fatty acid) in diets on hedonic feeding behaviors were investigated, and changes of feeding-related protein levels in the brain were detected to explore the possible mechanism underlying the effects of these fatty acids. As a result, mice fed a diet containing stearic acid, compared to a diet containing oleic acid, exhibited increased food intake, hedonic eating, and an operant response to sucrose and locomotor activity. Furthermore, stearic acid corresponded to a higher level of leptin in serum than oleic acid. In addition, the stearic acid treated group had lower protein levels of p-JAK2 and p-STAT3 in the VTA and a higher dopamine concentration in the NAc than the oleic acid-treated group. Meanwhile, the protein level of TH in the NAc was higher and the protein level of the DA transporter in the VTA was lower in the stearic acid-fed group than in the oleic acid-fed group. In conclusion, these findings indicated that a diet containing stearic acid can increase hedonic feeding behavior and affect mesolimbic dopamine system signals in mice. Moreover, the lowering of serum leptin and leptin signaling in the VTA may contribute to this effect.
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Affiliation(s)
- Yongxiang Li
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, Guangzhou, Guangdong 510642, China; National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong 510642, China
| | - Hanyu Wu
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, Guangzhou, Guangdong 510642, China; National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong 510642, China
| | - Ruixue Zhang
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, Guangzhou, Guangdong 510642, China; National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong 510642, China
| | - Gang Shu
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, Guangzhou, Guangdong 510642, China; National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong 510642, China
| | - Songbo Wang
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, Guangzhou, Guangdong 510642, China; National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong 510642, China
| | - Ping Gao
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, Guangzhou, Guangdong 510642, China; National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong 510642, China
| | - Xiaotong Zhu
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, Guangzhou, Guangdong 510642, China; National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong 510642, China
| | - Qingyan Jiang
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, Guangzhou, Guangdong 510642, China; National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong 510642, China.
| | - Lina Wang
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, Guangzhou, Guangdong 510642, China; National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong 510642, China.
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Mozafari R, Jamali S, Pourhamzeh M, Koruji M, Ahadi R, Haghparast A. The blockade of D1- and D2-like dopamine receptors within the dentate gyrus attenuates food deprivation stress-induced reinstatement of morphine-extinguished conditioned place preference in rats. Pharmacol Biochem Behav 2020; 196:172967. [DOI: 10.1016/j.pbb.2020.172967] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2019] [Revised: 05/14/2020] [Accepted: 06/13/2020] [Indexed: 11/29/2022]
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Blanco-Gandía MC, Miñarro J, Rodríguez-Arias M. Common Neural Mechanisms of Palatable Food Intake and Drug Abuse: Knowledge Obtained with Animal Models. Curr Pharm Des 2020; 26:2372-2384. [DOI: 10.2174/1381612826666200213123608] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Accepted: 01/23/2020] [Indexed: 02/07/2023]
Abstract
Eating is necessary for survival, but it is also one of the great pleasures enjoyed by human beings.
Research to date shows that palatable food can be rewarding in a similar way to drugs of abuse, indicating
considerable comorbidity between eating disorders and substance-use disorders. Analysis of the common characteristics
of both types of disorder has led to a new wave of studies proposing a Gateway Theory of food as a vulnerability
factor that modulates the development of drug addiction. The homeostatic and hedonic mechanisms of
feeding overlap with some of the mechanisms implicated in drug abuse and their interaction plays a crucial role in
the development of drug addiction. Studies in animal models have shown how palatable food sensitizes the reward
circuit and makes individuals more sensitive to other substances of abuse, such as cocaine or alcohol. However,
when palatable food is administered continuously as a model of obesity, the consequences are different, and
studies provide controversial data. In the present review, we will cover the main homeostatic and hedonic mechanisms
that regulate palatable food intake behavior and will explain, using animal models, how different types of
diet and their intake patterns have direct consequences on the rewarding effects of psychostimulants and ethanol.
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Affiliation(s)
- Maria C. Blanco-Gandía
- Department of Psychology and Sociology, University of Zaragoza, C/ Ciudad Escolar s/n, 44003, Teruel, Spain
| | - José Miñarro
- Unit of Research Psychobiology of Drug Dependence, Department of Psychobiology, Facultad de Psicologia, Universitat de Valencia, Avda. Blasco Ibanez, 21, 46010 Valencia, Spain
| | - Marta Rodríguez-Arias
- Unit of Research Psychobiology of Drug Dependence, Department of Psychobiology, Facultad de Psicologia, Universitat de Valencia, Avda. Blasco Ibanez, 21, 46010 Valencia, Spain
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Bach P, Koopmann A, Kiefer F. The Impact of Appetite-Regulating Neuropeptide Leptin on Alcohol Use, Alcohol Craving and Addictive Behavior: A Systematic Review of Preclinical and Clinical Data. Alcohol Alcohol 2020; 56:149-165. [PMID: 32490525 DOI: 10.1093/alcalc/agaa044] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Revised: 04/27/2020] [Accepted: 04/28/2020] [Indexed: 12/18/2022] Open
Abstract
AIMS The appetite regulating hormone leptin, which is mainly secreted from adipose tissue, is an important regulator of food intake and modulator of reward-driven behavior. Leptin exerts its biological actions via binding to the leptin receptor, which is expressed in the hypothalamus, but also in the hippocampus, the amygdala and the substantia nigra. In the ventral tegmental area (VTA), leptin attenuates the firing rate of dopaminergic neurons that project to the Nucleus accumbens (NAc), which serves as relay to other brain areas of the "addiction network", such as the prefrontal cortex. This suggests that leptin plays a role in the processing of rewards in the context of substance use disorders such as alcohol use disorder, especially through attenuation of dopaminergic activity in the mesolimbic reward system. This supports the plausibility of leptin's potential effects in alcohol use disorder. METHODS We searched MEDLINE from 1990 to February 2020. All abstracts were screened for relevance and we only included publications reporting original data with a full text available in English language. Studies that did not report leptin-data, reviews or case reports/series were not included. RESULTS We identified a total of N=293 studies of whom a total of N=55 preclinical and clinical studies met the specified criteria. N=40 studies investigated the effects of alcohol on leptin plasma levels, N=9 studies investigated the effects of leptin on alcohol craving and N=6 studies investigated the effects of leptin on relapse and alcohol consumption. CONCLUSIONS In this review of preclinical and clinical data, we assess the role of leptin in alcohol use and the development and maintenance of an alcohol use disorder, alcohol craving and relapse. Integrating the existing preclinical and clinical data on leptin may reveal new and innovative targets for the treatment of substance use disorders in the future.
