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Li Y, Kim M, Jiang L, Baron L, Faulkner LD, Olson DP, Li X, Gannot N, Li P, Rui L. SH2B1 Defends Against Energy Imbalance, Obesity, and Metabolic Disease via a Paraventricular Hypothalamus→Dorsal Raphe Nucleus Neurocircuit. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2400437. [PMID: 38885417 PMCID: PMC11336965 DOI: 10.1002/advs.202400437] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Revised: 05/01/2024] [Indexed: 06/20/2024]
Abstract
SH2B1 mutations are associated with obesity, type 2 diabetes, and metabolic dysfunction-associated steatotic liver disease (MASLD) in humans. Global deletion of Sh2b1 results in severe obesity, type 2 diabetes, and MASLD in mice. Neuron-specific restoration of SH2B1 rescues the obesity phenotype of Sh2b1-null mice, indicating that the brain is a main SH2B1 target. However, SH2B1 neurocircuits remain elusive. SH2B1-expressing neurons in the paraventricular hypothalamus (PVHSH2B1) and a PVHSH2B1→dorsal raphe nucleus (DRN) neurocircuit are identified here. PVHSH2B1 axons monosynaptically innervate DRN neurons. Optogenetic stimulation of PVHSH2B1 axonal fibers in the DRN suppresses food intake. Chronic inhibition of PVHSH2B1 neurons causes obesity. In male and female mice, either embryonic-onset or adult-onset deletion of Sh2b1 in PVH neurons causes energy imbalance, obesity, insulin resistance, glucose intolerance, and MASLD. Ablation of Sh2b1 in the DRN-projecting PVHSH2B1 subpopulation also causes energy imbalance, obesity, and metabolic disorders. Conversely, SH2B1 overexpression in either total or DRN-projecting PVHSH2B1 neurons protects against diet-induced obesity. SH2B1 binds to TrkB and enhances brain-derived neurotrophic factor (BDNF) signaling. Ablation of Sh2b1 in PVHSH2B1 neurons induces BDNF resistance in the PVH, contributing to obesity. In conclusion, these results unveil a previously unrecognized PVHSH2B1→DRN neurocircuit through which SH2B1 defends against obesity by enhancing BDNF/TrkB signaling.
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Affiliation(s)
- Yuan Li
- Department of Molecular & Integrative PhysiologyUniversity of Michigan Medical SchoolAnn ArborMI48109USA
| | - Min‐Hyun Kim
- Department of Molecular & Integrative PhysiologyUniversity of Michigan Medical SchoolAnn ArborMI48109USA
- College of Health SolutionsArizona State UniversityPhoenixAZ85004USA
| | - Lin Jiang
- Department of Molecular & Integrative PhysiologyUniversity of Michigan Medical SchoolAnn ArborMI48109USA
| | - Lorelei Baron
- Department of Molecular & Integrative PhysiologyUniversity of Michigan Medical SchoolAnn ArborMI48109USA
| | - Latrice D. Faulkner
- Department of PediatricsUniversity of Michigan Medical SchoolAnn ArborMI48109USA
| | - David P. Olson
- Department of Molecular & Integrative PhysiologyUniversity of Michigan Medical SchoolAnn ArborMI48109USA
- Department of PediatricsUniversity of Michigan Medical SchoolAnn ArborMI48109USA
- Elizabeth Weiser Caswell Diabetes InstituteUniversity of MichiganAnn ArborMI48109USA
| | - Xingyu Li
- Life Sciences InstituteUniversity of MichiganAnn ArborMI48109USA
| | - Noam Gannot
- Life Sciences InstituteUniversity of MichiganAnn ArborMI48109USA
- Department of Biologic and Materials SciencesSchool of DentistryUniversity of MichiganAnn ArborMI48109USA
| | - Peng Li
- Department of Molecular & Integrative PhysiologyUniversity of Michigan Medical SchoolAnn ArborMI48109USA
- Life Sciences InstituteUniversity of MichiganAnn ArborMI48109USA
- Department of Biologic and Materials SciencesSchool of DentistryUniversity of MichiganAnn ArborMI48109USA
| | - Liangyou Rui
- Department of Molecular & Integrative PhysiologyUniversity of Michigan Medical SchoolAnn ArborMI48109USA
- Elizabeth Weiser Caswell Diabetes InstituteUniversity of MichiganAnn ArborMI48109USA
- Division of Gastroenterology and HepatologyDepartment of Internal MedicineUniversity of Michigan Medical SchoolAnn ArborMI48109USA
