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Henin G, Loumaye A, Deldicque L, Leclercq IA, Lanthier N. Unlocking liver health: Can tackling myosteatosis spark remission in metabolic dysfunction-associated steatotic liver disease? Liver Int 2024; 44:1781-1796. [PMID: 38623714 DOI: 10.1111/liv.15938] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2024] [Revised: 03/12/2024] [Accepted: 04/02/2024] [Indexed: 04/17/2024]
Abstract
Myosteatosis is highly prevalent in metabolic dysfunction-associated steatotic liver disease (MASLD) and could reciprocally impact liver function. Decreasing muscle fat could be indirectly hepatoprotective in MASLD. We conducted a review to identify interventions reducing myosteatosis and their impact on liver function. Non-pharmacological interventions included diet (caloric restriction or lipid enrichment), bariatric surgery and physical activity. Caloric restriction in humans achieving a mean weight loss of 3% only reduces muscle fat. Lipid-enriched diet increases liver fat in human with no impact on muscle fat, except sphingomyelin-enriched diet which reduces both lipid contents exclusively in pre-clinical studies. Bariatric surgery, hybrid training (resistance exercise and electric stimulation) or whole-body vibration in human decrease both liver and muscle fat. Physical activity impacts both phenotypes by reducing local and systemic inflammation, enhancing insulin sensitivity and modulating the expression of key mediators of the muscle-liver-adipose tissue axis. The combination of diet and physical activity acts synergistically in liver, muscle and white adipose tissue, and further decrease muscle and liver fat. Several pharmacological interventions (patchouli alcohol, KBP-089, 2,4-dinitrophenol methyl ether, adipoRon and atglistatin) and food supplementation (vitamin D or resveratrol) improve liver and muscle phenotypes in pre-clinical studies by increasing fatty acid oxidation and anti-inflammatory properties. These interventions are effective in reducing myosteatosis in MASLD while addressing the liver disease itself. This review supports that disturbances in inter-organ crosstalk are key pathophysiological mechanisms involved in MASLD and myosteatosis pathogenesis. Focusing on the skeletal muscle might offer new therapeutic strategies to treat MASLD by modulating the interactions between liver and muscles.
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Affiliation(s)
- Guillaume Henin
- Service d'Hépato-Gastroentérologie, Cliniques universitaires Saint-Luc, UCLouvain, Brussels, Belgium
- Laboratory of Hepatogastroenterology, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain (UCLouvain), Brussels, Belgium
| | - Audrey Loumaye
- Service d'Endocrinologie, Diabétologie et Nutrition, Cliniques universitaires Saint-Luc, UCLouvain, Brussels, Belgium
| | | | - Isabelle A Leclercq
- Laboratory of Hepatogastroenterology, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain (UCLouvain), Brussels, Belgium
| | - Nicolas Lanthier
- Service d'Hépato-Gastroentérologie, Cliniques universitaires Saint-Luc, UCLouvain, Brussels, Belgium
- Laboratory of Hepatogastroenterology, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain (UCLouvain), Brussels, Belgium
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McKay EJ, Luijten I, Broadway-Stringer S, Thomson A, Weng X, Gehmlich K, Gray GA, Semple RK. Female Alms1-deficient mice develop echocardiographic features of adult but not infantile Alström syndrome cardiomyopathy. Dis Model Mech 2024; 17:dmm050561. [PMID: 38756069 PMCID: PMC11225586 DOI: 10.1242/dmm.050561] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Accepted: 04/03/2024] [Indexed: 05/18/2024] Open
Abstract
Alström syndrome (AS), a multisystem disorder caused by biallelic ALMS1 mutations, features major early morbidity and mortality due to cardiac complications. The latter are biphasic, including infantile dilated cardiomyopathy and distinct adult-onset cardiomyopathy, and poorly understood. We assessed cardiac function of Alms1 knockout (KO) mice by echocardiography. Cardiac function was unaltered in Alms1 global KO mice of both sexes at postnatal day 15 (P15) and 8 weeks. At 23 weeks, female - but not male - KO mice showed increased left atrial area and decreased isovolumic relaxation time, consistent with early restrictive cardiomyopathy, as well as reduced ejection fraction. No histological or transcriptional changes were seen in myocardium of 23-week-old female Alms1 global KO mice. Female mice with Pdgfra-Cre-driven Alms1 deletion in cardiac fibroblasts and in a small proportion of cardiomyocytes did not recapitulate the phenotype of global KO at 23 weeks. In conclusion, only female Alms1-deficient adult mice show echocardiographic evidence of cardiac dysfunction, consistent with the cardiomyopathy of AS. The explanation for sexual dimorphism remains unclear but might involve metabolic or endocrine differences between sexes.
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Affiliation(s)
- Eleanor J. McKay
- Centre for Cardiovascular Science, University of Edinburgh, Edinburgh EH16 4TJ, UK
| | - Ineke Luijten
- Centre for Cardiovascular Science, University of Edinburgh, Edinburgh EH16 4TJ, UK
| | | | - Adrian Thomson
- Centre for Cardiovascular Science, University of Edinburgh, Edinburgh EH16 4TJ, UK
| | - Xiong Weng
- Centre for Cardiovascular Science, University of Edinburgh, Edinburgh EH16 4TJ, UK
| | - Katya Gehmlich
- Institute of Cardiovascular Sciences, University of Birmingham, Birmingham B15 2TT, UK
- Division of Cardiovascular Medicine, Radcliffe Department of Medicine and British Heart Foundation Centre of Research Excellence Oxford, University of Oxford, Oxford OX3 9DU, UK
| | - Gillian A. Gray
- Centre for Cardiovascular Science, University of Edinburgh, Edinburgh EH16 4TJ, UK
| | - Robert K. Semple
- Centre for Cardiovascular Science, University of Edinburgh, Edinburgh EH16 4TJ, UK
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh EH4 2XU, UK
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McKay EJ, Luijten I, Weng X, Martinez de Morentin PB, De Frutos González E, Gao Z, Kolonin MG, Heisler LK, Semple RK. Mesenchymal-specific Alms1 knockout in mice recapitulates metabolic features of Alström syndrome. Mol Metab 2024; 84:101933. [PMID: 38583571 PMCID: PMC11047791 DOI: 10.1016/j.molmet.2024.101933] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Accepted: 04/01/2024] [Indexed: 04/09/2024] Open
Abstract
OBJECTIVE Alström Syndrome (AS), caused by biallelic ALMS1 mutations, includes obesity with disproportionately severe insulin resistant diabetes, dyslipidemia, and fatty liver. Prior studies suggest that hyperphagia is accounted for by loss of ALMS1 function in hypothalamic neurones, whereas disproportionate metabolic complications may be due to impaired adipose tissue expandability. We tested this by comparing the metabolic effects of global and mesenchymal stem cell (MSC)-specific Alms1 knockout. METHODS Global Alms1 knockout (KO) mice were generated by crossing floxed Alms1 and CAG-Cre mice. A Pdgfrα-Cre driver was used to abrogate Alms1 function selectively in MSCs and their descendants, including preadipocytes. We combined metabolic phenotyping of global and Pdgfrα+ Alms1-KO mice on a 45% fat diet with measurements of body composition and food intake, and histological analysis of metabolic tissues. RESULTS Assessed on 45% fat diet to promote adipose expansion, global Alms1 KO caused hyperphagia, obesity, insulin resistance, dyslipidaemia, and fatty liver. Pdgfrα-cre driven KO of Alms1 (MSC KO) recapitulated insulin resistance, fatty liver, and dyslipidaemia in both sexes. Other phenotypes were sexually dimorphic: increased fat mass was only present in female Alms1 MSC KO mice. Hyperphagia was not evident in male Alms1 MSC KO mice, but was found in MSC KO females, despite no neuronal Pdgfrα expression. CONCLUSIONS Mesenchymal deletion of Alms1 recapitulates metabolic features of AS, including fatty liver. This confirms a key role for Alms1 in the adipose lineage, where its loss is sufficient to cause systemic metabolic effects and damage to remote organs. Hyperphagia in females may depend on Alms1 deficiency in oligodendrocyte precursor cells rather than neurones. AS should be regarded as a forme fruste of lipodystrophy.
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Affiliation(s)
- Eleanor J McKay
- Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK
| | - Ineke Luijten
- Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK
| | - Xiong Weng
- Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK
| | - Pablo B Martinez de Morentin
- The Rowett Institute, University of Aberdeen, Aberdeen, UK; School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, Leeds, UK
| | - Elvira De Frutos González
- The Rowett Institute, University of Aberdeen, Aberdeen, UK; Área de Fisiología Humana, Departamento de Ciencias básicas de la Salud, Facultad de ciencias de la Salud, Universidad Rey Juan Carlos, 28922 Alcorcón, Madrid, Spain
| | - Zhanguo Gao
- Institute of Molecular Medicine, University of Texas Health Sciences Center at Houston, Houston, TX 77030, USA
| | - Mikhail G Kolonin
- Institute of Molecular Medicine, University of Texas Health Sciences Center at Houston, Houston, TX 77030, USA
| | - Lora K Heisler
- The Rowett Institute, University of Aberdeen, Aberdeen, UK
| | - Robert K Semple
- Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK; MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
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Stephenson EJ, Kinney CE, Stayton AS, Han JC. Energy expenditure deficits drive obesity in a mouse model of Alström syndrome. Obesity (Silver Spring) 2023; 31:2786-2798. [PMID: 37712194 DOI: 10.1002/oby.23877] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2023] [Accepted: 06/27/2023] [Indexed: 09/16/2023]
Abstract
OBJECTIVE Alström syndrome (AS) is a rare multisystem disorder of which early onset childhood obesity is a cardinal feature. Like humans with AS, animal models with Alms1 loss-of-function mutations develop obesity, supporting the notion that ALMS1 is required for the regulatory control of energy balance across species. This study aimed to determine which component(s) of energy balance are reliant on ALMS1. METHODS Comprehensive energy balance phenotyping was performed on Alms1tvrm102 mice at both 8 and 18 weeks of age. RESULTS It was found that adiposity gains occurred early and rapidly in Alms1tvrm102 male mice but much later in females. Rapid increases in body fat in males were due to a marked reduction in energy expenditure (EE) during early life and not due to any genotype-specific increases in energy intake under chow conditions. Energy intake did increase in a genotype-specific manner when mice were provided a high-fat diet, exacerbating the effects of reduced EE on obesity progression. The EE deficit observed in male Alms1tvrm102 mice did not persist as mice aged. CONCLUSIONS Either loss of ALMS1 causes a developmental delay in the mechanisms controlling early life EE or activation of compensatory mechanisms occurs after obesity is established in AS. Future studies will determine how ALMS1 modulates EE and how sex moderates this process.