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Affiliation(s)
- Patrick Bach
- Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, J5/68159 Mannheim, Germany.,Feuerlein Center on Translational Addiction Medicine (FCTS), University of Heidelberg, J5/68159 Mannheim, Germany
| | - Anne Koopmann
- Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, J5/68159 Mannheim, Germany.,Feuerlein Center on Translational Addiction Medicine (FCTS), University of Heidelberg, J5/68159 Mannheim, Germany
| | - Falk Kiefer
- Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, J5/68159 Mannheim, Germany.,Feuerlein Center on Translational Addiction Medicine (FCTS), University of Heidelberg, J5/68159 Mannheim, Germany
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Weinland C, Tanovska P, Kornhuber J, Mühle C, Lenz B. Serum lipids, leptin, and soluble leptin receptor in alcohol dependence: A cross-sectional and longitudinal study. Drug Alcohol Depend 2020; 209:107898. [PMID: 32163828 DOI: 10.1016/j.drugalcdep.2020.107898] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Revised: 01/29/2020] [Accepted: 02/03/2020] [Indexed: 12/17/2022]
Abstract
OBJECTIVE Alcohol dependence affects metabolic processes. Further research is needed to apply this knowledge clinically. In this study, possible differences in serum lipids and/or leptin activities between alcohol-dependent in-patients and healthy controls and possible associations with alcohol-related blood parameters and with prospective outcomes in alcohol dependence were assessed sex-specifically. METHOD We measured and compared (median) serum lipids (triglycerides and total, HDL, and LDL cholesterol) and leptin activities (leptin, soluble leptin receptor [ObRe], and free leptin index) in 200 (males 56.5 %) early-abstinent alcohol-dependent in-patients and 240 (males 55.4 %) healthy controls and assessed alcohol-related readmissions during a 24 -month post-inclusion period. RESULTS Male patients showed higher HDL cholesterol (61 versus 48 mg/dl), lower LDL/HDL ratios (2.06 versus 3.04), and lower free leptin index (0.30 versus 0.59) at study inclusion compared to healthy controls. In patients, ObRe levels were higher than in controls and decreased from inclusion to the second study-visit (at median 5 days later; males: 16.7-13.8 versus 11.0 ng/ml; females: 17.0-13.4 versus 12.1 ng/ml). The free leptin index increased between the two time points in females (0.80 versus 1.20). Lipids and leptin activities correlated with carbohydrate-deficient transferrin levels and liver enzyme activities. None of the serum parameters were significantly associated with alcohol-related readmissions. CONCLUSION Our data support that serum lipid levels and leptin activities are involved in alcohol dependence. The parameters appear as possible indirect biomarkers for alcohol dependence.
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Affiliation(s)
- Christian Weinland
- Department of Psychiatry and Psychotherapy, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Germany.
| | - Petya Tanovska
- Department of Psychiatry and Psychotherapy, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Germany
| | - Johannes Kornhuber
- Department of Psychiatry and Psychotherapy, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Germany
| | - Christiane Mühle
- Department of Psychiatry and Psychotherapy, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Germany
| | - Bernd Lenz
- Department of Psychiatry and Psychotherapy, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Germany; Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health (CIMH), Medical Faculty Mannheim, Heidelberg University, Germany
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A role for leptin and ghrelin in the augmentation of heroin seeking induced by chronic food restriction. Psychopharmacology (Berl) 2020; 237:787-800. [PMID: 31811350 DOI: 10.1007/s00213-019-05415-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2019] [Accepted: 11/25/2019] [Indexed: 12/14/2022]
Abstract
RATIONAL Caloric restriction increases the risk of relapse in abstinent drug users. Hormones involved in the regulation of energy balance and food intake, such as leptin and ghrelin, are implicated in drug-related behaviors. OBJECTIVES We investigated the role of leptin and ghrelin in the augmentation of heroin seeking induced by chronic food restriction. METHODS Rats self-administered heroin (0.1 mg/kg/infusion) for 10 days followed by 14 days of drug withdrawal. During withdrawal, rats were food restricted to 90% of their original body weight or were given free access to food. In experiment 1, we measured the plasma concentrations of leptin and ghrelin following heroin self-administration and withdrawal. In experiment 2, leptin was administered centrally (2.0 or 4.0 μg; i.c.v.) prior to a heroin-seeking test under extinction conditions. High density of both leptin and ghrelin receptors was previously identified in the ventral tegmental area (VTA), suggesting a direct effect on reward and motivation. Hence, we administered leptin (experiment 3; 0.125 or 0.250 μg/side), or ghrelin receptor antagonist JMV 2959 (experiment 4; 2.0 or 10.0 μg/side) directly into the VTA prior to the heroin-seeking test. RESULTS Chronic food restriction significantly decreased plasma levels of leptin and elevated plasma levels of ghrelin. Central administration of leptin had no statistically significant effect on heroin seeking. Intra-VTA administration of either leptin or JMV 2959 dose-dependently and selectively decreased heroin seeking in the food-restricted rats. CONCLUSIONS Leptin and ghrelin transmission in the VTA can modulate the augmentation of heroin seeking induced by chronic food restriction.