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Li J, Wu N, Yang Y, Zhai X, Yuan F, Zhang F, Yu N, Li D, Wang R, Wang J, Zhang L, Shi Y, He G, Liu B. Unique genetic variants of lean nonalcoholic fatty liver disease: a retrospective cohort study. BMC Endocr Disord 2023; 23:11. [PMID: 36627697 PMCID: PMC9830772 DOI: 10.1186/s12902-022-01234-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2022] [Accepted: 11/30/2022] [Indexed: 01/12/2023] Open
Abstract
We investigated the prevalence and clinical metabolic characteristics of lean nonalcoholic fatty liver disease (NAFLD) in an elderly Chinese population and assessed the relevance of lipid markers and genetic variation. All 5,338 community subjects underwent detailed clinical and laboratory examinations and were divided into three groups: lean (Body mass index (BMI) < 23 kg/m2, n = 2,012), overweight (BMI = 23-24.9 kg/m2, n = 1,354), and obese (BMI ≥ 25 kg/m2, n = 1,972). Single nucleotide polymorphisms were selected based on those reported in previous NAFLD or obesity genome-wide association studies. The frequencies of alleles and genotypes were calculated and statistically analyzed with Pearson's χ2 tests. One-way ANCOVA was used to test the association between positive SNPs and metabolic parameters in lean NAFLD individuals. Our results showed that the C allele frequency of rs2279026, the G allele of rs2279028, the C allele of rs780093, and the C allele frequency of rs1260326 were higher in obese NAFLD than in lean NAFLD (P < 0.05). In addition, we observed an association between the CC of rs1421085, TT of rs3751812, AA of rs8050136, and AA of rs9939609 genotypes in the FTO gene and low-density lipoprotein levels (P < 0.05). In conclusion, our findings provide a unique perspective on the prevalence, genetic characteristics, and metabolic profile of NAFLD in older lean individuals in China. This is the first study to examine the association between genetic variants in the FTO, TFAP2B and GCKR genes and NAFLD in a cohort of lean individuals.
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Affiliation(s)
- Jie Li
- Shanghai Innovation Center of Traditional Chinese Medicine Health Service, School of Public Health, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Na Wu
- Shanghai Innovation Center of Traditional Chinese Medicine Health Service, School of Public Health, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Shanghai Jiao Tong University, Shanghai, China
| | - Yukun Yang
- Changhai Hospital, Naval Military Medical University, Shanghai, China
| | - Xiangyu Zhai
- Graduate School of Sport Sciences, Waseda University, Saitama, Japan
| | - Fan Yuan
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Shanghai Jiao Tong University, Shanghai, China
| | - Fengwei Zhang
- Shanghai Innovation Center of Traditional Chinese Medicine Health Service, School of Public Health, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Ning Yu
- Shanghai Innovation Center of Traditional Chinese Medicine Health Service, School of Public Health, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Dong Li
- Zhangjiang Community Health Service Center of Pudong New District, Shanghai, China
| | - Ruirui Wang
- Shanghai Innovation Center of Traditional Chinese Medicine Health Service, School of Public Health, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jianying Wang
- Shanghai Innovation Center of Traditional Chinese Medicine Health Service, School of Public Health, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Lei Zhang
- Shanghai Innovation Center of Traditional Chinese Medicine Health Service, School of Public Health, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yi Shi
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Shanghai Jiao Tong University, Shanghai, China
| | - Guang He
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Shanghai Jiao Tong University, Shanghai, China.