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Affiliation(s)
- Erin J Stephenson
- Department of Anatomy, College of Graduate Studies and Chicago College of Osteopathic Medicine, Midwestern University, Downers Grove, Illinois, USA
- Department of Pediatrics, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, USA
- Children's Foundation Research Institute, Le Bonheur Children's Hospital, Memphis, Tennessee, USA
| | - Clint E Kinney
- Department of Pediatrics, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, USA
- Children's Foundation Research Institute, Le Bonheur Children's Hospital, Memphis, Tennessee, USA
| | - Amanda S Stayton
- Department of Pediatrics, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, USA
- Children's Foundation Research Institute, Le Bonheur Children's Hospital, Memphis, Tennessee, USA
- Department of Surgery, College of Medicine, James D. Eason Transplant Institute, University of Tennessee Health Science Center, Memphis, Tennessee, USA
| | - Joan C Han
- Department of Pediatrics, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, USA
- Children's Foundation Research Institute, Le Bonheur Children's Hospital, Memphis, Tennessee, USA
- Department of Pediatrics, Icahn School of Medicine at Mount Sinai and Kravis Children's Hospital, New York, New York, USA
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McKay EJ, Luijten I, Weng X, Martinez de Morentin PB, De Frutos González E, Gao Z, Kolonin MG, Heisler LK, Semple RK. Mesenchymal-specific Alms1 knockout in mice recapitulates key metabolic features of Alström Syndrome. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.10.12.562074. [PMID: 37873427 PMCID: PMC10592792 DOI: 10.1101/2023.10.12.562074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/25/2023]
Abstract
Background Alström Syndrome (AS), a multi-system disease caused by mutations in the ALMS1 gene, includes obesity with disproportionately severe insulin resistant diabetes, dyslipidemia, and hepatosteatosis. How loss of ALMS1 causes this phenotype is poorly understood, but prior studies have circumstancially implicated impaired adipose tissue expandability. We set out to test this by comparing the metabolic effects of selective Alms1 knockout in mesenchymal cells including preadipocytes to those of global Alms1 knockout. Methods Global Alms1 knockout (KO) mice were generated by crossing floxed Alms1 and CAG-Cre mice. A Pdgfrα -Cre driver was used to abrogate Alms1 function selectively in mesenchymal stem cells (MSCs) and their descendants, including preadipocytes. We combined metabolic phenotyping of global and Pdgfrα + Alms1 -KO mice on a 45% fat diet with measurements of body composition and food intake, and histological analysis of metabolic tissues. Results Global Alms1 KO caused hyperphagia, obesity, insulin resistance, dyslipidaemia, and fatty liver. Pdgfrα - cre driven KO of Alms1 (MSC KO) recapitulated insulin resistance, fatty liver, and dyslipidaemia in both sexes. Other phenotypes were sexually dimorphic: increased fat mass was only present in female Alms1 MSC KO mice. Hyperphagia was not evident in male Alms1 MSC KO mice, but was found in MSC KO females, despite no neuronal Pdgfr α expression. Conclusions Mesenchymal deletion of Alms1 recapitulates the metabolic features of AS, including severe fatty liver. This confirms a key role for Alms1 in the adipose lineage, where its loss is sufficient to cause systemic metabolic effects and damage to remote organs. AS should be regarded as a forme fruste of lipodystrophy. Therapies should prioritise targeting positive energy balance.
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Haczeyni F, Steensels S, Stein BD, Jordan JM, Li L, Dartigue V, Sarklioglu SS, Qiao J, Zhou XK, Dannenberg AJ, Iyengar NM, Yu H, Cantley LC, Ersoy BA. Submitochondrial Protein Translocation Upon Stress Inhibits Thermogenic Energy Expenditure. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.05.04.539294. [PMID: 37205525 PMCID: PMC10187325 DOI: 10.1101/2023.05.04.539294] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/21/2023]
Abstract
Mitochondria-rich brown adipocytes dissipate cellular fuel as heat by thermogenic energy expenditure (TEE). Prolonged nutrient excess or cold exposure impair TEE and contribute to the pathogenesis of obesity, but the mechanisms remain incompletely understood. Here we report that stress-induced proton leak into the matrix interface of mitochondrial innermembrane (IM) mobilizes a group of proteins from IM into matrix, which in turn alter mitochondrial bioenergetics. We further determine a smaller subset that correlates with obesity in human subcutaneous adipose tissue. We go on to show that the top factor on this short list, acyl-CoA thioesterase 9 (ACOT9), migrates from the IM into the matrix upon stress where it enzymatically deactivates and prevents the utilization of acetyl-CoA in TEE. The loss of ACOT9 protects mice against the complications of obesity by maintaining unobstructed TEE. Overall, our results introduce aberrant protein translocation as a strategy to identify pathogenic factors. One-Sentence Summary Thermogenic stress impairs mitochondrial energy utilization by forcing translocation of IM-bound proteins into the matrix.
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Peng X, Liu J, Li B, Wang S, Chen B, Zhang D. An Acyl Carrier Protein Gene Affects Fatty Acid Synthesis and Growth of Hermetia illucens. INSECTS 2023; 14:300. [PMID: 36975985 PMCID: PMC10052031 DOI: 10.3390/insects14030300] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/02/2023] [Revised: 03/10/2023] [Accepted: 03/16/2023] [Indexed: 06/18/2023]
Abstract
Acyl carrier protein (ACP) is an acyl carrier in fatty acid synthesis and is an important cofactor of fatty acid synthetase. Little is known about ACP in insects and how this protein may modulate the composition and storage of fatty acids. We used an RNAi-assisted strategy to study the potential function of ACP in Hermetia illucens (Diptera: Stratiomyidae). We identified a HiACP gene with a cDNA length of 501 bp and a classical conserved region of DSLD. This gene was highly expressed in the egg and late larval instars and was most abundant in the midgut and fat bodies of larvae. Injection of dsACP significantly inhibited the expression level of HiACP and further regulated the fatty acid synthesis in treated H. illucens larvae. The composition of saturated fatty acids was reduced, and the percentage of unsaturated fatty acids (UFAs) was increased. After interfering with HiACP, the cumulative mortality of H. illucens increased to 68.00% (p < 0.05). H. illucens growth was greatly influenced. The development duration increased to 5.5 days, the average final body weights of larvae and pupae were decreased by 44.85 mg and 14.59 mg, respectively, and the average body lengths of larvae and pupae were significantly shortened by 3.09 mm and 3.82 mm, respectively. The adult eclosion rate and the oviposition of adult females were also severely influenced. These results demonstrated that HiACP regulates fatty acid content and influences multiple biological processes of H. illucens.
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Wang Y, Ma P, Wang Z, Sun M, Hou B, Xu T, Li W, Yang X, Du G, Ji T, Qiang G. Uncovering the effect and mechanism of Panax notoginseng saponins on metabolic syndrome by network pharmacology strategy. JOURNAL OF ETHNOPHARMACOLOGY 2023; 300:115680. [PMID: 36058479 DOI: 10.1016/j.jep.2022.115680] [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: 06/14/2022] [Revised: 08/14/2022] [Accepted: 08/25/2022] [Indexed: 06/15/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Metabolic syndrome (MetS) is a cluster of disease centered on obesity, which is the result of stagnation of liver qi according to traditional Chinese medicine. Panax notoginseng is a traditional Chinese herbal medicine, entering liver and stomach meridians and dissipating blood stasis, in which panax notoginseng saponins (PNS) are the main active components. However, its effects and mechanism on metabolic syndrome has not been revealed yet. AIM OF STUDY To evaluate the anti-MetS effect of PNS, including body weight and adiposity, glucose metabolism and non-alcoholic fatty liver disease (NAFLD), as well as to explore the mechanism and signaling pathway of PNS on MetS effect. MATERIALS AND METHODS HPLC was utilized to affirm the percentages of saponins in PNS. In vivo, normal C57BL/6J mice and high-fat diet (HFD)-induced MetS mice were used to evaluate anti-MetS effect of PNS. Body weight, food and water intake were recorded. NMR imager was used for NMR imaging and lipid-water analysis. Blood glucose detection, glucose and insulin tolerance test were performed to evaluate glucose metabolism. Biochemical indexes analysis and histopathological staining were used to evaluate the effect on NAFLD. The expressions of mRNA and proteins related to thermogenesis in adipose tissue were determined using real-time PCR and Western blot. In silico, network pharmacology was utilized to predict potential mechanism. In vitro, matured 3T3-L1 adipocyte was used as subject to confirm the signaling pathway by Western blot. RESULTS We determined the content of PNS component by HPLC. In vivo, PNS could improve metabolic syndrome with weight loss, reduction of adiposity, improvement of adipose distribution, correction of glucose metabolism disorder and attenuation of NAFLD. Mechanismly, PNS boosted energy exhaustion and dramatically enhanced thermogenesis in brown adipose tissue (BAT), induced white adipose tissue (WAT) browning. In silico, utilizing network pharmacology strategy, we identified 307 candidate targets which were enriched in MAPK signaling pathway specifically in liver tissue and adipocyte. In vitro validation confirmed ERK and p38MAPK mediated anti-MetS effects of PNS, not JNK signaling pathway. CONCLUSION PNS exerted protective effect on metabolic syndrome through MAPK-mediated adipose thermogenic activation, which may serve as a prospective therapeutic drug for metabolic syndrome.
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Affiliation(s)
- Yisa Wang
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College and Beijing Key Laboratory of Drug Target and Screening Research, Beijing, 100050, China; College of Pharmacy, Harbin University of Commerce, Harbin, 150076, China
| | - Peng Ma
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College and Beijing Key Laboratory of Drug Target and Screening Research, Beijing, 100050, China
| | - Zijing Wang
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College and Beijing Key Laboratory of Drug Target and Screening Research, Beijing, 100050, China
| | - Mingxia Sun
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China
| | - Biyu Hou
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College and Beijing Key Laboratory of Drug Target and Screening Research, Beijing, 100050, China
| | - Tianshu Xu
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College and Beijing Key Laboratory of Drug Target and Screening Research, Beijing, 100050, China
| | - Wenlan Li
- College of Pharmacy, Harbin University of Commerce, Harbin, 150076, China
| | - Xiuying Yang
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College and Beijing Key Laboratory of Drug Target and Screening Research, Beijing, 100050, China
| | - Guanhua Du
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College and Beijing Key Laboratory of Drug Target and Screening Research, Beijing, 100050, China
| | - Tengfei Ji
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
| | - Guifen Qiang
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College and Beijing Key Laboratory of Drug Target and Screening Research, Beijing, 100050, China.
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Scamfer SR, Lee MD, Hilgendorf KI. Ciliary control of adipocyte progenitor cell fate regulates energy storage. Front Cell Dev Biol 2022; 10:1083372. [PMID: 36561368 PMCID: PMC9763467 DOI: 10.3389/fcell.2022.1083372] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Accepted: 11/21/2022] [Indexed: 12/12/2022] Open
Abstract
The primary cilium is a cellular sensory organelle found in most cells in our body. This includes adipocyte progenitor cells in our adipose tissue, a complex organ involved in energy storage, endocrine signaling, and thermogenesis. Numerous studies have shown that the primary cilium plays a critical role in directing the cell fate of adipocyte progenitor cells in multiple adipose tissue types. Accordingly, diseases with dysfunctional cilia called ciliopathies have a broad range of clinical manifestations, including obesity and diabetes. This review summarizes our current understanding of how the primary cilium regulates adipocyte progenitor cell fate in multiple contexts and illustrates the importance of the primary cilium in regulating energy storage and adipose tissue function.
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Affiliation(s)
| | | | - Keren I. Hilgendorf
- Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT, United States
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Lv S, Zhou Y, Chen J, Yuan H, Zhang ZN, Luan B. Hepatic ER stress suppresses adipose browning through ATF4-CIRP-ANGPTL3 cascade. Cell Rep 2022; 40:111422. [PMID: 36170814 DOI: 10.1016/j.celrep.2022.111422] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Revised: 07/28/2022] [Accepted: 09/07/2022] [Indexed: 12/01/2022] Open
Abstract
Hepatic endoplasmic reticulum (ER) stress is a hallmark of obesity-induced liver steatosis and contributes to the progress of steatosis and insulin resistance in liver. However, its influence on adipose function is still unclear. Here, we identify a hepatic ER stress-induced activating transcription factor 4 (ATF4)-cold-inducible RNA-binding protein (CIRP)-angiopoietin-related protein3 (ANGPTL3) cascade critical for the regulation of adipose browning. We find that obesity increases CIRP expression in liver through ER stress-induced ATF4. CIRP in turn binds to the 3' UTR and increases mRNA stability of ANGPTL3. ANGPTL3 secreted from liver suppresses uncoupling protein 1 expression through integrin αvβ3 and c-Jun N-terminal kinase in adipose tissue. While hepatic expression of either ATF4, CIRP, or ANGPTL3 suppresses adipose browning, knockdown of CIRP and ANGPTL3 in liver or administration of integrin αvβ3 inhibitor cilengitide increases adipose browning process. Taken together, we identify a communication mechanism to link hepatic ER stress and adipose browning that may imply a reciprocal regulation of obesity and liver steatosis.