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Duriez P, Ramoz N, Gorwood P, Viltart O, Tolle V. A Metabolic Perspective on Reward Abnormalities in Anorexia Nervosa. Trends Endocrinol Metab 2019; 30:915-928. [PMID: 31648936 DOI: 10.1016/j.tem.2019.08.004] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2019] [Revised: 08/04/2019] [Accepted: 08/08/2019] [Indexed: 12/17/2022]
Abstract
Anorexia nervosa (AN) is the psychiatric disorder with the highest mortality rate; however, the mechanisms responsible for its pathogenesis remain largely unknown. Large-scale genome-wide association studies (GWAS) have identified genetic loci associated with metabolic features in AN. Metabolic alterations that occur in AN have been mostly considered as consequences of the chronic undernutrition state but until recently have not been linked to the etiology of the disorder. We review the molecular basis of AN based on human genetics, with an emphasis on the molecular components controlling energy homeostasis, highlight the main metabolic and endocrine alterations occurring in AN, and decipher the possible connection between metabolic factors and abnormalities of reward processes that are central in AN.
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Affiliation(s)
- Philibert Duriez
- Institute of Psychiatry and Neurosciences of Paris, Unité Mixte de Recherche en Santé (UMRS) 1266 Institut National de la Santé et de la Recherche Médicale (INSERM), University Paris Descartes, Paris, France; Clinique des Maladies Mentales et de l'Encéphale, Groupement Hospitalier Universitaire (GHU) Paris Psychiatry and Neuroscience, Sainte-Anne Hospital, Paris, France
| | - Nicolas Ramoz
- Institute of Psychiatry and Neurosciences of Paris, Unité Mixte de Recherche en Santé (UMRS) 1266 Institut National de la Santé et de la Recherche Médicale (INSERM), University Paris Descartes, Paris, France
| | - Philip Gorwood
- Institute of Psychiatry and Neurosciences of Paris, Unité Mixte de Recherche en Santé (UMRS) 1266 Institut National de la Santé et de la Recherche Médicale (INSERM), University Paris Descartes, Paris, France; Clinique des Maladies Mentales et de l'Encéphale, Groupement Hospitalier Universitaire (GHU) Paris Psychiatry and Neuroscience, Sainte-Anne Hospital, Paris, France
| | - Odile Viltart
- Institute of Psychiatry and Neurosciences of Paris, Unité Mixte de Recherche en Santé (UMRS) 1266 Institut National de la Santé et de la Recherche Médicale (INSERM), University Paris Descartes, Paris, France; University of Lille, Lille, France
| | - Virginie Tolle
- Institute of Psychiatry and Neurosciences of Paris, Unité Mixte de Recherche en Santé (UMRS) 1266 Institut National de la Santé et de la Recherche Médicale (INSERM), University Paris Descartes, Paris, France.
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Lucka A, Wysokiński A. Association between adiposity and fasting serum levels of appetite-regulating peptides: Leptin, neuropeptide Y, desacyl ghrelin, peptide YY(1-36), obestatin, cocaine and amphetamine-regulated transcript, and agouti-related protein in nonobese participants. CHINESE J PHYSIOL 2019; 62:217-225. [PMID: 31670286 DOI: 10.4103/cjp.cjp_29_19] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
The objective of this study was to evaluate the association between adiposity parameters and fasting serum levels of appetite-regulating peptides: leptin, neuropeptide Y (NPY), desacyl ghrelin, peptide YY(1-36), obestatin, cocaine- and amphetamine-regulated transcript (CART), and agouti-related protein in 30 healthy, non-obese subjects. Thirty European Caucasian adult participants were included in the study (17 men and 13 women). Body composition (body fat and lean body mass) was determined using bioelectrical impedance analysis. Concentrations of peptides in serum were assessed using the enzyme-linked immunosorbent assay. Women had higher level of leptin (P < 0.001), with no other differences for analyzed peptides. We have found a significant correlation between serum concentrations of CART and NPY (P < 0.001). Fasting leptin level was associated with age (P = 0.002), waist circumference (P < 0.001), and lean body mass (P < 0.001). Levels of ghrelin were lower in participants with dyslipidemia (P = 0.009). Levels of obestatin (P = 0.008) and leptin (P = 0.02) were higher in participants with insulin resistance. Associations between body fat and appetite-regulating peptides are more complex than simple feedback loops. Leptin is probably the first signal in the pathway that regulates body fat content, as of all analyzed peptides leptin was the only one that was associated with body composition or anthropometric measurements.