| | - Baocheng Liu
- Shanghai Innovation Center of Traditional Chinese Medicine Health Service, School of Public Health, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
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SH2B1 variants as potential causes of non-syndromic monogenic obesity in a Brazilian cohort. Eat Weight Disord 2022; 27:3665-3674. [PMID: 36436143 DOI: 10.1007/s40519-022-01506-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Accepted: 10/29/2022] [Indexed: 11/28/2022] Open
Abstract
PURPOSE SH2B1 gene encodes an important adaptor protein to receptor tyrosine kinases or cytokine receptors associated with Janus kinases. This gene has been associated with the structural and functional modulation of neurons and other cells, and impacts on energy and glucose homeostasis. Several studies suggested that alterations in this gene are strong candidates for the development of obesity. However, only a few studies have screened SH2B1 point variants in individuals with obesity. Therefore, the aim of this study was to investigate the prevalence of SH2B1 variants in a Brazilian cohort of patients with severe obesity and candidates to bariatric surgery. METHODS The cohort comprised 122 individuals with severe obesity, who developed this phenotype during childhood. As controls, 100 normal-weight individuals were included. The coding region of SH2B1 gene was screened by Sanger sequencing. RESULTS A total of eight variants were identified in SH2B1, of which p.(Val345Met) and p.(Arg630Gln) variants were rare and predicted as potentially pathogenic by the in the silico algorithms used in this study. The p.(Val345Met) was not found in either the control group or in publicly available databases. This variant was identified in a female patient with severe obesity, metabolic syndrome and hyperglycemia. The p.(Arg630Gln) was also absent in our control group, but it was reported in gnomAD with an extremely low frequency. This variant was observed in a female patient with morbid obesity, metabolic syndrome, hypertension and severe binge-eating disorder. CONCLUSION Our study reported for the first time two rare and potentially pathogenic variants in Brazilian patients with severe obesity. Further functional studies will be necessary to confirm and elucidate the impact of these variants on SH2B1 protein function and stability, and their impact on energetic metabolism. LEVEL OF EVIDENCE Level V, cross-sectional descriptive study.
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Souza Junior MLF, de Sousa JV, Guerreiro JF. Analysis of coding variants in the human FTO gene from the gnomAD database. PLoS One 2022; 17:e0248610. [PMID: 34990463 PMCID: PMC8735611 DOI: 10.1371/journal.pone.0248610] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Accepted: 11/25/2021] [Indexed: 11/19/2022] Open
Abstract
Single nucleotide polymorphisms (SNPs) in the first intron of the FTO gene reported in 2007 continue to be the known variants with the greatest effect on adiposity in different human populations. Coding variants in the FTO gene, on the other hand, have been little explored, although data from complete sequencing of the exomes of various populations are available in public databases and provide an excellent opportunity to investigate potential functional variants in FTO. In this context, this study aimed to track nonsynonymous variants in the exons of the FTO gene in different population groups employing the gnomAD database and analyze the potential functional impact of these variants on the FTO protein using five publicly available pathogenicity prediction programs. The findings revealed 345 rare mutations, of which 321 are missense (93%), 19 are stop gained (5.6%) and five mutations are located in the splice region (1.4%). Of these, 134 (38.8%) were classified as pathogenic, 144 (41.7%) as benign and 67 (19.5%) as unknown. The available data, however, suggest that these variants are probably not associated with BMI and obesity, but instead, with other diseases. Functional studies are, therefore, required to identify the role of these variants in disease genesis.
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Affiliation(s)
| | | | - João Farias Guerreiro
- Laboratory of Human and Medical Genetics, Institute of Biological Sciences, Federal University of Pará, Belém, PA, Brazil
- * E-mail:
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Leptin receptor-expressing neuron Sh2b1 supports sympathetic nervous system and protects against obesity and metabolic disease. Nat Commun 2020; 11:1517. [PMID: 32251290 PMCID: PMC7089966 DOI: 10.1038/s41467-020-15328-3] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2018] [Accepted: 03/03/2020] [Indexed: 01/08/2023] Open
Abstract
Leptin stimulates the sympathetic nervous system (SNS), energy expenditure, and weight loss; however, the underlying molecular mechanism remains elusive. Here, we uncover Sh2b1 in leptin receptor (LepR) neurons as a critical component of a SNS/brown adipose tissue (BAT)/thermogenesis axis. LepR neuron-specific deletion of Sh2b1 abrogates leptin-stimulated sympathetic nerve activation and impairs BAT thermogenic programs, leading to reduced core body temperature and cold intolerance. The adipose SNS degenerates progressively in mutant mice after 8 weeks of age. Adult-onset ablation of Sh2b1 in the mediobasal hypothalamus also impairs the SNS/BAT/thermogenesis axis; conversely, hypothalamic overexpression of human SH2B1 has the opposite effects. Mice with either LepR neuron-specific or adult-onset, hypothalamus-specific ablation of Sh2b1 develop obesity, insulin resistance, and liver steatosis. In contrast, hypothalamic overexpression of SH2B1 protects against high fat diet-induced obesity and metabolic syndromes. Our results unravel an unrecognized LepR neuron Sh2b1/SNS/BAT/thermogenesis axis that combats obesity and metabolic disease.