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Affiliation(s)
- Sihan Lv
- Department of Endocrinology, Tongji Hospital Affiliated to Tongji University, School of Medicine, Tongji University, Shanghai 200072, China
| | - Yingqun Zhou
- Department of Gastroenterology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200072, China
| | - Jiaojiao Chen
- Department of Gastroenterology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200072, China; School of Clinical Medicine, Nanjing Medical University, Nanjing 211166, China
| | - Huiwen Yuan
- Department of Endocrinology, Tongji Hospital Affiliated to Tongji University, School of Medicine, Tongji University, Shanghai 200072, China
| | - Zhen-Ning Zhang
- Translational Medical Center for Stem Cell Therapy & Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200120, China
| | - Bing Luan
- Department of Endocrinology, Tongji Hospital Affiliated to Tongji University, School of Medicine, Tongji University, Shanghai 200072, China.
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Yin X, Chen Y, Ruze R, Xu R, Song J, Wang C, Xu Q. The evolving view of thermogenic fat and its implications in cancer and metabolic diseases. Signal Transduct Target Ther 2022; 7:324. [PMID: 36114195 PMCID: PMC9481605 DOI: 10.1038/s41392-022-01178-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 08/30/2022] [Accepted: 09/05/2022] [Indexed: 02/07/2023] Open
Abstract
AbstractThe incidence of metabolism-related diseases like obesity and type 2 diabetes mellitus has reached pandemic levels worldwide and increased gradually. Most of them are listed on the table of high-risk factors for malignancy, and metabolic disorders systematically or locally contribute to cancer progression and poor prognosis of patients. Importantly, adipose tissue is fundamental to the occurrence and development of these metabolic disorders. White adipose tissue stores excessive energy, while thermogenic fat including brown and beige adipose tissue dissipates energy to generate heat. In addition to thermogenesis, beige and brown adipocytes also function as dynamic secretory cells and a metabolic sink of nutrients, like glucose, fatty acids, and amino acids. Accordingly, strategies that activate and expand thermogenic adipose tissue offer therapeutic promise to combat overweight, diabetes, and other metabolic disorders through increasing energy expenditure and enhancing glucose tolerance. With a better understanding of its origins and biological functions and the advances in imaging techniques detecting thermogenesis, the roles of thermogenic adipose tissue in tumors have been revealed gradually. On the one hand, enhanced browning of subcutaneous fatty tissue results in weight loss and cancer-associated cachexia. On the other hand, locally activated thermogenic adipocytes in the tumor microenvironment accelerate cancer progression by offering fuel sources and is likely to develop resistance to chemotherapy. Here, we enumerate current knowledge about the significant advances made in the origin and physiological functions of thermogenic fat. In addition, we discuss the multiple roles of thermogenic adipocytes in different tumors. Ultimately, we summarize imaging technologies for identifying thermogenic adipose tissue and pharmacologic agents via modulating thermogenesis in preclinical experiments and clinical trials.
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Yuan X, Lu H, Han M, Han K, Zhang Y, Liang P, Liu S, Cheng J. HCBP6-induced activation of brown adipose tissue and upregulated of BAT cytokines genes. J Therm Biol 2022; 109:103306. [DOI: 10.1016/j.jtherbio.2022.103306] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 06/15/2022] [Accepted: 08/18/2022] [Indexed: 11/27/2022]
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Fetuin-A in Activated Liver Macrophages Is a Key Feature of Non-Alcoholic Steatohepatitis. Metabolites 2022; 12:metabo12070625. [PMID: 35888749 PMCID: PMC9319870 DOI: 10.3390/metabo12070625] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Revised: 06/28/2022] [Accepted: 07/04/2022] [Indexed: 02/04/2023] Open
Abstract
Fetuin-A, a plasma multifunctional protein known to play a role in insulin resistance, is usually presented as a liver secreted protein. However, fetuin-A adipose tissue production has been also described. Here, we evaluated fetuin-A production by the liver and the adipose tissue during metabolic dysfunction-associated fatty liver disease (MAFLD)-non-alcoholic steatohepatitis (NASH) development. Fetuin-A was evaluated by enzyme-linked immunosorbent assay (ELISA), polymerase chain reaction (PCR), Western blot, and immunofluorescence in male foz−/− mice fed a normal diet (ND) or a high fat diet (HFD) at various timepoints and in MAFLD-NASH patients. Foz−/− mice fed a short-term HFD developed liver steatosis, insulin resistance, and increased circulating levels of fetuin-A compared to ND-fed mice. In mice and patients with NASH, fetuin-A was located not only in healthy or steatotic hepatocytes but also in some macrophages forming lipogranulomas. In both mice and humans, a significant amount of fetuin-A was present in the adipose tissue compared to the liver. However, messenger ribonucleic acid levels and cell culture experiments indicate that fetuin-A is produced by the liver but not by the adipose tissue. In conclusion, fetuin-A is produced by steatotic hepatocytes at early timepoints in MAFLD and correlates with insulin resistance both in mice and humans. In NASH, fetuin-A also co-localizes with activated liver macrophages and could be interpreted as a signal released by damaged hepatocytes.
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Gillard J, Picalausa C, Ullmer C, Adorini L, Staels B, Tailleux A, Leclercq IA. Enterohepatic Takeda G-Protein Coupled Receptor 5 Agonism in Metabolic Dysfunction-Associated Fatty Liver Disease and Related Glucose Dysmetabolism. Nutrients 2022; 14:nu14132707. [PMID: 35807885 PMCID: PMC9268629 DOI: 10.3390/nu14132707] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 06/24/2022] [Accepted: 06/25/2022] [Indexed: 12/11/2022] Open
Abstract
Metabolic dysfunction-associated fatty liver disease (MAFLD) is a major health concern with no approved pharmacological therapies. Molecules developed to activate the bile acid-receptor TGR5 regulate pathways involved in MALFD pathogenesis, but the therapeutic value of TGR5 activation on the active form of MAFLD, non-alcoholic steatohepatitis (NASH), still needs to be evaluated. As TGR5 agonism is low in MAFLD, we used strategies to promote the production of endogenous TGR5 ligands or administered pharmacological TGR5 agonists, INT-777 and RO5527239, to study the effect of TGR5 activation on liver and metabolic diseases in high-fat diet-fed foz/foz mice. Although described in the literature, treatment with fexaramine, an intestine-restricted FXR agonist, did not raise the concentrations of TGR5 ligands nor modulate TGR5 signaling and, accordingly, did not improve dysmetabolic status. INT-777 and RO5527239 directly activated TGR5. INT-777 only increased the TGR5 activation capacity of the portal blood; RO5527239 also amplified the TGR5 activation capacity of systemic blood. Both molecules improved glucose tolerance. In spite of the TGR5 activation capacity, INT-777, but not RO5527239, reduced liver disease severity. In conclusion, TGR5 activation in enterohepatic, rather than in peripheral, tissues has beneficial effects on glucose tolerance and MAFLD.
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Affiliation(s)
- Justine Gillard
- Laboratory of Hepato-Gastroenterology, Institute of Experimental and Clinical Research, Université Catholique de Louvain, 1200 Brussels, Belgium; (J.G.); (C.P.)
| | - Corinne Picalausa
- Laboratory of Hepato-Gastroenterology, Institute of Experimental and Clinical Research, Université Catholique de Louvain, 1200 Brussels, Belgium; (J.G.); (C.P.)
| | - Christoph Ullmer
- Pharma Research & Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., 4070 Basel, Switzerland;
| | | | - Bart Staels
- Inserm, CHU Lille, Institut Pasteur de Lille, University Lille, U1011-EGID, F-59000 Lille, France; (B.S.); (A.T.)
| | - Anne Tailleux
- Inserm, CHU Lille, Institut Pasteur de Lille, University Lille, U1011-EGID, F-59000 Lille, France; (B.S.); (A.T.)
| | - Isabelle A. Leclercq
- Laboratory of Hepato-Gastroenterology, Institute of Experimental and Clinical Research, Université Catholique de Louvain, 1200 Brussels, Belgium; (J.G.); (C.P.)
- Correspondence: ; Tel.: +32-2-764-5273
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15
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Tint MT, Michael N, Sadananthan SA, Huang JY, Khoo CM, Godfrey KM, Shek LPC, Lek N, Tan KH, Yap F, Velan SS, Gluckman PD, Chong YS, Karnani N, Chan SY, Leow MKS, Lee KJ, Lee YS, Hu HH, Zhang C, Fortier MV, Eriksson JG. Brown Adipose Tissue, Adiposity, and Metabolic Profile in Preschool Children. J Clin Endocrinol Metab 2021; 106:2901-2914. [PMID: 34143868 PMCID: PMC8475202 DOI: 10.1210/clinem/dgab447] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Indexed: 02/08/2023]
Abstract
CONTEXT An inverse relationship between brown adipose tissue (BAT) and obesity has previously been reported in older children and adults but is unknown in young children. OBJECTIVE We investigated the influence of BAT in thermoneutral condition on adiposity and metabolic profile in Asian preschool children. DESIGN, SETTING, AND PARTICIPANTS A total of 198 children aged 4.5 years from a prospective birth cohort study, Growing Up in Singapore Towards Healthy Outcomes (GUSTO) were successfully studied with water-fat magnetic resonance imaging of the supraclavicular and axillary fat depot (FDSA). Regions within FDSA with fat-signal-fraction between 20% and 80% were considered BAT, and percentage BAT (%BAT; 100*BAT volume/ FDSA volume) was calculated. MAIN OUTCOME MEASURES Abdominal adipose tissue compartment volumes, ectopic fat in the soleus muscle and liver, fatty liver index, metabolic syndrome scores, and markers of insulin sensitivity. RESULTS A 1% unit increase in %BAT was associated with lower body mass index, difference (95% CI), -0.08 (-0.10, -0.06) kg/m2 and smaller abdominal adipose tissue compartment volumes. Ethnicity and sex modified these associations. In addition, each unit increase in %BAT was associated with lower ectopic fat at 4.5 years in the liver, -0.008% (-0.013%, -0.003%); soleus muscle, -0.003% (-0.006%, -0.001%) of water content and lower fatty liver index at 6 years. CONCLUSIONS Higher %BAT is associated with a more favorable metabolic profile. BAT may thus play a role in the pathophysiology of obesity and related metabolic disorders. The observed ethnic and sex differences imply that the protective effect of BAT may vary among different groups.