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Affiliation(s)
- Anna Lucka
- Department of Old Age Psychiatry and Psychotic Disorders, Medical University of Lodz, Łódź, Poland
| | - Adam Wysokiński
- Department of Old Age Psychiatry and Psychotic Disorders, Medical University of Lodz, Łódź, Poland
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MacCormack JK, Muscatell KA. The metabolic mind: A role for leptin and ghrelin in affect and social cognition. SOCIAL AND PERSONALITY PSYCHOLOGY COMPASS 2019. [DOI: 10.1111/spc3.12496] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Alhadeff AL, Conway SM, Ong ZY, Wald HS, Roitman MF, Grill HJ. Central leptin signaling transmits positive valence. Brain Res 2019; 1724:146441. [PMID: 31513793 DOI: 10.1016/j.brainres.2019.146441] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Revised: 09/04/2019] [Accepted: 09/06/2019] [Indexed: 01/06/2023]
Abstract
Hunger resulting from food deprivation is associated with negative affect. This is supported by recent evidence showing that hunger-sensitive neurons drive feeding through a negative valence teaching signal. However, the complementary hypothesis that hormonal signals of energy surfeit counteract this negative valence, or even transmit positive valence, has received less attention. The adipose-derived hormone leptin signals in proportion to fat mass, is an indicator of energy surplus, and reduces food intake. Here, we showed that centrally-delivered leptin reduced food intake and conditioned a place preference in food-restricted as well as ad libitum fed rats. In contrast, leptin did not reduce food intake nor condition a place preference in obese rats, likely due to leptin resistance. Despite a well-known role for hindbrain leptin receptor signaling in energy balance control, hindbrain leptin delivery did not condition a place preference in food-restricted rats, suggesting that leptin acting in midbrain or forebrain sites mediates place preference conditioning. Supporting the hypothesis that leptin signaling induces a positive affective state, leptin also decreased the threshold for ventral tegmental area brain stimulation reward. Together, these data suggest that leptin signaling is intrinsically preferred, and support the view that signals of energy surfeit are associated with positive affect. Harnessing the positive valence of signals such as leptin may attenuate the negative affect associated with hunger, providing a compelling new approach for weight loss maintenance.
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Affiliation(s)
- Amber L Alhadeff
- Department of Biology, University of Pennsylvania, Philadelphia, PA, United States; Department of Psychology, University of Pennsylvania, Philadelphia, PA, United States.
| | - Sineadh M Conway
- Department of Psychology, University of Illinois at Chicago, Chicago, IL, United States
| | - Zhi Yi Ong
- Department of Psychology, University of Pennsylvania, Philadelphia, PA, United States
| | - Hallie S Wald
- Department of Psychology, University of Pennsylvania, Philadelphia, PA, United States
| | - Mitchell F Roitman
- Department of Psychology, University of Illinois at Chicago, Chicago, IL, United States
| | - Harvey J Grill
- Department of Psychology, University of Pennsylvania, Philadelphia, PA, United States
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de Vrind VA, Rozeboom A, Wolterink‐Donselaar IG, Luijendijk‐Berg MC, Adan RA. Effects of GABA and Leptin Receptor-Expressing Neurons in the Lateral Hypothalamus on Feeding, Locomotion, and Thermogenesis. Obesity (Silver Spring) 2019; 27:1123-1132. [PMID: 31087767 PMCID: PMC6617814 DOI: 10.1002/oby.22495] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2018] [Accepted: 02/28/2019] [Indexed: 12/19/2022]
Abstract
OBJECTIVE The lateral hypothalamus (LH) is known for its role in feeding, and it also regulates other aspects of energy homeostasis. How genetically defined LH neuronal subpopulations mediate LH effects on energy homeostasis remains poorly understood. The behavioral effects of chemogenetically activating LH gamma-aminobutyric acid (GABA) and the more selective population of LH GABA neurons that coexpress the leptin receptor (LepR) were compared. METHODS LepR-cre and VGAT-cre mice were injected with AAV5-hSyn-DIO-hM3DGq-mCherry in the LH. The behavioral effects of LH GABA or LH LepR neuronal activation on feeding, locomotion, thermogenesis, and body weight were assessed. RESULTS The activation of LH GABA neurons increased body temperature (P ≤ 0.008) and decreased body weight (P ≤ 0.01) despite decreased locomotor activity (P = 0.03) and transiently increased chow intake (P ≤ 0.009). Also, similar to other studies, this study found that activation of LH GABA neurons induced gnawing on both food and nonfood (P = 0.001) items. Activation of LH LepR neurons decreased body weight (P ≤ 0.01) and chow intake when presented on the cage floor (P ≤ 0.04) but not when presented in the cage top and increased locomotor activity (P = 0.002) and body temperature (P = 0.03). CONCLUSIONS LH LepR neurons are a subset of LH GABA neurons, and LH LepR activation more specifically regulates energy homeostasis to promote a negative energy balance.
