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Horikoshi N, Miyake R, Sogawa-Fujiwara C, Ogasawara M, Takizawa Y, Kurumizaka H. Cryo-EM structures of the BAF-Lamin A/C complex bound to nucleosomes. Nat Commun 2025; 16:1495. [PMID: 39929866 PMCID: PMC11811190 DOI: 10.1038/s41467-025-56823-9] [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: 10/03/2024] [Accepted: 01/31/2025] [Indexed: 02/13/2025] Open
Abstract
Barrier-to-autointegration factor (BAF) associates with mitotic chromosomes and promotes nuclear envelope assembly by recruiting proteins, such as Lamins, required for the reconstruction of the nuclear envelope and lamina. BAF also mediates chromatin anchoring to the nuclear lamina via Lamin A/C. However, the mechanism by which BAF and Lamin A/C bind chromatin and affect the chromatin organization remains elusive. Here we report the cryo-electron microscopy structures of BAF-Lamin A/C-nucleosome complexes. We find that the BAF dimer complexed with the Lamin A/C IgF domain occupies the nucleosomal dyad position, forming a tripartite nucleosomal DNA binding structure. We also show that the Lamin A/C Lys486 and His506 residues, which are reportedly mutated in lipodystrophy patients, directly contact the DNA at the nucleosomal dyad. Excess BAF-Lamin A/C complexes symmetrically bind other nucleosomal DNA sites and connect two BAF-Lamin A/C-nucleosome complexes. Although the linker histone H1 competes with BAF-Lamin A/C binding at the nucleosomal dyad region, the two BAF-Lamin A/C molecules still bridge two nucleosomes. These findings provide insights into the mechanism by which BAF, Lamin A/C, and/or histone H1 bind nucleosomes and influence chromatin organization within the nucleus.
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Affiliation(s)
- Naoki Horikoshi
- Laboratory of Chromatin Structure and Function, Institute for Quantitative Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, Japan
- Department of Cell Biology and Anatomy, Graduate School of Medicine, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, Japan
| | - Ryosuke Miyake
- Laboratory of Chromatin Structure and Function, Institute for Quantitative Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, Japan
- Department of Biological Sciences, Graduate School of Science, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, Japan
| | - Chizuru Sogawa-Fujiwara
- Laboratory of Chromatin Structure and Function, Institute for Quantitative Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, Japan
| | - Mitsuo Ogasawara
- Laboratory of Chromatin Structure and Function, Institute for Quantitative Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, Japan
| | - Yoshimasa Takizawa
- Laboratory of Chromatin Structure and Function, Institute for Quantitative Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, Japan
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, Japan
| | - Hitoshi Kurumizaka
- Laboratory of Chromatin Structure and Function, Institute for Quantitative Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, Japan.
- Department of Biological Sciences, Graduate School of Science, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, Japan.
- Laboratory for Transcription Structural Biology, RIKEN Center for Biosystems Dynamics Research, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Japan.
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Santos JL, Miranda JP, Lagos CF, Cortés VA. Case Report: Concurrent de novo pathogenic variants in the LMNA gene as a cause of sporadic partial lipodystrophy. Front Genet 2024; 15:1468878. [PMID: 39669119 PMCID: PMC11634843 DOI: 10.3389/fgene.2024.1468878] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Accepted: 11/07/2024] [Indexed: 12/14/2024] Open
Abstract
Introduction Inherited lipodystrophies are a group of rare diseases defined by severe reduction in adipose tissue mass and classified as generalized or partial. We report a non-familial (sporadic) case of partial lipodystrophy caused by a novel genetic mechanism involving closely linked de novo pathogenic variants in the LMNA gene. Methods A female adult with partial lipodystrophy and her parents were evaluated for gene variants across the exome under different mendelian inheritance models (autosomal dominant, recessive, compound heterozygous, and X-linked) to find pathogenic variants. Body composition was assessed via dual-energy X-ray absorptiometry (DXA). Results The patient showed absence of adipose tissue in the limbs; preservation of adiposity in the face, neck, and trunk; muscular hypertrophy, hypertriglyceridemia and insulin resistance. DXA revealed a fat mass of 15.4%, with android-to-gynoid ratio, trunk/limb, and trunk/leg ratios exceeding the published upper limits of 90% reference intervals. Two heterozygous missense de novo pathogenic variants in cis within the LMNA gene were found in the proband: p.Y481H and p.K486N (NP_733821.1). These variants have functional effects and were reported in inherited Emery-Dreifuss muscular dystrophy 2 (p.Y481H) and familial partial lipodystrophy type 2 (p.K486N). Molecular modeling analyses provided additional insights into the protein instability conferred by these variants in the lamin A/C Ig-like domain. Conclusion In a case of sporadic partial lipodystrophy, we describe two concurrent de novo pathogenic variants within the same gene (LMNA) as a novel pathogenic mechanism. This finding expands the genetic and phenotypic spectrum of partial lipodystrophy and laminopathy syndromes.