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Affiliation(s)
- Mya Thway Tint
- Singapore Institute for Clinical Sciences (SICS), Agency for Science, Technology and Research (A*STAR), Singapore
- Department of Obstetrics & Gynecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Navin Michael
- Singapore Institute for Clinical Sciences (SICS), Agency for Science, Technology and Research (A*STAR), Singapore
| | - Suresh Anand Sadananthan
- Singapore Institute for Clinical Sciences (SICS), Agency for Science, Technology and Research (A*STAR), Singapore
| | - Jonathan Yinhao Huang
- Singapore Institute for Clinical Sciences (SICS), Agency for Science, Technology and Research (A*STAR), Singapore
| | - Chin Meng Khoo
- Division of Endocrinology, Department of Medicine, National University Health System, Singapore
| | - Keith M Godfrey
- MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK
- NIHR Southampton Biomedical Research Centre, University Hospital Southampton, NHS Foundation Trust, Southampton, UK
| | - Lynette Pei-Chi Shek
- Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Ngee Lek
- Department of Pediatric Endocrinology, KK Women’s and Children’s Hospital, Singapore
| | - Kok Hian Tan
- Department of Obstetrics and Gynaecology, KK Women’s and Children’s Hospital, Singapore
| | - Fabian Yap
- Department of Pediatric Endocrinology, KK Women’s and Children’s Hospital, Singapore
- Duke-NUS Graduate Medical School, Singapore
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore
| | - S Sendhil Velan
- Singapore Institute for Clinical Sciences (SICS), Agency for Science, Technology and Research (A*STAR), Singapore
- Singapore Bioimaging Consortium (SBIC), Agency for Science, Technology and Research (A*STAR), Singapore
| | - Peter D Gluckman
- Singapore Institute for Clinical Sciences (SICS), Agency for Science, Technology and Research (A*STAR), Singapore
- Liggins Institute, University of Auckland, Auckland, New Zealand
| | - Yap-Seng Chong
- Singapore Institute for Clinical Sciences (SICS), Agency for Science, Technology and Research (A*STAR), Singapore
- Department of Obstetrics & Gynecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Neerja Karnani
- Singapore Institute for Clinical Sciences (SICS), Agency for Science, Technology and Research (A*STAR), Singapore
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Shiao-Yng Chan
- Singapore Institute for Clinical Sciences (SICS), Agency for Science, Technology and Research (A*STAR), Singapore
- Department of Obstetrics & Gynecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Melvin Khee-Shing Leow
- Singapore Institute for Clinical Sciences (SICS), Agency for Science, Technology and Research (A*STAR), Singapore
- Department of Endocrinology, Tan Tock Seng Hospital, Singapore
- Metabolic Disorders Research Programme, Lee Kong Chian School of Medicine, Singapore
- Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, Singapore
| | - Kuan Jin Lee
- Singapore Bioimaging Consortium (SBIC), Agency for Science, Technology and Research (A*STAR), Singapore
| | - Yung-Seng Lee
- Singapore Institute for Clinical Sciences (SICS), Agency for Science, Technology and Research (A*STAR), Singapore
- Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- Division of Paediatric Endocrinology, Department of Paediatrics, Khoo Teck Puat–National University Children’s Medical Institute, National University Health System, Singapore
| | - Houchun Harry Hu
- Department of Radiology, Nationwide Children’s Hospital, Columbus, OH, USA
| | - Cuilin Zhang
- Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Rockville, MD, USA
| | - Marielle V Fortier
- Singapore Institute for Clinical Sciences (SICS), Agency for Science, Technology and Research (A*STAR), Singapore
- Department of Diagnostic and Interventional Imaging, KK Women’s and Children’s Hospital, Singapore
| | - Johan G Eriksson
- Singapore Institute for Clinical Sciences (SICS), Agency for Science, Technology and Research (A*STAR), Singapore
- Department of Obstetrics & Gynecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- Department of General Practice and Primary Health Care, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Folkhälsan Research Center, Helsinki, Finland
- Correspondence: Johan G. Eriksson, Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, MD1, Tahir Foundation Building, Level 12, #12-02/03, 12 Science Drive 2, Singapore 117549, Singapore. ;
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16
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Miranda GDS, de Lima TAL, Costermani HDO, Ricken CLRDS, Parrela JPSDS, Membrive BLA, de Almeida RE, Facchi JC, de Oliveira LR, Miranda RA, de Moura EG, Lisboa PC, de Oliveira JC. Breastfeeding undernutrition changes iBAT-involved thermogenesis protein expression and leads to a lean phenotype in adult rat offspring. J Nutr Biochem 2021; 99:108857. [PMID: 34520852 DOI: 10.1016/j.jnutbio.2021.108857] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 07/04/2021] [Accepted: 08/10/2021] [Indexed: 01/09/2023]
Abstract
Nutritional insults early in life have been associated with metabolic diseases in adulthood. We aimed to evaluate the effects of maternal food restriction during the suckling period on metabolism and interscapular brown adipose tissue (iBAT) thermogenically involved proteins in adult rat offspring. Wistar rats underwent food restriction by 50% during the first two-thirds of lactation (FR50 group). Control rats were fed ad libitum throughout lactation (CONT group). At birth, the litter size was adjusted to eight pups, and weaning was performed at 22 days old. Body weight and food and water intake were assessed every two days. High- (HCD, 4,589 cal) and normal-caloric diet (NCD, 3,860 cal) preferences, as well as food intake during the dark part of the cycle, were assessed. At 100 days old, the rats were euthanized, and blood and tissues were removed for further analyses. Adult FR50 rats, although hyperphagic and preferring to eat HCD (P<.001), were leaner (P<.001) than the CONT group. The FR50 rats, were normoglycemic (P=.962) and had hypertriglyceridemia (P<.01). In addition, the FR50 rats were dyslipidemic (P<.01), presenting with a high atherogenic risk by the Castelli indexes (P<.01), had a higher iBAT mass (P<.01), fewer β3 adrenergic receptors (β3-AR, P<.05) and higher iBAT expression of uncoupled protein 1 (UCP1, P<.05) and peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α, P<.001) than the CONT rats. In conclusion, maternal food restriction during early breastfeeding programs rat offspring to have a lean phenotype, despite hyperphagia, and increased iBAT UCP1 and PGC-1α protein expression.
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Affiliation(s)
- Ginislene Dias Souza Miranda
- Research Group on Perinatal Programming of Metabolic Diseases: DOHaD paradigm, Laboratory of Metabolic and Cardiovascular Diseases, Health Education and Research Center (NUPADS), Institute of Health Sciences, Federal University of Mato Grosso, University Campus of Sinop, Sinop, MT, Brazil
| | - Thalyne Aparecida Leite de Lima
- Research Group on Perinatal Programming of Metabolic Diseases: DOHaD paradigm, Laboratory of Metabolic and Cardiovascular Diseases, Health Education and Research Center (NUPADS), Institute of Health Sciences, Federal University of Mato Grosso, University Campus of Sinop, Sinop, MT, Brazil
| | - Hercules de Oliveira Costermani
- Research Group on Perinatal Programming of Metabolic Diseases: DOHaD paradigm, Laboratory of Metabolic and Cardiovascular Diseases, Health Education and Research Center (NUPADS), Institute of Health Sciences, Federal University of Mato Grosso, University Campus of Sinop, Sinop, MT, Brazil
| | - Camila Luiza Rodrigues Dos Santos Ricken
- Research Group on Perinatal Programming of Metabolic Diseases: DOHaD paradigm, Laboratory of Metabolic and Cardiovascular Diseases, Health Education and Research Center (NUPADS), Institute of Health Sciences, Federal University of Mato Grosso, University Campus of Sinop, Sinop, MT, Brazil
| | - Jocemara Patrícia Silva de Souza Parrela
- Research Group on Perinatal Programming of Metabolic Diseases: DOHaD paradigm, Laboratory of Metabolic and Cardiovascular Diseases, Health Education and Research Center (NUPADS), Institute of Health Sciences, Federal University of Mato Grosso, University Campus of Sinop, Sinop, MT, Brazil
| | - Bárbara Letícia Antonio Membrive
- Research Group on Perinatal Programming of Metabolic Diseases: DOHaD paradigm, Laboratory of Metabolic and Cardiovascular Diseases, Health Education and Research Center (NUPADS), Institute of Health Sciences, Federal University of Mato Grosso, University Campus of Sinop, Sinop, MT, Brazil
| | - Raul Evangelista de Almeida
- Research Group on Perinatal Programming of Metabolic Diseases: DOHaD paradigm, Laboratory of Metabolic and Cardiovascular Diseases, Health Education and Research Center (NUPADS), Institute of Health Sciences, Federal University of Mato Grosso, University Campus of Sinop, Sinop, MT, Brazil
| | - Júlia Cristina Facchi
- Research Group on Perinatal Programming of Metabolic Diseases: DOHaD paradigm, Laboratory of Metabolic and Cardiovascular Diseases, Health Education and Research Center (NUPADS), Institute of Health Sciences, Federal University of Mato Grosso, University Campus of Sinop, Sinop, MT, Brazil
| | - Lucas Ryba de Oliveira
- Research Group on Perinatal Programming of Metabolic Diseases: DOHaD paradigm, Laboratory of Metabolic and Cardiovascular Diseases, Health Education and Research Center (NUPADS), Institute of Health Sciences, Federal University of Mato Grosso, University Campus of Sinop, Sinop, MT, Brazil
| | - Rosiane Aparecida Miranda
- Laboratory of Endocrine Physiology, Department of Physiological Sciences, State University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
| | - Egberto Gaspar de Moura
- Laboratory of Endocrine Physiology, Department of Physiological Sciences, State University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
| | - Patrícia Cristina Lisboa
- Laboratory of Endocrine Physiology, Department of Physiological Sciences, State University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
| | - Júlio Cezar de Oliveira
- Research Group on Perinatal Programming of Metabolic Diseases: DOHaD paradigm, Laboratory of Metabolic and Cardiovascular Diseases, Health Education and Research Center (NUPADS), Institute of Health Sciences, Federal University of Mato Grosso, University Campus of Sinop, Sinop, MT, Brazil.
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17
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Ozaki-Masuzawa Y, Kosaka H, Abiru R, Toda Y, Kawabata K, Nagata M, Hara S, Konishi M, Itoh N, Hosono T, Takenaka A, Seki T. The role of increased FGF21 in VLDL-TAG secretion and thermogenic gene expression in mice under protein malnutrition. Biosci Biotechnol Biochem 2021; 85:1104-1113. [PMID: 33751045 DOI: 10.1093/bbb/zbab030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Accepted: 02/13/2021] [Indexed: 11/13/2022]
Abstract
Protein malnutrition promotes hepatic lipid accumulation in growing animals. In these animals, fibroblast growth factor 21 (FGF21) rapidly increases in the liver and circulation and plays a protective role in hepatic lipid accumulation. To investigate the mechanism by which FGF21 protects against liver lipid accumulation under protein malnutrition, we determined whether upregulated FGF21 promotes the thermogenesis or secretion of very-low-density lipoprotein (VLDL)-triacylglycerol (TAG). The results showed that protein malnutrition decreased VLDL-TAG secretion, but the upregulation of FGF21 did not oppose this effect. In addition, protein malnutrition increased expression of the thermogenic gene uncoupling protein 1 in inguinal white adipose and brown adipose tissue in an FGF21-dependent manner. However, surgically removing inguinal white adipose tissue did not affect liver triglyceride levels in protein-malnourished mice. These data suggest that FGF21 stimulates thermogenesis under protein malnutrition, but this is not the causative factor underlying the protective role of FGF21 against liver lipid accumulation.