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Affiliation(s)
- Véronne A.J. de Vrind
- Brain Center Rudolf Magnus, Department of Translational NeuroscienceUniversity Medical Center Utrecht and University UtrechtUtrechtThe Netherlands
| | - Annemieke Rozeboom
- Brain Center Rudolf Magnus, Department of Translational NeuroscienceUniversity Medical Center Utrecht and University UtrechtUtrechtThe Netherlands
| | - Inge G. Wolterink‐Donselaar
- Brain Center Rudolf Magnus, Department of Translational NeuroscienceUniversity Medical Center Utrecht and University UtrechtUtrechtThe Netherlands
| | - Mieneke C.M. Luijendijk‐Berg
- Brain Center Rudolf Magnus, Department of Translational NeuroscienceUniversity Medical Center Utrecht and University UtrechtUtrechtThe Netherlands
| | - Roger A.H. Adan
- Brain Center Rudolf Magnus, Department of Translational NeuroscienceUniversity Medical Center Utrecht and University UtrechtUtrechtThe Netherlands
- Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of GothenburgGothenburgSweden
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Hebebrand J, Milos G, Wabitsch M, Teufel M, Führer D, Bühlmeier J, Libuda L, Ludwig C, Antel J. Clinical Trials Required to Assess Potential Benefits and Side Effects of Treatment of Patients With Anorexia Nervosa With Recombinant Human Leptin. Front Psychol 2019; 10:769. [PMID: 31156489 PMCID: PMC6533856 DOI: 10.3389/fpsyg.2019.00769] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2019] [Accepted: 03/20/2019] [Indexed: 12/16/2022] Open
Abstract
The core phenotype of anorexia nervosa (AN) comprises the age and stage dependent intertwining of both its primary and secondary (i.e., starvation induced) somatic and mental symptoms. Hypoleptinemia acts as a key trigger for the adaptation to starvation by affecting diverse brain regions including the reward system and by induction of alterations of the hypothalamus-pituitary-“target-organ” axes, e.g., resulting in amenorrhea as a characteristic symptom of AN. Particularly, the rat model activity-based anorexia (ABA) convincingly demonstrates the pivotal role of hypoleptinemia in the development of starvation-induced hyperactivity. STAT3 signaling in dopaminergic neurons in the ventral tegmental area (VTA) plays a crucial role in the transmission of the leptin signal in ABA. In patients with AN, an inverted U-shaped relationship has been observed between their serum leptin levels and physical activity. Albeit obese and therewith of a very different phenotype, humans diagnosed with rare congenital leptin deficiency have starvation like symptoms including hypothalamic amenorrhea in females. Over the past 20 years, such patients have been successfully treated with recombinant human (rh) leptin (metreleptin) within a compassionate use program. The extreme hunger of these patients subsides within hours upon initiation of treatment; substantial weight loss and menarche in females ensue after medium term treatment. In contrast, metreleptin had little effect in patients with multifactorial obesity. Small clinical trials have been conducted for hypothalamic amenorrhea and to increase bone mineral density, in which metreleptin proved beneficial. Up to now, metreleptin has not yet been used to treat patients with AN. Metreleptin has been approved by the FDA under strict regulations solely for the treatment of generalized lipodystrophy. The recent approval by the EMA may offer, for the first time, the possibility to treat extremely hyperactive patients with AN off-label. Furthermore, a potential dissection of hypoleptinemia-induced AN symptoms from the primary cognitions and behaviors of these patients could ensue. Accordingly, the aim of this article is to review the current state of the art of leptin in relation to AN to provide the theoretical basis for the initiation of clinical trials for treatment of this eating disorder.
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Affiliation(s)
- Johannes Hebebrand
- Department of Child and Adolescent Psychiatry, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Gabriella Milos
- Department of Consultation-Liaison Psychiatry and Psychosomatic Medicine, University Hospital of Zürich, Zurich, Switzerland
| | - Martin Wabitsch
- Division of Paediatric Endocrinology and Diabetes, Department of Paediatrics and Adolescent Medicine, Ulm University Hospital, Ulm, Germany
| | - Martin Teufel
- Department of Psychosomatic Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Dagmar Führer
- Department of Endocrinology and Metabolism, Medical Center and Central Laboratory, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Judith Bühlmeier
- Department of Child and Adolescent Psychiatry, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Lars Libuda
- Department of Child and Adolescent Psychiatry, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Christine Ludwig
- Department of Child and Adolescent Psychiatry, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Jochen Antel
- Department of Child and Adolescent Psychiatry, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
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Effects of leptin and ghrelin on neural cue-reactivity in alcohol addiction: Two streams merge to one river? Psychoneuroendocrinology 2019; 100:1-9. [PMID: 30268001 DOI: 10.1016/j.psyneuen.2018.09.026] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2018] [Revised: 08/31/2018] [Accepted: 09/16/2018] [Indexed: 11/22/2022]
Abstract
Leptin and ghrelin and a "cross-talk" between both hormones were implicated in the pathophysiology of alcohol dependence, both modulating alcohol craving and drug-seeking. To date, the neurobiological mechanisms underlying those effects are still little-known. We thus investigated the effect of leptin and ghrelin on alcohol cue-induced brain response, alcohol craving and relapse risk in alcohol-dependent subjects. Seventy abstinent alcohol dependent individuals underwent a functional magnetic resonance imaging (fMRI) alcohol cue-reactivity task and patients` alcohol craving was assessed. Plasma levels of leptin, total and acylated, active ghrelin were measured prior to the fMRI session. Additionally, relapse data was collected during a three-month follow-up. Associations between hormone levels, mesolimbic cue-reactivity, alcohol craving and relapse risk were tested. Leptin levels showed a significant negative association to alcohol cue-induced brain response in the striatum and alcohol craving. In addition, there was a significant effect of leptin on time to first heavy relapse in which higher leptin levels predicted longer times to first heavy relapse. Moreover, positive associations between acylated ghrelin and increased cue-reactivity in bilateral insulae as well as increased craving for alcohol during the fMRI task were revealed. Leptin and acylated ghrelin show opposing effects on mesolimbic cue-reactivity and alcohol craving. We suspect that the reduced striatal cue-reactivity might be the neurobiological correlate of leptin's effect on relapse-risk. The reported results further support the relevance of appetite regulating hormones in the pathophysiology of addiction and their potential role as future treatment targets.