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Martin Carli JF, LeDuc CA, Zhang Y, Stratigopoulos G, Leibel RL. FTO mediates cell-autonomous effects on adipogenesis and adipocyte lipid content by regulating gene expression via 6mA DNA modifications. J Lipid Res 2018; 59:1446-1460. [PMID: 29934339 DOI: 10.1194/jlr.m085555] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2018] [Revised: 04/30/2018] [Indexed: 12/18/2022] Open
Abstract
SNPs in the first intron of α-ketoglutarate-dependent dioxygenase (FTO) convey effects on adiposity by mechanisms that remain unclear, but appear to include modulation of expression of FTO itself, as well as other genes in cisFTO expression is lower in fibroblasts and iPSC-derived neurons of individuals segregating for FTO obesity risk alleles. We employed in vitro adipogenesis models to investigate the molecular mechanisms by which Fto affects adipocyte development and function. Fto expression was upregulated during adipogenesis, and was required for the maintenance of CEBPB and Cebpd/CEBPD expression in murine and human adipocytes in vitro. Fto knockdown decreased the number of 3T3-L1 cells that differentiated into adipocytes as well as the amount of lipid per mature adipocyte. This effect on adipocyte programming was conveyed, in part, by modulation of CCAAT enhancer binding protein (C/ebp)β-regulated transcription. We found that Fto also affected Cebpd transcription by demethylating DNA N6-methyldeoxyadenosine in the Cebpd promoter. Fto is permissive for adipogenesis and promotes maintenance of lipid content in mature adipocytes by enabling C/ebpβ-driven transcription and expression of Cebpd These findings are consistent with the loss of fat mass in mice segregating for a dominant-negative Fto allele.
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Affiliation(s)
| | | | - Yiying Zhang
- Columbia University Medical Center, New York, NY 10032
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Geets E, Meuwissen MEC, Van Hul W. Clinical, molecular genetics and therapeutic aspects of syndromic obesity. Clin Genet 2018; 95:23-40. [PMID: 29700824 DOI: 10.1111/cge.13367] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2018] [Revised: 04/05/2018] [Accepted: 04/16/2018] [Indexed: 12/13/2022]
Abstract
Obesity has become a major health problem worldwide. To date, more than 25 different syndromic forms of obesity are known in which one (monogenic) or multiple (polygenic) genes are involved. This review gives an overview of these forms and focuses more in detail on 6 syndromes: Prader Willi Syndrome and Prader Willi like phenotype, Bardet Biedl Syndrome, Alström Syndrome, Wilms tumor, Aniridia, Genitourinary malformations and mental Retardation syndrome and 16p11.2 (micro)deletions. Years of research provided plenty of information on the molecular genetics of these disorders and the obesity phenotype leading to a more individualized treatment of the symptoms, however, many questions still remain unanswered. As these obesity syndromes have different signs and symptoms in common, it makes it difficult to accurately diagnose patients which may result in inappropriate treatment of the disease. Therefore, the big challenge for clinicians and scientists is to more clearly differentiate all syndromic forms of obesity to provide conclusive genetic explanations and eventually deliver accurate genetic counseling and treatment. In addition, further delineation of the (functions of the) underlying genes with the use of array- or next-generation sequencing-based technology will be helpful to unravel the mechanisms of energy metabolism in the general population.
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Affiliation(s)
- E Geets
- Department of Medical Genetics, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium
| | - M E C Meuwissen
- Department of Medical Genetics, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium
| | - W Van Hul
- Department of Medical Genetics, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium
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Giuranna J, Volckmar AL, Heinen A, Peters T, Schmidt B, Spieker A, Straub H, Grallert H, Müller TD, Antel J, Haußmann U, Klafki H, Liangyou R, Hebebrand J, Hinney A. The Effect of SH2B1 Variants on Expression of Leptin- and Insulin-Induced Pathways in Murine Hypothalamus. Obes Facts 2018; 11:93-108. [PMID: 29631267 PMCID: PMC5981666 DOI: 10.1159/000486962] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2017] [Accepted: 01/15/2018] [Indexed: 12/30/2022] Open
Abstract
OBJECTIVE We aimed to determine the effect of human SH2B1 variants on leptin and insulin signaling, major regulators of energy homeostasis, on the RNA level. METHODS We analyzed the expression of infrequent alleles of seven SH2B1 variants (Arg67Cys, Lys150Arg, Thr175Ala, Thr343Met, Thr484Ala, Ser616Pro and Pro689Leu) in response to insulin or leptin cell stimulation. Two of these were identified in own mutation screens, the others were predicted to be deleterious or to serve as controls. The variants were analyzed in a homologous system of mouse hypothalamic cells. Changes in expression of downstream genes were measured. Student’s t-test for independent samples was applied and effect sizes using Cohen’s d were calculated. RESULTS In 34 of 54 analyzed genes involved in leptin (JAK/STAT or AKT) signaling, variants nominally changed expression. The expression of three genes was considerably increased (p values ≤ 0.001: Gbp2b (67Cys; d = 25.11), Irf9 (689Leu; d = 44.65) and Isg15 (150Arg; d = 20.35)). Of 32 analyzed genes in the insulin signaling pathway, the expression of 10 genes nominally changed (p ≤ 0.05), three resulted in p values ≤ 0.01 ( Cap1 (150Arg; d = 7.48), Mapk1 (343Met; d = –6.80) and Sorbs1 (689Leu; d = 7.82)). CONCLUSION The increased expression of genes in leptin (JAK/STAT or AKT) signaling implies that the main mode of action for human SH2B1 mutations might affect leptin signaling rather than insulin signaling.