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Affiliation(s)
- Yori Ozaki-Masuzawa
- Department of Chemistry and Life Science, College of Bioresource Sciences, Nihon University, Fujisawa, Kanagawa, Japan
| | - Hiroki Kosaka
- Department of Applied Life Science, Graduate School of Bioresource Sciences, Nihon University, Fujisawa, Kanagawa, Japan
| | - Rino Abiru
- Department of Chemistry and Life Science, College of Bioresource Sciences, Nihon University, Fujisawa, Kanagawa, Japan
| | - Yumiko Toda
- Department of Chemistry and Life Science, College of Bioresource Sciences, Nihon University, Fujisawa, Kanagawa, Japan
| | - Kota Kawabata
- Department of Chemistry and Life Science, College of Bioresource Sciences, Nihon University, Fujisawa, Kanagawa, Japan
| | - Mari Nagata
- Department of Chemistry and Life Science, College of Bioresource Sciences, Nihon University, Fujisawa, Kanagawa, Japan
| | - Shohei Hara
- Department of Chemistry and Life Science, College of Bioresource Sciences, Nihon University, Fujisawa, Kanagawa, Japan
| | - Morichika Konishi
- Laboratory of Microbial Chemistry, Kobe Pharmaceutical University, Kobe, Hyogo, Japan
| | - Nobuyuki Itoh
- Kyoto University Graduate School of Pharmaceutical Sciences, Sakyo, Kyoto, Japan
| | - Takashi Hosono
- Department of Chemistry and Life Science, College of Bioresource Sciences, Nihon University, Fujisawa, Kanagawa, Japan.,Department of Applied Life Science, Graduate School of Bioresource Sciences, Nihon University, Fujisawa, Kanagawa, Japan
| | - Asako Takenaka
- Department of Agricultural Chemistry, School of Agriculture, Meiji University, Kawasaki, Kanagawa, Japan
| | - Taiichiro Seki
- Department of Chemistry and Life Science, College of Bioresource Sciences, Nihon University, Fujisawa, Kanagawa, Japan.,Department of Applied Life Science, Graduate School of Bioresource Sciences, Nihon University, Fujisawa, Kanagawa, Japan
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18
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Chan CC, Harley ITW, Pfluger PT, Trompette A, Stankiewicz TE, Allen JL, Moreno-Fernandez ME, Damen MSMA, Oates JR, Alarcon PC, Doll JR, Flick MJ, Flick LM, Sanchez-Gurmaches J, Mukherjee R, Karns R, Helmrath M, Inge TH, Weisberg SP, Pamp SJ, Relman DA, Seeley RJ, Tschöp MH, Karp CL, Divanovic S. A BAFF/APRIL axis regulates obesogenic diet-driven weight gain. Nat Commun 2021; 12:2911. [PMID: 34006859 PMCID: PMC8131685 DOI: 10.1038/s41467-021-23084-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2019] [Accepted: 04/12/2021] [Indexed: 02/07/2023] Open
Abstract
The impact of immune mediators on weight homeostasis remains underdefined. Interrogation of resistance to diet-induced obesity in mice lacking a negative regulator of Toll-like receptor signaling serendipitously uncovered a role for B cell activating factor (BAFF). Here we show that overexpression of BAFF in multiple mouse models associates with protection from weight gain, approximating a log-linear dose response relation to BAFF concentrations. Gene expression analysis of BAFF-stimulated subcutaneous white adipocytes unveils upregulation of lipid metabolism pathways, with BAFF inducing white adipose tissue (WAT) lipolysis. Brown adipose tissue (BAT) from BAFF-overexpressing mice exhibits increased Ucp1 expression and BAFF promotes brown adipocyte respiration and in vivo energy expenditure. A proliferation-inducing ligand (APRIL), a BAFF homolog, similarly modulates WAT and BAT lipid handling. Genetic deletion of both BAFF and APRIL augments diet-induced obesity. Lastly, BAFF/APRIL effects are conserved in human adipocytes and higher BAFF/APRIL levels correlate with greater BMI decrease after bariatric surgery. Together, the BAFF/APRIL axis is a multifaceted immune regulator of weight gain and adipose tissue function.
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Affiliation(s)
- Calvin C Chan
- Department of Pediatrics, The University of Cincinnati College of Medicine, Cincinnati, OH, USA
- Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
- Medical Scientist Training Program, The University of Cincinnati College of Medicine and Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
- Immunology Graduate Program, The University of Cincinnati College of Medicine and Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Isaac T W Harley
- Department of Pediatrics, The University of Cincinnati College of Medicine, Cincinnati, OH, USA
- Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
- Medical Scientist Training Program, The University of Cincinnati College of Medicine and Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
- Immunology Graduate Program, The University of Cincinnati College of Medicine and Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
- Division of Rheumatology, Department of Internal Medicine and Department of Immunology & Microbiology, The University of Colorado Denver, Aurora, CO, USA
| | - Paul T Pfluger
- Research Unit NeuroBiology of Diabetes, Helmholtz Center Munich, Neuherberg, Germany
- Institute for Diabetes and Obesity, Helmholtz Center Munich, Neuherberg, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
- Division of Metabolic Diseases, Technische Universität München, Munich, Germany
| | - Aurelien Trompette
- Department of Pediatrics, The University of Cincinnati College of Medicine, Cincinnati, OH, USA
- Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
- University of Lausanne, Service de Pneumologie, CHUV, CLED 02.206, Epalinges, Switzerland
| | - Traci E Stankiewicz
- Department of Pediatrics, The University of Cincinnati College of Medicine, Cincinnati, OH, USA
- Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Jessica L Allen
- Department of Pediatrics, The University of Cincinnati College of Medicine, Cincinnati, OH, USA
- Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
- Immunology Graduate Program, The University of Cincinnati College of Medicine and Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
- , Charlotte, NC, USA
| | - Maria E Moreno-Fernandez
- Department of Pediatrics, The University of Cincinnati College of Medicine, Cincinnati, OH, USA
- Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Michelle S M A Damen
- Department of Pediatrics, The University of Cincinnati College of Medicine, Cincinnati, OH, USA
- Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Jarren R Oates
- Department of Pediatrics, The University of Cincinnati College of Medicine, Cincinnati, OH, USA
- Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
- Immunology Graduate Program, The University of Cincinnati College of Medicine and Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Pablo C Alarcon
- Department of Pediatrics, The University of Cincinnati College of Medicine, Cincinnati, OH, USA
- Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
- Medical Scientist Training Program, The University of Cincinnati College of Medicine and Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
- Immunology Graduate Program, The University of Cincinnati College of Medicine and Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Jessica R Doll
- Department of Pediatrics, The University of Cincinnati College of Medicine, Cincinnati, OH, USA
- Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Matthew J Flick
- Department of Pediatrics, The University of Cincinnati College of Medicine, Cincinnati, OH, USA
- Division of Experimental Hematology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
- The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Leah M Flick
- Department of Pediatrics, The University of Cincinnati College of Medicine, Cincinnati, OH, USA
- Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
- , Chapel Hill, NC, USA
| | - Joan Sanchez-Gurmaches
- Department of Pediatrics, The University of Cincinnati College of Medicine, Cincinnati, OH, USA
- Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
- Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Rajib Mukherjee
- Department of Pediatrics, The University of Cincinnati College of Medicine, Cincinnati, OH, USA
- Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Rebekah Karns
- Department of Pediatrics, The University of Cincinnati College of Medicine, Cincinnati, OH, USA
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Michael Helmrath
- Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
- Stem Cell & Organoid Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Thomas H Inge
- Department of Surgery, Children's Hospital Colorado, Aurora, CO, USA
| | | | - Sünje J Pamp
- Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA
- Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
- National Food Institute, Technical University of Denmark, Kgs. Lyngby, Denmark
| | - David A Relman
- Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA
- Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
- Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA
| | - Randy J Seeley
- Department of Surgery, Internal Medicine and Nutritional Sciences, University of Michigan, Ann Arbor, MI, USA
| | - Matthias H Tschöp
- Institute for Diabetes and Obesity, Helmholtz Center Munich, Neuherberg, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
- Division of Metabolic Diseases, Technische Universität München, Munich, Germany
| | - Christopher L Karp
- Department of Pediatrics, The University of Cincinnati College of Medicine, Cincinnati, OH, USA
- Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
- Medical Scientist Training Program, The University of Cincinnati College of Medicine and Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
- Immunology Graduate Program, The University of Cincinnati College of Medicine and Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
- Global Health Discovery & Translational Sciences, Bill & Melinda Gates Foundation, Seattle, WA, USA
| | - Senad Divanovic
- Department of Pediatrics, The University of Cincinnati College of Medicine, Cincinnati, OH, USA.
- Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
- Medical Scientist Training Program, The University of Cincinnati College of Medicine and Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
- Immunology Graduate Program, The University of Cincinnati College of Medicine and Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
- Center for Inflammation and Tolerance, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
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19
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Zhang JJ, Wang JQ, Sun MQ, Xu D, Xiao Y, Lu WL, Dong ZY. Alström syndrome with a novel mutation of ALMS1 and Graves’ hyperthyroidism: A case report and review of the literature. World J Clin Cases 2021; 9:3200-3211. [PMID: 33969109 PMCID: PMC8080750 DOI: 10.12998/wjcc.v9.i13.3200] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 01/21/2021] [Accepted: 02/08/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Alström syndrome (AS, OMIM ID 203800) is a rare disease involving multiple organs in children and is mostly reported in non-Chinese patients. In the Chinese population, there are few reports on the clinical manifestations and pathogenesis of AS. This is the first report on the association between AS and Graves’ hyperthyroidism.
CASE SUMMARY An 8-year-old Chinese girl was diagnosed with AS. Two years later, Graves’ hyperthyroidism developed with progressive liver dysfunction. The patient’s clinical data were collected; DNA from peripheral blood of the proband, parents and sibling was collected for gene mutation detection using the second-generation sequencing method and gene panel for diabetes. The association between the patient’s genotype and clinical phenotype was analyzed. She carried the pathogenic compound heterozygous mutation of ALMS1 (c.2296_2299del4 and c.11460C>A). These stop-gain mutations likely caused truncation of the ALMS1 protein.
CONCLUSION The manifestation of hyperthyroidism may suggest rapid progression of AS.
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Affiliation(s)
- Juan-Juan Zhang
- Department of Pediatrics, Ruijin Hospital, Shanghai Jiao-Tong University, School of Medicine, Shanghai 200025, China
| | - Jun-Qi Wang
- Department of Pediatrics, Ruijin Hospital, Shanghai Jiao-Tong University, School of Medicine, Shanghai 200025, China
| | - Man-Qing Sun
- Department of Pediatrics, Ruijin Hospital, Shanghai Jiao-Tong University, School of Medicine, Shanghai 200025, China
| | - De Xu
- Department of Pediatrics, Ruijin Hospital, Shanghai Jiao-Tong University, School of Medicine, Shanghai 200025, China
| | - Yuan Xiao
- Department of Pediatrics, Ruijin Hospital, Shanghai Jiao-Tong University, School of Medicine, Shanghai 200025, China
| | - Wen-Li Lu
- Department of Pediatrics, Ruijin Hospital, Shanghai Jiao-Tong University, School of Medicine, Shanghai 200025, China
| | - Zhi-Ya Dong
- Department of Pediatrics, Ruijin Hospital, Shanghai Jiao-Tong University, School of Medicine, Shanghai 200025, China
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20
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Kwon J, Lee C, Heo S, Kim B, Hyun CK. DSS-induced colitis is associated with adipose tissue dysfunction and disrupted hepatic lipid metabolism leading to hepatosteatosis and dyslipidemia in mice. Sci Rep 2021; 11:5283. [PMID: 33674694 PMCID: PMC7935975 DOI: 10.1038/s41598-021-84761-1] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Accepted: 02/18/2021] [Indexed: 02/06/2023] Open
Abstract
Considering high prevalence of non-alcoholic fatty liver diseases (NAFLD) in patients with inflammatory bowel disease (IBD), this study aimed to elucidate molecular mechanisms for how intestinal inflammatory conditions are causally linked to hepatic steatosis and dyslipidemia. Both younger and older mice treated with acute or chronic dextran sodium sulfate (DSS) developed colitis, which was evidenced by weight loss, colon length shortening, and elevated disease activity index and inflammation score. They also showed decreased expression of intestinal barrier function-related proteins and elevated plasma lipopolysaccharide level, indicating DSS-induced barrier dysfunction and thereby increased permeability. Interestingly, they displayed phenotypes of hepatic fat accumulation and abnormal blood lipid profiles. This DSS-induced colitis-associated lipid metabolic dysfunction was due to overall disruption of metabolic processes including fatty acid oxidation, lipogenesis, lipolysis, reverse cholesterol transport, bile acid synthesis, and white adipose tissue browning and brown adipose tissue thermogenesis, most of which are mediated by key regulators of energy homeostasis such as FGF21, adiponectin, and irisin, via SIRT1/PGC-1α- and LXRα-dependent pathways. Our study suggests a potential molecular mechanism underlying the comorbidity of NAFLD and IBD, which could provide a key to understanding how the two diseases are pathogenically linked and discovering critical therapeutic targets for their treatment.