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Abstract
Endocrine Consequences of Anorexia Nervosa Abstract. Anorexia nervosa is a perilous disease of unknown etiology that causes a variety of endocrine effects. Characteristic for anorexia nervosa are a reduced food intake and thus significant underweight, as well as the fear of gaining weight. Often sufferers also have a distorted self-perception, the urge to move and amenorrhea. AN is difficult to treat and often has a chronic course, and is associated with an increased mortality risk. The endocrinological changes occur in several endocrine axes, their extent is related to the degree of malnutrition. Low leptin levels, due to the underweight, signal a potentially dangerous lack of energy to the brain. There is a cascade of neuroendocrine adaptive responses to help the organism to survive. The effects of starvation are extensive, affecting the pituitary gland, thyroid gland, as well as the adrenal glands, gonads and bones. In positive cases, most dysfunctions are reversible; the compromised bone stability recovers only slowly.
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Affiliation(s)
- Gabriella Milos
- Universitätsspital Zürich, Klinik für Konsiliarpsychiatrie und Psychosomatik, Zentrum für Essstörungen, Zürich
| | - Johannes Hebebrand
- LVR-Klinikum, Kliniken/Institut der Universität Duisburg-Essen; Klinik für Psychiatrie, Psychosomatik und Psychotherapie des Kindes- und Jugendalters, Essen, Deutschland
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You ZB, Wang B, Gardner EL, Wise RA. Cocaine and cocaine expectancy increase growth hormone, ghrelin, GLP-1, IGF-1, adiponectin, and corticosterone while decreasing leptin, insulin, GIP, and prolactin. Pharmacol Biochem Behav 2019; 176:53-56. [DOI: 10.1016/j.pbb.2018.11.001] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2018] [Revised: 10/12/2018] [Accepted: 11/07/2018] [Indexed: 12/23/2022]
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Audira G, Sarasamma S, Chen JR, Juniardi S, Sampurna BP, Liang ST, Lai YH, Lin GM, Hsieh MC, Hsiao CD. Zebrafish Mutants Carrying Leptin a (lepa) Gene Deficiency Display Obesity, Anxiety, Less Aggression and Fear, and Circadian Rhythm and Color Preference Dysregulation. Int J Mol Sci 2018; 19:ijms19124038. [PMID: 30551684 PMCID: PMC6320766 DOI: 10.3390/ijms19124038] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2018] [Revised: 12/05/2018] [Accepted: 12/11/2018] [Indexed: 01/14/2023] Open
Abstract
Leptin, a hormone secreted by peripheral adipose tissues, regulates the appetite in animals. Recently, evidence has shown that leptin also plays roles in behavioral response in addition to controlling appetite. In this study, we examined the potential function of leptin on non-appetite behaviors in zebrafish model. By using genome editing tool of Transcription activator-like effector nuclease (TALEN), we successfully knocked out leptin a (lepa) gene by deleting 4 bp within coding region to create a premature-translation stop. Morphological and appetite analysis showed the lepa KO fish display a phenotype with obese, good appetite and elevation of Agouti-related peptide (AgRP) and Ghrelin hormones, consistent with the canonical function of leptin in controlling food intake. By multiple behavior endpoint analyses, including novel tank, mirror biting, predator avoidance, social interaction, shoaling, circadian rhythm, and color preference assay, we found the lepa KO fish display an anxiogenic phenotype showing hyperactivity with rapid swimming, less freezing time, less fear to predator, loose shoaling area forming, and circadian rhythm and color preference dysregulations. Using biochemical assays, melatonin, norepinephrine, acetylcholine and serotonin levels in the brain were found to be significantly reduced in lepa KO fish, while the levels of dopamine, glycine and cortisol in the brain were significantly elevated. In addition, the brain ROS level was elevated, and the anti-oxidative enzyme catalase level was reduced. Taken together, by performing loss-of-function multiple behavior endpoint testing and biochemical analysis, we provide strong evidence for a critical role of lepa gene in modulating anxiety, aggression, fear, and circadian rhythm behaviors in zebrafish for the first time.
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Affiliation(s)
- Gilbert Audira
- Department of Chemistry, Chung Yuan Christian University, Chung-Li 32023, Taiwan.