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Affiliation(s)
- Johanna Giuranna
- Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Anna-Lena Volckmar
- Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
- Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
| | - Anna Heinen
- Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Triinu Peters
- Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Börge Schmidt
- Institute for Medical Informatics, Biometry and Epidemiology (IMIBE), University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Anne Spieker
- Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Helena Straub
- Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Harald Grallert
- Institute of Epidemiology, Helmholtz-Zentrum Munich, Munich, Germany
| | - Timo D. Müller
- Institute of Diabetes and Obesity, Helmholtz-Zentrum Munich, Munich, Germany
| | - Jochen Antel
- Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Ute Haußmann
- Department of Psychiatry and Psychotherapy, Faculty of Medicine, University Hospital Essen, Essen, Germany
| | - Hans Klafki
- Department of Psychiatry and Psychotherapy, Faculty of Medicine, University Hospital Essen, Essen, Germany
- Department of Psychiatry and Psychotherapy, University Medical Center Göttingen (UMG), Georg-August-University Göttingen, Göttingen, Germany
| | - Rui Liangyou
- Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Johannes Hebebrand
- Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Anke Hinney
- Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
- *Prof. Dr. Anke Hinney, Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Essen, University of Duisburg-Essen, Wickenburgstraße 21, 45147 Essen, Germany,
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Stratigopoulos G, Burnett LC, Rausch R, Gill R, Penn DB, Skowronski AA, LeDuc CA, Lanzano AJ, Zhang P, Storm DR, Egli D, Leibel RL. Hypomorphism of Fto and Rpgrip1l causes obesity in mice. J Clin Invest 2016; 126:1897-910. [PMID: 27064284 DOI: 10.1172/jci85526] [Citation(s) in RCA: 68] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2015] [Accepted: 02/25/2016] [Indexed: 01/19/2023] Open
Abstract
Noncoding polymorphisms in the fat mass and obesity-associated (FTO) gene represent common alleles that are strongly associated with effects on food intake and adiposity in humans. Previous studies have suggested that the obesity-risk allele rs8050136 in the first intron of FTO alters a regulatory element recognized by the transcription factor CUX1, thereby leading to decreased expression of FTO and retinitis pigmentosa GTPase regulator-interacting protein-1 like (RPGRIP1L). Here, we evaluated the effects of rs8050136 and another potential CUX1 element in rs1421085 on expression of nearby genes in human induced pluripotent stem cell-derived (iPSC-derived) neurons. There were allele-dosage effects on FTO, RPGRIP1L, and AKT-interacting protein (AKTIP) expression, but expression of other vicinal genes, including IRX3, IRX5, and RBL2, which have been implicated in mediating functional effects, was not altered. In vivo manipulation of CUX1, Fto, and/or Rpgrip1l expression in mice affected adiposity in a manner that was consistent with CUX1 influence on adiposity via remote effects on Fto and Rpgrip1l expression. In support of a mechanism, mice hypomorphic for Rpgrip1l exhibited hyperphagic obesity, as the result of diminished leptin sensitivity in Leprb-expressing neurons. Together, the results of this study indicate that the effects of FTO-associated SNPs on energy homeostasis are due in part to the effects of these genetic variations on hypothalamic FTO, RPGRIP1L, and possibly other genes.