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Affiliation(s)
- José L. Santos
- Department of Nutrition, Diabetes and Metabolism, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
- Department of Health Sciences, Institute for Sustainability and Food Chain Innovation (IS-FOOD), Public University of Navarre, Pamplona, Spain
| | - José Patricio Miranda
- Department of Nutrition, Diabetes and Metabolism, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
- Bupa Lab, Part of Bupa Chile, Santiago, Chile
| | - Carlos F. Lagos
- Chemical Biology and Drug Discovery Laboratory, Escuela de Química y Farmacia, Facultad de Medicina y Ciencia, Universidad San Sebastián, Santiago, Chile
- Centro Ciencia and Vida, Fundación Ciencia and Vida, Santiago, Chile
| | - Víctor A. Cortés
- Department of Nutrition, Diabetes and Metabolism, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
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Bauer R, Parker C, Gorsic LK, Hayes MG, Kunselman AR, Legro RS, Welt CK, Urbanek M. Rare variation in LMNA underlies polycystic ovary syndrome (PCOS) pathogenesis in two independent cohorts. J Clin Endocrinol Metab 2024:dgae761. [PMID: 39484826 DOI: 10.1210/clinem/dgae761] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Revised: 10/09/2024] [Accepted: 10/29/2024] [Indexed: 11/03/2024]
Abstract
CONTEXT Polycystic ovary syndrome (PCOS) is a common, heritable endocrinopathy that is a common cause of anovulatory infertility in reproductive age women. Variants in LMNA cause partial lipodystrophy, a syndrome with overlapping features to PCOS. OBJECTIVE We tested the hypothesis that rare variation in LMNA contributes to PCOS pathogenesis and selects a lipodystrophy-like subtype of PCOS. DESIGN, SETTING, AND PARTICIPANTS We sequenced LMNA by targeted sequencing a discovery cohort of 811 PCOS patients and 164 healthy controls. We then analyzed LMNA from whole-exome sequencing (WES) of a replication cohort of 718 PCOS patients and 281 healthy controls. MAIN OUTCOME MEASURES Variation in the LMNA gene, hormone and lipid profiles of participants. RESULTS In the discovery cohort, we identified 8 missense variants in 15/811 cases, and 1 variant in 1/172 reproductively healthy controls. There is strong evidence for association between the variants and PCOS compared to gnomAD non-Finnish European population controls (χ2=17, p=3.7x10-5, OR=2.9). In the replication cohort, we identified 11 unique variants in 15/718 cases, and 1 variant in 281 reproductively healthy controls. Again, there is strong evidence for association with population controls (χ2=30.5, p=3.4x10-8, OR= 4.0). In both the discovery and replication cohorts, variants in LMNA identify women with PCOS with high triglycerides and extreme insulin resistance. CONCLUSIONS Rare missense variation in LMNA is reproducibly associated with PCOS and identifies some individuals with lipodystrophy-like features. The overlap between this PCOS phenotype and genetic partial lipodystrophy syndromes warrants further investigation into additional lipodystrophy genes and their potential in PCOS etiology.