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Affiliation(s)
- Jeonghyeon Kwon
- grid.411957.f0000 0004 0647 2543School of Life Science, Handong Global University, Pohang, Gyungbuk 37554 South Korea
| | - Chungho Lee
- grid.411957.f0000 0004 0647 2543School of Life Science, Handong Global University, Pohang, Gyungbuk 37554 South Korea
| | - Sungbaek Heo
- grid.411957.f0000 0004 0647 2543School of Life Science, Handong Global University, Pohang, Gyungbuk 37554 South Korea
| | - Bobae Kim
- grid.411957.f0000 0004 0647 2543School of Life Science, Handong Global University, Pohang, Gyungbuk 37554 South Korea
| | - Chang-Kee Hyun
- grid.411957.f0000 0004 0647 2543School of Life Science, Handong Global University, Pohang, Gyungbuk 37554 South Korea
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21
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Dassie F, Favaretto F, Bettini S, Parolin M, Valenti M, Reschke F, Danne T, Vettor R, Milan G, Maffei P. Alström syndrome: an ultra-rare monogenic disorder as a model for insulin resistance, type 2 diabetes mellitus and obesity. Endocrine 2021; 71:618-625. [PMID: 33566311 DOI: 10.1007/s12020-021-02643-y] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Accepted: 01/19/2021] [Indexed: 12/16/2022]
Abstract
BACKGROUND Alström syndrome (ALMS) is a monogenic ultra-rare disorder with a prevalence of one per million inhabitants caused by pathogenic variants of ALMS1 gene. ALMS1 is located on chromosome 2p13, spans 23 exons and encodes a predicted 461.2-kDa protein of 4169 amino acids. The infantile cone-rod dystrophy with nystagmus and severe visual impairment is the earliest and most consistent clinical manifestation of ALMS. In addition, infantile transient cardiomyopathy, early childhood obesity with hyperphagia, deafness, insulin resistance (IR), type 2 diabetes mellitus (T2DM), systemic fibrosis and progressive renal or liver dysfunction are common findings. ALMS1 encodes a large ubiquitously expressed protein that is associated with the centrosome and the basal body of primary cilium. CURRENT RESEARCH The localisation of ALMS1 to the ciliary basal body suggests its contribution to ciliogenesis and/or normal ciliary function, or centriolar stability. ALMS1 regulate glucose transport through the actin cytoskeleton, which plays an important role in insulin-stimulated GLUT4 transport. Both extreme IR and β-cell failure are the two determinant factors responsible for the development of glucose metabolism alterations in ALMS. TREATMENT Currently, there is no known cure for ALMS other than managing the underlying systemic diseases. When possible, individuals with ALMS and families should be referred to a centre of expertise and followed by a multidisciplinary team. Lifestyle modification, aerobic exercise and dietary induced weight loss are highly recommended as primary treatment for ALMS patients with T2DM and obesity. CONCLUSION Managing a rare disease requires not only medical care but also a support network including patient associations.
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Affiliation(s)
- Francesca Dassie
- Department of Medicine (DIMED), Clinica Medica 3, Padua University Hospital, Padua, Italy
| | - Francesca Favaretto
- Department of Medicine (DIMED), Clinica Medica 3, Padua University Hospital, Padua, Italy
| | - Silvia Bettini
- Department of Medicine (DIMED), Clinica Medica 3, Padua University Hospital, Padua, Italy
| | - Matteo Parolin
- Department of Medicine (DIMED), Clinica Medica 3, Padua University Hospital, Padua, Italy
| | - Marina Valenti
- Italian Association of Alström Syndrome Patients-ASS.A.I., Endo-ERN ePAG, Padua, Italy
| | - Felix Reschke
- Department of General Pediatrics, Endocrinology/Diabetology and Clinical Research, Children's Hospital Auf der Bult, Hannover, Germany
| | - Thomas Danne
- Department of General Pediatrics, Endocrinology/Diabetology and Clinical Research, Children's Hospital Auf der Bult, Hannover, Germany
| | - Roberto Vettor
- Department of Medicine (DIMED), Clinica Medica 3, Padua University Hospital, Padua, Italy
| | - Gabriella Milan
- Department of Medicine (DIMED), Clinica Medica 3, Padua University Hospital, Padua, Italy
| | - Pietro Maffei
- Department of Medicine (DIMED), Clinica Medica 3, Padua University Hospital, Padua, Italy.
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22
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De Munck TJI, Xu P, Vanderfeesten BLJ, Elizalde M, Masclee AAM, Nevens F, Cassiman D, Schaap FG, Jonkers DMAE, Verbeek J. The Role of Brown Adipose Tissue in the Development and Treatment of Nonalcoholic Steatohepatitis: An Exploratory Gene Expression Study in Mice. Horm Metab Res 2020; 52:869-876. [PMID: 33260239 DOI: 10.1055/a-1301-2378] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Brown adipose tissue (BAT) might be a beneficial mediator in the development and treatment of nonalcoholic steatohepatitis (NASH). We aim to evaluate the gene expression of BAT activity-related genes during the development and the dietary and surgical treatment of NASH. BAT was collected from male C57BL/6J mice that received a high fat-high sucrose diet (HF-HSD) or a normal chow diet (NCD) for 4 and 20 weeks (n=8-9 per dietary group and timepoint) and from mice that underwent dietary intervention (return to NCD) (n=8), roux-en-y gastric bypass (RYGB) (n=6), or sham procedure (n=6) after 12 weeks HF-HSD. Expression of BAT genes involved in lipid metabolism (Cd36 and Cpt1b; p<0.05) and energy expenditure (Ucp1 and Ucp3; p<0.05) were significantly increased after 4 weeks HF-HSD compared with NCD, whereas in the occurrence of NASH after 20 weeks HF-HSD no difference was observed. We observed no differences in gene expression regarding lipid metabolism or energy expenditure at 8 weeks after dietary intervention (no NASH) compared with HF-HSD mice (NASH), nor in mice that underwent RYGB compared with SHAM. However, dietary intervention and RYGB both decreased the BAT gene expression of inflammatory cytokines (Il1b, Tnf-α and MCP-1; p<0.05). Gene expression of the batokine neuregulin 4 was significantly decreased after 20 weeks HF-HSD (p<0.05) compared with NCD, but was restored by dietary intervention and RYGB (p<0.05). In conclusion, BAT is hallmarked by dynamic alterations in the gene expression profile during the development of NASH and can be modulated by dietary intervention and bariatric surgery.
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Affiliation(s)
- Toon J I De Munck
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Maastricht University Medical Centre, Maastricht, The Netherlands
- School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, The Netherlands
| | - Pan Xu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Maastricht University Medical Centre, Maastricht, The Netherlands
- School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, The Netherlands
| | - Brechtje L J Vanderfeesten
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Maastricht University Medical Centre, Maastricht, The Netherlands
| | - Montserrat Elizalde
- School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, The Netherlands
| | - Ad A M Masclee
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Maastricht University Medical Centre, Maastricht, The Netherlands
- School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, The Netherlands
| | - Frederik Nevens
- Department of Gastroenterology and Hepatology, University Hospitals KU Leuven, Leuven, Belgium
| | - David Cassiman
- Department of Gastroenterology and Hepatology, University Hospitals KU Leuven, Leuven, Belgium
| | - Frank G Schaap
- School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, The Netherlands
- Department of Surgery, Maastricht University Medical Centre, Maastricht, The Netherlands
- Department of General, Visceral and Transplantation Surgery, RWTH University Hospital Aachen, Aachen, Germany
| | - Daisy M A E Jonkers
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Maastricht University Medical Centre, Maastricht, The Netherlands
- School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, The Netherlands
| | - Jef Verbeek
- Department of Gastroenterology and Hepatology, University Hospitals KU Leuven, Leuven, Belgium
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23
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Lu H, Yuan X, Zhang Y, Han M, Liu S, Han K, Liang P, Cheng J. HCBP6 deficiency exacerbates glucose and lipid metabolism disorders in non-alcoholic fatty liver mice. Biomed Pharmacother 2020; 129:110347. [PMID: 32535386 DOI: 10.1016/j.biopha.2020.110347] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2019] [Revised: 05/23/2020] [Accepted: 06/01/2020] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD), which often accompanied by metabolic syndrome, such as obesity, diabetes and dyslipidemia, has become a global health problem. Our previous results show that HCV core protein binding protein 6 (HCBP6) could maintain the triglyceride homeostasis in liver cells. However, the role of HCBP6 in NAFLD and its associated metabolic disorders remains incompletely understood. METHODS Hepatic HCBP6 expression was determined by qRT-PCR, Western blot and immunohistochemistry analysis. HCBP6 knockout (HCBP6-KO) mice were constructed and fed a high-fat diet (HFD) to induce NAFLD. The effects of HCBP6 on glucose and lipid metabolism were measured by HE staining, qRT-PCR, Western blot and GTT. Wild-type and HCBP6-KO mice kept on a HFD were treated with ginsenosides Rh2, and HE staining and GTT were used to study the function of Rh2 in metabolism disorders. RESULTS HCBP6 is reduced in HFD-fed mice. HCBP6 deficiency increased the body weight, aggravated fatty liver and deteriorated lipid homeostasis as well as glucose homeostasis in HFD-induced mouse model of NAFLD. Moreover, HCBP6-KO mice failed to maintain body temperature upon cold challenge. Mechanistically, HCBP6 could regulate lipolysis and fatty acid oxidation via activation of AMKP in vivo. In addition, HCBP6 expression was upregulated by ginsenosides Rh2. Accordingly, ginsenosides Rh2 administrations improved HFD-induced fatty liver and glucose tolerance. CONCLUSIONS These findings indicated that HCBP6 is essential in maintaining lipid and glucose homeostasis and body temperature. HCBP6 augmented by ginsenosides Rh2 may be a promising therapeutic strategy for the treatment of metabolic disorders in NAFLD mice.
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Affiliation(s)
- Hongping Lu
- Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China; Beijing Key Laboratory of Emerging Infectious Diseases, Beijing 100015, China
| | - Xiaoxue Yuan
- Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China; Beijing Key Laboratory of Emerging Infectious Diseases, Beijing 100015, China.
| | - Yu Zhang
- Beijing Key Laboratory of Emerging Infectious Diseases, Beijing 100015, China; Department of Hepatology Division 3, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Ming Han
- Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China; Beijing Key Laboratory of Emerging Infectious Diseases, Beijing 100015, China
| | - Shunai Liu
- Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China; Beijing Key Laboratory of Emerging Infectious Diseases, Beijing 100015, China
| | - Kai Han
- Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China; Beijing Key Laboratory of Emerging Infectious Diseases, Beijing 100015, China
| | - Pu Liang
- Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China; Beijing Key Laboratory of Emerging Infectious Diseases, Beijing 100015, China
| | - Jun Cheng
- Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China; Beijing Key Laboratory of Emerging Infectious Diseases, Beijing 100015, China; Beijing Advanced Innovation Center for Big Data-Based Precision Medicine, Beihang University & Capital Medical University, Beijing 100191, China.