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Analysis of Genes Involved in Body Weight Regulation by Targeted Re-Sequencing. PLoS One 2016; 11:e0147904. [PMID: 26828654 PMCID: PMC4734691 DOI: 10.1371/journal.pone.0147904] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2015] [Accepted: 01/11/2016] [Indexed: 12/16/2022] Open
Abstract
Introduction Genes involved in body weight regulation that were previously investigated in genome-wide association studies (GWAS) and in animal models were target-enriched followed by massive parallel next generation sequencing. Methods We enriched and re-sequenced continuous genomic regions comprising FTO, MC4R, TMEM18, SDCCAG8, TKNS, MSRA and TBC1D1 in a screening sample of 196 extremely obese children and adolescents with age and sex specific body mass index (BMI) ≥ 99th percentile and 176 lean adults (BMI ≤ 15th percentile). 22 variants were confirmed by Sanger sequencing. Genotyping was performed in up to 705 independent obesity trios (extremely obese child and both parents), 243 extremely obese cases and 261 lean adults. Results and Conclusion We detected 20 different non-synonymous variants, one frame shift and one nonsense mutation in the 7 continuous genomic regions in study groups of different weight extremes. For SNP Arg695Cys (rs58983546) in TBC1D1 we detected nominal association with obesity (pTDT = 0.03 in 705 trios). Eleven of the variants were rare, thus were only detected heterozygously in up to ten individual(s) of the complete screening sample of 372 individuals. Two of them (in FTO and MSRA) were found in lean individuals, nine in extremely obese. In silico analyses of the 11 variants did not reveal functional implications for the mutations. Concordant with our hypothesis we detected a rare variant that potentially leads to loss of FTO function in a lean individual. For TBC1D1, in contrary to our hypothesis, the loss of function variant (Arg443Stop) was found in an obese individual. Functional in vitro studies are warranted.
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A patient with a novel homozygous missense mutation in FTO and concomitant nonsense mutation in CETP. J Hum Genet 2016; 61:395-403. [PMID: 26740239 PMCID: PMC4880488 DOI: 10.1038/jhg.2015.160] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2015] [Revised: 11/30/2015] [Accepted: 11/30/2015] [Indexed: 12/19/2022]
Abstract
The fat mass and obesity associated gene (FTO) has previously been associated with a variety of diseases and conditions, notably obesity, acute coronary syndrome and metabolic syndrome. Reports describing mutations in FTO as well as FTO animal models have further demonstrated a role for FTO in the development of the brain and other organs. Here, we describe a patient born of consanguineous union who presented with microcephaly, developmental delay, behavioral abnormalities, dysmorphic facial features, hypotonia, and other various phenotypic abnormalities. Whole exome sequencing revealed a novel homozygous missense mutation in FTO and a nonsense mutation in the cholesteryl ester transfer protein (CETP). Exome CNV analysis revealed no disease causing large duplications or deletions within coding regions. Patient’s, her parents’ and non-related control’ fibroblasts were analyzed for morphologic defects, abnormal proliferation, apoptosis and transcriptome profile. We have shown that FTO is located in nucleus of cells from each tested samples. Western blot analysis demonstrated no changes in patient FTO. Q-PCR analysis revealed slightly decreased levels of FTO expression in patient cells compared to controls. No morphological or proliferation differences between the patient and control fibroblasts were observed. There is still much to be learned about the molecular mechanisms by which mutations in FTO contribute to such severe phenotypes.