- Department of Bioscience Technology, Chung Yuan Christian University, Chung-Li 32023, Taiwan.
| | - Sreeja Sarasamma
- Department of Chemistry, Chung Yuan Christian University, Chung-Li 32023, Taiwan.
- Department of Bioscience Technology, Chung Yuan Christian University, Chung-Li 32023, Taiwan.
| | - Jung-Ren Chen
- Department of Biological Science & Technology College of Medicine, I-Shou University, Kaohsiung, 82445, Taiwan.
| | - Stevhen Juniardi
- Department of Bioscience Technology, Chung Yuan Christian University, Chung-Li 32023, Taiwan.
| | | | - Sung-Tzu Liang
- Department of Bioscience Technology, Chung Yuan Christian University, Chung-Li 32023, Taiwan.
| | - Yu-Heng Lai
- Department of Chemistry, Chinese Culture University, Taipei 11114, Taiwan.
| | - Geng-Ming Lin
- Laboratory of Marine Biology and Ecology, Third Institute of Oceanography, State OceanicAdministration, Xiamen 361005, China.
| | - Ming-Chia Hsieh
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Changhua Christian Hospital, Changhua 50094, Taiwan.
| | - Chung-Der Hsiao
- Department of Chemistry, Chung Yuan Christian University, Chung-Li 32023, Taiwan.
- Department of Bioscience Technology, Chung Yuan Christian University, Chung-Li 32023, Taiwan.
- Center of Nanotechnology, Chung Yuan Christian University, Chung-Li 32023, Taiwan.
- Center of Biomedical Technology, Chung Yuan Christian University, Chung-Li 32023, Taiwan.
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Abstract
Acupuncture is an ancient therapy with a variety of different explanatory models. A cascade of physiological effects has been reported, both in the peripheral and the central nervous system, following the insertion of a needle or light tapping of the skin. Clinical trials testing the specific claims of acupuncture have generally tried to focus on testing the efficacy of applying specific techniques and/or specified points. However, different conditions may respond differently to different modes of stimulation. Recently, it was demonstrated that both superficial and deep needling (with de qi/Hibiki) resulted in amelioration of patellofemoral pain and unpleasantness. The pleasurable aspect of the acupuncture experience has largely been ignored as it has been considered secondary to its pain alleviating effects. This aspect of acupuncture treatment is likely to be related to activation of self-appraisal and the reward system. When a patient seeks a therapist there are expectations of a specific effect. These expectations are partly based on self-relevant phenomena and self-referentia introspection and constitute the preference. Also, when asked about the effect of the treatment, processes that orientate pre-attentive anticipatory or mnemonic information and processes that mediate self-reflection and recollection are integrated together with sensory detection to enable a decision about the patient's perception of the effect of acupuncture treatment. These ‘self-appraisal’ processes are dependent on two integrated networks: a ventral medial prefrontal cortex paralimbic limbic ‘affective’ pathway and a dorsal medial prefrontal cortex cortical hippocampal ‘cognitive’ pathway. The limbic structures are implicated in the reward system and play a key role in most diseases and illness responses including chronic pain and depression, regulating mood and neuromodulatory responses (eg sensory, autonomic, and endocrine). The pleasurable and neuromodulatory aspects of acupuncture as well as ‘placebo needling’ may partly be explained by the activation or deactivation of limbic structures including the hippocampus, amygdala, and their connections with the hypothalamus. In patients with patellofemoral pain, the effects of superficial and deep needling remained for six months. These long term pain-alleviating effects have been attributed to activation of pain inhibiting systems in cortical and subcortical pathways. When considering long term effects the cortical cerebellar system needs to be taken into account. The cortical cerebellar system is probably central to the development of neural models that learn and eventually stimulate routinely executed (eg motor skills) and long term (eg pain alleviation) cognitive processes. These higher order cognitive processes are initially mediated in prefrontal cortical loci but later shift control iteratively to internal cerebellar representations of these processes. Possibly part of the long term healing effects of acupuncture may be attributed to changes in the cerebellar system thereby sparing processing load in cortical and subcortical areas. As cortical and subcortical structures are activated and/or de-activated following stimulation of receptors in the skin, disregarding site, ‘placebo or sham needling’ does not exist and conclusions drawn on the basis that it is an inert control are invalid. ‘Self’ may be seen as a shifting illusion, ceaselessly constructed and deconstructed, and the effect of acupuncture may reflect its status (as well as that of the therapist).
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Affiliation(s)
- Thomas Lundeberg
- Rehabilitation Medicine, UniversityClinic, Danderyds Hospital, Stockholm, Sweden.
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47
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Doucet É, McInis K, Mahmoodianfard S. Compensation in response to energy deficits induced by exercise or diet. Obes Rev 2018; 19 Suppl 1:36-46. [PMID: 30511511 DOI: 10.1111/obr.12783] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2018] [Accepted: 09/11/2018] [Indexed: 02/06/2023]
Abstract
Obesity is an extremely resilient condition. Weight loss is most challenging, and weight recidivism is rampant. There is accumulating evidence highlighting that energy deficits meant to produce increased mobilization of energy stores trigger a number of somewhat persistent adaptations that together increase the drive to eat and decrease energy output. These adaptations ostensibly enable a context where the likelihood of energy compensation is heightened. In fact, energy compensation is present for both diet and exercise induced energy deficits although at different magnitudes. For the most part, the energy compensation in response to exercise induced energy deficits seems to be larger. Interestingly, energy compensation appears to be greater for longer interventions, an effect independent of whether the energy deficit is induced through diet or exercise. The latter suggests that the increased drive to eat and the reduced energy expenditure that accompany weight loss might be successfully fought off initially. However, with time there seems to be increasing erosion of the behaviours that initially opposed adaptations to weight loss and increased energy compensation progressively sets in. Under such conditions, it would seem prudent to propose weight loss targets that align with a level of behaviour modifications that can be sustained indefinitely.