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24
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Gomez-Hernandez A, Lopez-Pastor AR, Rubio-Longas C, Majewski P, Beneit N, Viana-Huete V, García-Gómez G, Fernandez S, Hribal ML, Sesti G, Escribano O, Benito M. Specific knockout of p85α in brown adipose tissue induces resistance to high-fat diet-induced obesity and its metabolic complications in male mice. Mol Metab 2019; 31:1-13. [PMID: 31918912 PMCID: PMC6977168 DOI: 10.1016/j.molmet.2019.10.010] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2019] [Revised: 10/14/2019] [Accepted: 10/30/2019] [Indexed: 12/19/2022] Open
Abstract
Objective An increase in mass and/or brown adipose tissue (BAT) functionality leads to an increase in energy expenditure, which may be beneficial for the prevention and treatment of obesity. Moreover, distinct class I PI3K isoforms can participate in metabolic control as well as in systemic dysfunctions associated with obesity. In this regard, we analyzed in vivo whether the lack of p85α in BAT (BATp85αKO) could modulate the activity and insulin signaling of this tissue, thereby improving diet-induced obesity and its associated metabolic complications. Methods We generated BATp85αKO mice using Cre-LoxP technology, specifically deleting p85α in a conditional manner. To characterize this new mouse model, we used mice of 6 and 12 months of age. In addition, BATp85αKO mice were submitted to a high-fat diet (HFD) to challenge BAT functionality. Results Our results suggest that the loss of p85α in BAT improves its thermogenic functionality, high-fat diet–induced adiposity and body weight, insulin resistance, and liver steatosis. The potential mechanisms involved in the improvement of obesity include (1) increased insulin signaling and lower activation of JNK in BAT, (2) enhanced insulin receptor isoform B (IRB) expression and association with IRS-1 in BAT, (3) lower production of proinflammatory cytokines by the adipose organ, (4) increased iWAT browning, and (5) improved liver steatosis. Conclusions Our results provide new mechanisms involved in the resistance to obesity development, supporting the hypothesis that the gain of BAT activity induced by the lack of p85α has a direct impact on the prevention of diet-induced obesity and its associated metabolic complications.
The lack of p85α in brown adipose tissue confers obesity resistance. BATp85αKO mice show improved thermogenic function, fatty liver and insulin resistance. High IRB levels in BAT and iWAT browning might explain the improvement of obesity. Increase in BAT functionality has a direct impact on the prevention of obesity.
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Affiliation(s)
- Almudena Gomez-Hernandez
- Biochemistry and Molecular Biology Department, School of Pharmacy, Complutense University of Madrid, Spain; Health Research Institute of San Carlos Clinic Hospital (IdISSC), Madrid, Spain; CIBER of Diabetes and Associated Metabolic Diseases (CIBERDEM), Spain.
| | - Andrea R Lopez-Pastor
- Biochemistry and Molecular Biology Department, School of Pharmacy, Complutense University of Madrid, Spain; Health Research Institute of San Carlos Clinic Hospital (IdISSC), Madrid, Spain.
| | - Carlota Rubio-Longas
- Biochemistry and Molecular Biology Department, School of Pharmacy, Complutense University of Madrid, Spain.
| | - Patrik Majewski
- Biochemistry and Molecular Biology Department, School of Pharmacy, Complutense University of Madrid, Spain.
| | - Nuria Beneit
- Biochemistry and Molecular Biology Department, School of Pharmacy, Complutense University of Madrid, Spain; Health Research Institute of San Carlos Clinic Hospital (IdISSC), Madrid, Spain.
| | - Vanesa Viana-Huete
- Biochemistry and Molecular Biology Department, School of Pharmacy, Complutense University of Madrid, Spain; Health Research Institute of San Carlos Clinic Hospital (IdISSC), Madrid, Spain.
| | - Gema García-Gómez
- Health Research Institute of San Carlos Clinic Hospital (IdISSC), Madrid, Spain; CIBER of Diabetes and Associated Metabolic Diseases (CIBERDEM), Spain.
| | - Silvia Fernandez
- Health Research Institute of San Carlos Clinic Hospital (IdISSC), Madrid, Spain; CIBER of Diabetes and Associated Metabolic Diseases (CIBERDEM), Spain.
| | - Marta Letizia Hribal
- Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, Italy.
| | - Giorgio Sesti
- Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, Italy.
| | - Oscar Escribano
- Biochemistry and Molecular Biology Department, School of Pharmacy, Complutense University of Madrid, Spain; Health Research Institute of San Carlos Clinic Hospital (IdISSC), Madrid, Spain; CIBER of Diabetes and Associated Metabolic Diseases (CIBERDEM), Spain.
| | - Manuel Benito
- Biochemistry and Molecular Biology Department, School of Pharmacy, Complutense University of Madrid, Spain; Health Research Institute of San Carlos Clinic Hospital (IdISSC), Madrid, Spain; CIBER of Diabetes and Associated Metabolic Diseases (CIBERDEM), Spain.
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25
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Farrell G, Schattenberg JM, Leclercq I, Yeh MM, Goldin R, Teoh N, Schuppan D. Mouse Models of Nonalcoholic Steatohepatitis: Toward Optimization of Their Relevance to Human Nonalcoholic Steatohepatitis. Hepatology 2019; 69:2241-2257. [PMID: 30372785 DOI: 10.1002/hep.30333] [Citation(s) in RCA: 238] [Impact Index Per Article: 39.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2018] [Accepted: 10/23/2018] [Indexed: 12/14/2022]
Abstract
Nonalcoholic steatohepatitis (NASH) arises from a variable interplay between environmental factors and genetic determinants that cannot be completely replicated in animals. Notwithstanding, preclinical models are needed to understand NASH pathophysiology and test mechanism-based therapies. Among several mouse models of NASH, some exhibit the key pathophysiologic as well as histopathologic criteria for human NASH, whereas others may be useful to address specific questions. Models based on overnutrition with adipose restriction/inflammation and metabolic complications, particularly insulin resistance, may be most useful to investigate critical etiopathogenic factors. In-depth pathologic description is required for all models. Some models demonstrate hepatocyte ballooning, which can be confused with microvesicular steatosis, whereas demonstration of an inflammatory infiltrate and pattern of liver fibrosis compatible with human NASH is desirable in models used for pharmacologic testing. When mice with specific genetic strains or mutations that cause overeating consume a diet enriched with fat, modest amounts of cholesterol, and/or simple sugars ("Western diet"), they readily develop obesity with liver disease similar to human NASH, including significant fibrosis. Purely dietary models, such as high-fat/high-cholesterol, Western diet, and choline-deficient, amino acid-defined, are similarly promising. We share concern about using models without weight gain, adipose pathology, or insulin resistance/hyperinsulinemia and with inadequate documentation of liver pathology. NASH-related fibrosis is a key endpoint in trials of possible therapies. When studied for this purpose, NASH models should be reproducible and show steatohepatitis (ideally with ballooning) and at least focal bridging fibrosis, while metabolic factors/disordered lipid partitioning should contribute to etiopathogenesis. Because murine models are increasingly used to explore pharmacologic therapies for NASH, we propose a minimum set of requirements that investigators, drug companies, and journals should consider to optimize their translational value.
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Affiliation(s)
- Geoff Farrell
- Liver Research Group, Australian National University Medical School at the Canberra Hospital, Canberra, Australian Capital Territory, Australia
| | | | - Isabelle Leclercq
- Laboratory of Hepato-gastroenterology, Institut de Recherche Experimentale et Clinique, Université catholique de Louvain, Brussels, Belgium
| | - Matthew M Yeh
- Department of Pathology, University of Washington, Seattle, WA
| | - Robert Goldin
- Department of Histopathology, Imperial College, London, UK
| | - Narci Teoh
- Department of Gastroenterology and Hepatology, Australian National University at The Canberra Hospital, Australian Capital Territory, Australia
| | - Detlef Schuppan
- Institute of Translational Immunology and Research Center for Immunotherapy, University Medical Center, Mainz, Germany.,Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
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Abstract
White adipose tissue (WAT) dysfunction is generally thought to promote the development of alcoholic liver disease (ALD) in alcoholics by releasing free fatty acids and inflammatory mediators. This explains, at least in part, the synergistic or additive effects of alcohol and obesity on liver disease progression. In this issue of the JCI, Shen et al. establish a previously unrecognized concept that brain alcohol sensing enhances thermogenesis of brown adipose tissue (BAT) through sympathetic nerve activation. BAT functions as hepatoprotective machinery to counteract the development of ALD, implying a therapeutic potential of BAT activity modulation for the treatment of ALD.
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27
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Emerging awareness on the importance of skeletal muscle in liver diseases: time to dig deeper into mechanisms! Clin Sci (Lond) 2019; 133:465-481. [DOI: 10.1042/cs20180421] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2018] [Revised: 01/09/2019] [Accepted: 01/23/2019] [Indexed: 02/07/2023]
Abstract
Abstract
Skeletal muscle is a tissue that represents 30–40% of total body mass in healthy humans and contains up to 75% of total body proteins. It is thus the largest organ in non-obese subjects. The past few years have seen increasing awareness of the prognostic value of appreciating changes in skeletal muscle compartment in various chronic diseases. Hence, a low muscle mass, a low muscle function and muscle fatty infiltration are linked with poor outcomes in many pathological conditions. In particular, an affluent body of evidence links the severity, the complications and mortality of chronic liver disease (CLD) with skeletal muscle depletion. Yet it is still not clear whether low muscle mass is a cause, an aggravating factor, a consequence of the ongoing disease, or an epiphenomenon reflecting general alteration in the critically ill patient. The mechanisms by which the muscle compartment influences disease prognosis are still largely unknown. In addition, whether muscle alterations contribute to liver disease progression is an unanswered question. Here, we first review basic knowledge about muscle compartment to draw a conceptual framework for interpreting skeletal muscle alteration in CLD. We next describe recent literature on muscle wasting in cirrhosis and liver transplantation. We then discuss the implication of skeletal muscle compartment in non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH), focusing on plausible metabolic disruption in muscle compartment that might participate in NAFLD progression. Finally, we discuss shortcomings and challenges we need to address in the near future prior to designate the muscle compartment as a therapeutic target in CLD.
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Activation of brown adipose tissue enhances the efficacy of caloric restriction for treatment of nonalcoholic steatohepatitis. J Transl Med 2019; 99:4-16. [PMID: 30258096 DOI: 10.1038/s41374-018-0120-x] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Revised: 07/27/2018] [Accepted: 08/02/2018] [Indexed: 12/11/2022] Open
Abstract
Nonalcoholic steatohepatitis (NASH) is the form of nonalcoholic fatty liver disease that can evolve into cirrhosis. Lifestyle modifications achieving 10% weight loss reverse NASH, but there are no effective approved drug treatments. We previously identified defective adaptive thermogenesis as a factor contributing to metabolic syndrome and hepatic steatosis. We have now tested whether increasing nonshivering thermogenesis can improve preexisting NASH in mice. In high-fat diet-fed foz/foz mice with established NASH, treatment with β3AR agonist restored brown adipose tissue (BAT) function, decreased body weight, improved glucose tolerance, and reduced hepatic lipid content compared to untreated counterparts, but had no impact on liver inflammation or on nonalcoholic fatty liver disease activity score (NAS). Similarly, β3AR agonist did not alter liver pathology in other steatohepatitis models, including MCD diet-fed diabetic obese db/db mice. Caloric restriction alone alleviated the hepatic inflammatory signature in foz/foz mice. Addition of a β3AR agonist to mice subjected to caloric restriction enhanced weight loss and glucose tolerance, and improved liver steatosis, hepatocellular injury, and further reduced liver inflammation. These changes contributed to a significantly lower NAS score such as no (0/9) animals in this group fulfilled the criteria for NASH pathology compared to eight out of ten mice under caloric restriction alone. In conclusion, β3AR agonist counteracts features of the metabolic syndrome and alleviates steatosis, but does not reverse NASH. However, when coupled with weight loss therapy, BAT stimulation provides additional therapeutic advantages and reverses NASH.