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Daoud H, Zhang D, McMurray F, Yu A, Luco SM, Vanstone J, Jarinova O, Carson N, Wickens J, Shishodia S, Choi H, McDonough MA, Schofield CJ, Harper ME, Dyment DA, Armour CM. Identification of a pathogenicFTOmutation by next-generation sequencing in a newborn with growth retardation and developmental delay. J Med Genet 2015; 53:200-7. [DOI: 10.1136/jmedgenet-2015-103399] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2015] [Accepted: 08/28/2015] [Indexed: 11/04/2022]
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Fine Mapping of a GWAS-Derived Obesity Candidate Region on Chromosome 16p11.2. PLoS One 2015; 10:e0125660. [PMID: 25955518 PMCID: PMC4425372 DOI: 10.1371/journal.pone.0125660] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2014] [Accepted: 03/17/2015] [Indexed: 11/19/2022] Open
Abstract
INTRODUCTION Large-scale genome-wide association studies (GWASs) have identified 97 chromosomal loci associated with increased body mass index in population-based studies on adults. One of these SNPs, rs7359397, tags a large region (approx. 1MB) with high linkage disequilibrium (r2>0.7), which comprises five genes (SH2B1, APOBR, sulfotransferases: SULT1A1 and SULT1A2, TUFM). We had previously described a rare mutation in SH2B1 solely identified in extremely obese individuals but not in lean controls. METHODS The coding regions of the genes APOBR, SULT1A1, SULT1A2, and TUFM were screened for mutations (dHPLC, SSCP, Sanger re-sequencing) in 95 extremely obese children and adolescents. Detected non-synonymous variants were genotyped (TaqMan SNP Genotyping, MALDI TOF, PCR-RFLP) in independent large study groups (up to 3,210 extremely obese/overweight cases, 485 lean controls and 615 obesity trios). In silico tools were used for the prediction of potential functional effects of detected variants. RESULTS Except for TUFM we detected non-synonymous variants in all screened genes. Two polymorphisms rs180743 (APOBR p.Pro428Ala) and rs3833080 (APOBR p.Gly369_Asp370del9) showed nominal association to (extreme) obesity (uncorrected p = 0.003 and p = 0.002, respectively). In silico analyses predicted a functional implication for rs180743 (APOBR p.Pro428Ala). Both APOBR variants are located in the repetitive region with unknown function. CONCLUSION Variants in APOBR contributed as strongly as variants in SH2B1 to the association with extreme obesity in the chromosomal region chr16p11.2. In silico analyses implied no functional effect of several of the detected variants. Further in vitro or in vivo analyses on the functional implications of the obesity associated variants are warranted.
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Abstract
The fat mass and obesity-associated (FTO) gene was placed center stage when common intronic variants within the gene were robustly associated with human obesity. Murine models of perturbed Fto expression have shown effects on body weight and composition. However, a clear understanding of the link between FTO intronic variants and FTO activity has remained elusive. Two recent reports now indicate that obesity-associated SNPs appear functionally connected not with FTO but with two neighboring genes: IRX3 and RPGRIP1L. Here, we review these new findings and consider the implications for future analysis of GWAS hits.
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Affiliation(s)
- Y C Loraine Tung
- Medical Research Council Metabolic Diseases Unit, University of Cambridge Metabolic Research Laboratories, Level 4, Wellcome Trust-MRC Institute of Metabolic Science, Box 289, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK
| | - Giles S H Yeo
- Medical Research Council Metabolic Diseases Unit, University of Cambridge Metabolic Research Laboratories, Level 4, Wellcome Trust-MRC Institute of Metabolic Science, Box 289, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK
| | - Stephen O'Rahilly
- Medical Research Council Metabolic Diseases Unit, University of Cambridge Metabolic Research Laboratories, Level 4, Wellcome Trust-MRC Institute of Metabolic Science, Box 289, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK
| | - Anthony P Coll
- Medical Research Council Metabolic Diseases Unit, University of Cambridge Metabolic Research Laboratories, Level 4, Wellcome Trust-MRC Institute of Metabolic Science, Box 289, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
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Rui L. SH2B1 regulation of energy balance, body weight, and glucose metabolism. World J Diabetes 2014; 5:511-526. [PMID: 25126397 PMCID: PMC4127586 DOI: 10.4239/wjd.v5.i4.511] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2013] [Revised: 03/06/2014] [Accepted: 06/03/2014] [Indexed: 02/05/2023] Open
Abstract
The Src homology 2B (SH2B) family members (SH2B1, SH2B2 and SH2B3) are adaptor signaling proteins containing characteristic SH2 and PH domains. SH2B1 (also called SH2-B and PSM) and SH2B2 (also called APS) are able to form homo- or hetero-dimers via their N-terminal dimerization domains. Their C-terminal SH2 domains bind to tyrosyl phosphorylated proteins, including Janus kinase 2 (JAK2), TrkA, insulin receptors, insulin-like growth factor-1 receptors, insulin receptor substrate-1 (IRS1), and IRS2. SH2B1 enhances leptin signaling by both stimulating JAK2 activity and assembling a JAK2/IRS1/2 signaling complex. SH2B1 promotes insulin signaling by both enhancing insulin receptor catalytic activity and protecting against dephosphorylation of IRS proteins. Accordingly, genetic deletion of SH2B1 results in severe leptin resistance, insulin resistance, hyperphagia, obesity, and type 2 diabetes in mice. Neuron-specific overexpression of SH2B1β transgenes protects against diet-induced obesity and insulin resistance. SH2B1 in pancreatic β cells promotes β cell expansion and insulin secretion to counteract insulin resistance in obesity. Moreover, numerous SH2B1 mutations are genetically linked to leptin resistance, insulin resistance, obesity, and type 2 diabetes in humans. Unlike SH2B1, SH2B2 and SH2B3 are not required for the maintenance of normal energy and glucose homeostasis. The metabolic function of the SH2B family is conserved from insects to humans.