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Affiliation(s)
- É Doucet
- School of Human Kinetics, Faculty of Health Sciences, University of Ottawa, Ottawa, Canada
| | - K McInis
- School of Human Kinetics, Faculty of Health Sciences, University of Ottawa, Ottawa, Canada
| | - S Mahmoodianfard
- School of Human Kinetics, Faculty of Health Sciences, University of Ottawa, Ottawa, Canada
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48
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Novelle MG, Diéguez C. Unravelling the role and mechanism of adipokine and gastrointestinal signals in animal models in the nonhomeostatic control of energy homeostasis: Implications for binge eating disorder. EUROPEAN EATING DISORDERS REVIEW 2018; 26:551-568. [PMID: 30280451 DOI: 10.1002/erv.2641] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2018] [Revised: 07/12/2018] [Accepted: 09/02/2018] [Indexed: 12/16/2022]
Affiliation(s)
- Marta G. Novelle
- Department of Physiology, Centre for Research in Molecular Medicine and Chronic Diseases (CIMUS); University of Santiago de Compostela-Instituto de Investigación Sanitaria (IDIS), CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III; Santiago de Compostela Spain
| | - Carlos Diéguez
- Department of Physiology, Centre for Research in Molecular Medicine and Chronic Diseases (CIMUS); University of Santiago de Compostela-Instituto de Investigación Sanitaria (IDIS), CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III; Santiago de Compostela Spain
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49
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Casquero-Veiga M, García-García D, Pascau J, Desco M, Soto-Montenegro ML. Stimulating the nucleus accumbens in obesity: A positron emission tomography study after deep brain stimulation in a rodent model. PLoS One 2018; 13:e0204740. [PMID: 30261068 PMCID: PMC6160153 DOI: 10.1371/journal.pone.0204740] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2018] [Accepted: 09/13/2018] [Indexed: 12/17/2022] Open
Abstract
PURPOSE The nucleus accumbens (NAcc) has been suggested as a possible target for deep brain stimulation (DBS) in the treatment of obesity. Our hypothesis was that NAcc-DBS would modulate brain regions related to reward and food intake regulation, consequently reducing the food intake and, finally, the weight gain. Therefore, we examined changes in brain glucose metabolism, weight gain and food intake after NAcc-DBS in a rat model of obesity. PROCEDURES Electrodes were bilaterally implanted in 2 groups of obese Zucker rats targeting the NAcc. One group received stimulation one hour daily during 15 days, while the other remained as control. Weight and daily consumption of food and water were everyday registered the days of stimulation, and twice per week during the following month. Positron emission tomography (PET) studies with 2-deoxy-2-[18F]fluoro-D-glucose (FDG) were performed 1 day after the end of DBS. PET data was assessed by statistical parametric mapping (SPM12) software and region of interest (ROI) analyses. RESULTS NAcc-DBS lead to increased metabolism in the cingulate-retrosplenial-parietal association cortices, and decreased metabolism in the NAcc, thalamic and pretectal nuclei. Furthermore, ROIs analyses confirmed these results by showing a significant striatal and thalamic hypometabolism, and a cortical hypermetabolic region. However, NAcc-DBS did not induce a decrease in either weight gain or food intake. CONCLUSIONS NAcc-DBS led to changes in the metabolism of regions associated with cognitive and reward systems, whose impairment has been described in obesity.
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Affiliation(s)
| | | | - Javier Pascau
- Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
- CIBER de Salud Mental (CIBERSAM), Madrid, Spain
- Departamento de Bioingeniería e Ingeniería Aeroespacial, Universidad Carlos III de Madrid, Leganés, Spain
| | - Manuel Desco
- Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
- CIBER de Salud Mental (CIBERSAM), Madrid, Spain
- Departamento de Bioingeniería e Ingeniería Aeroespacial, Universidad Carlos III de Madrid, Leganés, Spain
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
| | - María Luisa Soto-Montenegro
- Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
- CIBER de Salud Mental (CIBERSAM), Madrid, Spain
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50
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Abstract
PURPOSE OF REVIEW Obesity in the United States has been on a constant rise since the Center for Disease Control and Prevention (CDC) began tracking it over 50 years ago. Despite focused attention on this epidemic, pharmacological treatments aimed at obesity are lacking. Here, we briefly give perspective on the central and peripheral mechanisms underlying feeding behaviors and describe the existing pharmacological treatments for obesity. With this lens, I suggest future targets for the treatment of obesity. RECENT FINDINGS Given the development of genetic and molecular tools, understanding of how energy expenditure is modulated is becoming more nuanced. There is growing evidence for a link between obesity and addiction, which should be utilized in the development of new pharmacological treatments. SUMMARY More focus is needed on identifying targets for anti-obesity pharmacology. In doing so, research should include intensive investigation of the brain's reward circuitry.
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