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Hearn T. ALMS1 and Alström syndrome: a recessive form of metabolic, neurosensory and cardiac deficits. J Mol Med (Berl) 2018; 97:1-17. [PMID: 30421101 PMCID: PMC6327082 DOI: 10.1007/s00109-018-1714-x] [Citation(s) in RCA: 68] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2018] [Revised: 10/25/2018] [Accepted: 10/30/2018] [Indexed: 12/12/2022]
Abstract
Alström syndrome (AS) is characterised by metabolic deficits, retinal dystrophy, sensorineural hearing loss, dilated cardiomyopathy and multi-organ fibrosis. Elucidating the function of the mutated gene, ALMS1, is critical for the development of specific treatments and may uncover pathways relevant to a range of other disorders including common forms of obesity and type 2 diabetes. Interest in ALMS1 is heightened by the recent discovery of its involvement in neonatal cardiomyocyte cell cycle arrest, a process with potential relevance to regenerative medicine. ALMS1 encodes a ~ 0.5 megadalton protein that localises to the base of centrioles. Some studies have suggested a role for this protein in maintaining centriole-nucleated sensory organelles termed primary cilia, and AS is now considered to belong to the growing class of human genetic disorders linked to ciliary dysfunction (ciliopathies). However, mechanistic details are lacking, and recent studies have implicated ALMS1 in several processes including endosomal trafficking, actin organisation, maintenance of centrosome cohesion and transcription. In line with a more complex picture, multiple isoforms of the protein likely exist and non-centrosomal sites of localisation have been reported. This review outlines the evidence for both ciliary and extra-ciliary functions of ALMS1.
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Affiliation(s)
- Tom Hearn
- Institute of Life Science, Swansea University Medical School, Singleton Park, Swansea, SA2 8PP, UK.
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Lepannetier S, Gualdani R, Tempesta S, Schakman O, Seghers F, Kreis A, Yerna X, Slimi A, de Clippele M, Tajeddine N, Voets T, Bon RS, Beech DJ, Tissir F, Gailly P. Activation of TRPC1 Channel by Metabotropic Glutamate Receptor mGluR5 Modulates Synaptic Plasticity and Spatial Working Memory. Front Cell Neurosci 2018; 12:318. [PMID: 30271326 PMCID: PMC6149316 DOI: 10.3389/fncel.2018.00318] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2018] [Accepted: 08/30/2018] [Indexed: 01/10/2023] Open
Abstract
Group I metabotropic glutamate receptors, in particular mGluR5, have been implicated in various forms of synaptic plasticity that are believed to underlie declarative memory. We observed that mGluR5 specifically activated a channel containing TRPC1, an isoform of the canonical family of transient receptor potential (TRPC) channels highly expressed in CA1-3 regions of the hippocampus. TRPC1 is able to form tetrameric complexes with TRPC4 and/or TRPC5 isoforms. TRPC1/4/5 complexes have recently been involved in the efficiency of synaptic transmission in the hippocampus. We therefore used a mouse model devoid of TRPC1 expression to investigate the involvement of mGluR5-TRPC1 pathway in synaptic plasticity and memory formation. Trpc1-/- mice showed alterations in spatial working memory and fear conditioning. Activation of mGluR increased synaptic excitability in neurons from WT but not from Trpc1-/- mice. LTP triggered by a theta burst could not maintain over time in brain slices from Trpc1-/- mice. mGluR-induced LTD was also impaired in these mice. Finally, acute inhibition of TRPC1 by Pico145 on isolated neurons or on brain slices mimicked the genetic depletion of Trpc1 and inhibited mGluR-induced entry of cations and subsequent effects on synaptic plasticity, excluding developmental or compensatory mechanisms in Trpc1-/- mice. In summary, our results indicate that TRPC1 plays a role in synaptic plasticity and spatial working memory processes.
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Affiliation(s)
- Sophie Lepannetier
- Cell Physiology, Institute of Neuroscience, Université catholique de Louvain, Brussels, Belgium
| | - Roberta Gualdani
- Cell Physiology, Institute of Neuroscience, Université catholique de Louvain, Brussels, Belgium
| | - Sabrina Tempesta
- Cell Physiology, Institute of Neuroscience, Université catholique de Louvain, Brussels, Belgium
| | - Olivier Schakman
- Cell Physiology, Institute of Neuroscience, Université catholique de Louvain, Brussels, Belgium
| | - François Seghers
- Cell Physiology, Institute of Neuroscience, Université catholique de Louvain, Brussels, Belgium
| | - Anna Kreis
- Cell Physiology, Institute of Neuroscience, Université catholique de Louvain, Brussels, Belgium
| | - Xavier Yerna
- Cell Physiology, Institute of Neuroscience, Université catholique de Louvain, Brussels, Belgium
| | - Amina Slimi
- Cell Physiology, Institute of Neuroscience, Université catholique de Louvain, Brussels, Belgium
| | - Marie de Clippele
- Cell Physiology, Institute of Neuroscience, Université catholique de Louvain, Brussels, Belgium
| | - Nicolas Tajeddine
- Cell Physiology, Institute of Neuroscience, Université catholique de Louvain, Brussels, Belgium
| | - Thomas Voets
- Laboratory of Ion Channel Research (VIB-KU Leuven Center for Brain & Disease Research), Department of Cellular and Molecular Medicine, Katholieke Universiteit Leuven, KU Leuven, Leuven, Belgium
| | - Robin S Bon
- School of Medicine, Faculty of Medicine and Health, University of Leeds, Leeds, United Kingdom
| | - David J Beech
- School of Medicine, Faculty of Medicine and Health, University of Leeds, Leeds, United Kingdom
| | - Fadel Tissir
- Developmental Neurobiology Group, Institute of NeuroScience, Université catholique de Louvain, Brussels, Belgium
| | - Philippe Gailly
- Cell Physiology, Institute of Neuroscience, Université catholique de Louvain, Brussels, Belgium
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Lee SJ, Sanchez-Watts G, Krieger JP, Pignalosa A, Norell PN, Cortella A, Pettersen KG, Vrdoljak D, Hayes MR, Kanoski SE, Langhans W, Watts AG. Loss of dorsomedial hypothalamic GLP-1 signaling reduces BAT thermogenesis and increases adiposity. Mol Metab 2018; 11:33-46. [PMID: 29650350 PMCID: PMC6001878 DOI: 10.1016/j.molmet.2018.03.008] [Citation(s) in RCA: 67] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2018] [Revised: 03/09/2018] [Accepted: 03/14/2018] [Indexed: 12/15/2022] Open
Abstract
Objective Glucagon-like peptide-1 (GLP-1) neurons in the hindbrain densely innervate the dorsomedial hypothalamus (DMH), a nucleus strongly implicated in body weight regulation and the sympathetic control of brown adipose tissue (BAT) thermogenesis. Therefore, DMH GLP-1 receptors (GLP-1R) are well placed to regulate energy balance by controlling sympathetic outflow and BAT function. Methods We investigate this possibility in adult male rats by using direct administration of GLP-1 (0.5 ug) into the DMH, knocking down DMH GLP-1R mRNA with viral-mediated RNA interference, and by examining the neurochemical phenotype of GLP-1R expressing cells in the DMH using in situ hybridization. Results GLP-1 administered into the DMH increased BAT thermogenesis and hepatic triglyceride (TG) mobilization. On the other hand, Glp1r knockdown (KD) in the DMH increased body weight gain and adiposity, with a concomitant reduction in energy expenditure (EE), BAT temperature, and uncoupling protein 1 (UCP1) expression. Moreover, DMH Glp1r KD induced hepatic steatosis, increased plasma TG, and elevated liver specific de-novo lipogenesis, effects that collectively contributed to insulin resistance. Interestingly, DMH Glp1r KD increased neuropeptide Y (NPY) mRNA expression in the DMH. GLP-1R mRNA in the DMH, however, was found in GABAergic not NPY neurons, consistent with a GLP-1R-dependent inhibition of NPY neurons that is mediated by local GABAergic neurons. Finally, DMH Glp1r KD attenuated the anorexigenic effects of the GLP-1R agonist exendin-4, highlighting an important role of DMH GLP-1R signaling in GLP-1-based therapies. Conclusions Collectively, our data show that DMH GLP-1R signaling plays a key role for BAT thermogenesis and adiposity.
DMH GLP-1R stimulation acutely increases BAT thermogenesis. DMH GLP-1R mRNA knockdown decreases EE and BAT thermogenesis. DMH GLP-1R mRNA knockdown impairs lipid and glucose metabolism. Reduced DMH GLP-1R signaling blunts the anorexigenic responses to Ex-4. DMH GLP-1R signaling indirectly regulates NPY gene expression.
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Affiliation(s)
- Shin J Lee
- Physiology and Behavior Laboratory, ETH Zürich, 8603 Schwerzenbach, Switzerland.
| | - Graciela Sanchez-Watts
- Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA
| | | | - Angelica Pignalosa
- Physiology and Behavior Laboratory, ETH Zürich, 8603 Schwerzenbach, Switzerland
| | - Puck N Norell
- Physiology and Behavior Laboratory, ETH Zürich, 8603 Schwerzenbach, Switzerland
| | - Alyssa Cortella
- Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA
| | - Klaus G Pettersen
- Physiology and Behavior Laboratory, ETH Zürich, 8603 Schwerzenbach, Switzerland
| | - Dubravka Vrdoljak
- Physiology and Behavior Laboratory, ETH Zürich, 8603 Schwerzenbach, Switzerland
| | - Matthew R Hayes
- Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Scott E Kanoski
- Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA
| | - Wolfgang Langhans
- Physiology and Behavior Laboratory, ETH Zürich, 8603 Schwerzenbach, Switzerland
| | - Alan G Watts
- Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA
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Turning up the heat against metabolic syndrome and non-alcoholic fatty liver disease. Clin Sci (Lond) 2017; 131:327-328. [PMID: 28138103 DOI: 10.1042/cs20160855] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2016] [Revised: 12/20/2016] [Accepted: 12/20/2016] [Indexed: 11/17/2022]
Abstract
Brown adipose tissue (BAT), an organ specialized in the conversion of chemical energy from nutrients into heat through a process denominated as nonshivering thermogenesis, plays an important role in defence of body weight and homoeothermy in mammals. BAT nonshivering thermogenesis relies on the activity of the uncoupling protein 1 (UCP-1), a mitochondrial protein that, on demand, deviates proton gradient from ATP synthesis to heat generation. Energetically, this process is supported by BAT-elevated mitochondrial density and outstanding capacity to oxidize fatty acids and glucose. These unique features place BAT as an important determinant of whole-body energy, lipid and glucose homoeostases. In the present issue of Clinical Science, Poekes et al. have gathered supporting evidence indicating that, along with hyperphagia, impaired BAT diet-induced thermogenesis is an important factor driving the exacerbated diet-induced obesity, glucose intolerance and hepatic steatosis featured by foz/foz, a mouse strain that carries mutations in Alström syndrome protein 1 (ALMS1) gene mimicking human Alström syndrome. They also show that restoration of BAT nonshivering thermogenesis by intermittent cold exposure attenuated foz/foz mice obesity, glucose intolerance and liver steatosis. Altogether, these findings highlight the important contribution of BAT nonshivering thermogenesis to whole-body energy expenditure, lipid and glucose homoeostases and further support its potential utilization as a therapeutic strategy to treat metabolic diseases.
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