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Coto E, Tavira B, Gómez J, Tranche S, Corte CD. Effect of the FTO rs9930506 Polymorphism on the Main Comorbidities of the Cardiorenal Metabolic Syndrome in an Elderly Spanish Cohort. Cardiorenal Med 2014; 4:82-7. [PMID: 25254029 PMCID: PMC4164085 DOI: 10.1159/000361054] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2013] [Accepted: 03/03/2014] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND/AIM Fat mass and obesity-associated (FTO) gene polymorphisms have been linked to the risk of obesity and diabetes, two well-recognized risk factors for renal disease. Our aim was to determine whether a common FTO polymorphism was associated with a reduced estimated glomerular filtration rate (eGFR) independently of body mass index (BMI) and type 2 diabetes mellitus (T2DM) in a cohort of elderly individuals from the region of Asturias (Northern Spain; RENASTUR cohort). METHODS A total of 544 Spanish Caucasians aged 55-85 years were genotyped for the FTO rs9930506 single-nucleotide polymorphism (SNP). Individuals with a previous diagnosis of renal disease were not eligible for the study. The eGFR was calculated with the Modification of Diet in Renal Disease formula, and individuals with an eGFR of <60 ml/min/1.73 m(2) (n = 91) were considered as having impaired renal function. The effect of alleles and genotypes on BMI, hypertension, diabetes, eGFR and blood lipid values was statistically determined. RESULTS The rs9930506 GG genotype was significantly more common in the group with a BMI of >25 (p = 0.03; odds ratio = 2.43; 95% CI: 1.09-5.43). Age and T2DM were significant risk factors for a reduced eGFR, but neither obesity nor the FTO genotypes were associated with a reduced eGFR. CONCLUSION The common FTO rs9930506 polymorphism was a risk factor for overweight and obesity in the RENASTUR cohort. However, this SNP was not associated with other comorbidities of the cardiorenal metabolic syndrome in this population.
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Affiliation(s)
- Eliecer Coto
- Genética Molecular-Laboratorio Medicina-Fundación Renal (IRSIN-FRIAT), Oviedo, Spain
- Departamento de Medicina, Universidad Oviedo, Oviedo, Spain
| | - Beatriz Tavira
- Genética Molecular-Laboratorio Medicina-Fundación Renal (IRSIN-FRIAT), Oviedo, Spain
| | - Juan Gómez
- Genética Molecular-Laboratorio Medicina-Fundación Renal (IRSIN-FRIAT), Oviedo, Spain
| | | | - Carmen Díaz Corte
- Nefrología, Hospital Universitario Central de Asturias, Oviedo, Spain
- Departamento de Medicina, Universidad Oviedo, Oviedo, Spain
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Abstract
Single nucleotide polymorphisms (SNPs) that cluster in the first intron of fat mass and obesity associated (FTO) gene are associated obesity traits in genome-wide association studies. The minor allele increases BMI by 0.39 kg/m(2) (or 1,130 g in body weight) and risk of obesity by 1.20-fold. This association has been confirmed across age groups and populations of diverse ancestry; the largest effect is seen in young adulthood. The effect of FTO SNPs on obesity traits in populations of African and Asian ancestry is similar or somewhat smaller than in European ancestry populations. However, the BMI-increasing allele in FTO is substantially less prevalent in populations with non-European ancestry. FTO SNPs do not influence physical activity levels; yet, in physically active individuals, FTO's effect on obesity susceptibility is attenuated by approximately 30%. Evidence from epidemiological and functional studies suggests that FTO confers an increased risk of obesity by subtly changing food intake and preference. Moreover, emerging data suggest a role for FTO in nutrient sensing, regulation of mRNA translation and general growth. In this Review, we discuss the genetic epidemiology of FTO and discuss how its complex biology might link to the regulation of body weight.
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Affiliation(s)
- Ruth J F Loos
- The Genetics of Obesity and Related Metabolic Traits Program, The Charles Bronfman Institute for Personalized Medicine, The Mindich Child Health and Development Institute, The Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1003, New York, NY 10029-6574, USA
| | - Giles S H Yeo
- MRC Metabolic Diseases Unit, University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Box 289, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK
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