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Affiliation(s)
- Rosemary Bauer
- Division of Endocrinology, Metabolism, and Molecular Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611
- Center for Reproductive Science, Northwestern University, Chicago IL 60611
| | - Chloe Parker
- Division of Endocrinology, Metabolism, and Molecular Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611
| | - Lidija K Gorsic
- Division of Endocrinology, Metabolism, and Molecular Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611
| | - M Geoffrey Hayes
- Division of Endocrinology, Metabolism, and Molecular Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611
- Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611
- Department of Anthropology, Northwestern University, Evanston, IL 60208
| | - Allen R Kunselman
- Public Health Sciences, Penn State College of Medicine, Hershey, PA 17033
| | - Richard S Legro
- Department of Obstetrics and Gynecology, Penn State College of Medicine, Hershey, PA 17033
| | - Corrine K Welt
- Division of Endocrinology, Metabolism, and Diabetes, University of Utah, Salt Lake City, Utah 84132
| | - Margrit Urbanek
- Division of Endocrinology, Metabolism, and Molecular Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611
- Center for Reproductive Science, Northwestern University, Chicago IL 60611
- Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611
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Wang X, Ma L, Lu D, Zhao G, Ren H, Lin Q, Jia M, Huang F, Wang S, Xu Z, Yang Z, Chu Y, Xu Z, Li W, Yu L, Jiang Q, Zhang C. Nuclear envelope budding inhibition slows down progerin-induced aging process. Proc Natl Acad Sci U S A 2024; 121:e2321378121. [PMID: 39352925 PMCID: PMC11474064 DOI: 10.1073/pnas.2321378121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Accepted: 08/08/2024] [Indexed: 10/04/2024] Open
Abstract
Progerin causes Hutchinson-Gilford progeria syndrome (HGPS), but how progerin accelerates aging is still an interesting question. Here, we provide evidence linking nuclear envelope (NE) budding and accelerated aging. Mechanistically, progerin disrupts nuclear lamina to induce NE budding in concert with lamin A/C, resulting in transport of chromatin into the cytoplasm where it is removed via autophagy, whereas emerin antagonizes this process. Primary cells from both HGPS patients and mouse models express progerin and display NE budding and chromatin loss, and ectopically expressing progerin in cells can mimic this process. More excitingly, we screen a NE budding inhibitor chaetocin by high-throughput screening, which can dramatically sequester progerin from the NE and prevent this NE budding through sustaining ERK1/2 activation. Chaetocin alleviates NE budding-induced chromatin loss and ameliorates HGPS defects in cells and mice and significantly extends lifespan of HGPS mice. Collectively, we propose that progerin-induced NE budding participates in the induction of progeria, highlight the roles of chaetocin and sustained ERK1/2 activation in anti-aging, and provide a distinct avenue for treating HGPS.
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Affiliation(s)
- Xiangyang Wang
- The Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, College of Life Sciences, Peking University, Beijing100871, China
- The Academy for Cell and Life Health, Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming650500, China
| | - Lin Ma
- Department of Dermatology, Beijing Children’s Hospital, Capital Medical University, National Center for Children's Health, Beijing100045, China
| | - Di Lu
- The State Key Laboratory of Membrane Biology, Tsinghua University-Peking University Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing100084, China
| | - Gan Zhao
- The Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, College of Life Sciences, Peking University, Beijing100871, China
| | - He Ren
- The Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, College of Life Sciences, Peking University, Beijing100871, China
| | - Qiaoyu Lin
- The Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, College of Life Sciences, Peking University, Beijing100871, China
| | - Mingkang Jia
- The Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, College of Life Sciences, Peking University, Beijing100871, China
| | - Fan Huang
- The Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, College of Life Sciences, Peking University, Beijing100871, China
| | - Shan Wang
- Department of Dermatology, Beijing Children’s Hospital, Capital Medical University, National Center for Children's Health, Beijing100045, China
| | - Zhe Xu
- Department of Dermatology, Beijing Children’s Hospital, Capital Medical University, National Center for Children's Health, Beijing100045, China
| | - Zhou Yang
- Department of Dermatology, Beijing Children’s Hospital, Capital Medical University, National Center for Children's Health, Beijing100045, China
| | - Yan Chu
- Department of Dermatology, Beijing Children’s Hospital, Capital Medical University, National Center for Children's Health, Beijing100045, China
| | - Zigang Xu
- Department of Dermatology, Beijing Children’s Hospital, Capital Medical University, National Center for Children's Health, Beijing100045, China
| | - Wei Li
- Genetics and Birth Defects Control Center, Beijing Children’s Hospital, Capital Medical University, National Center for Children's Health, Beijing100045, China
| | - Li Yu
- The State Key Laboratory of Membrane Biology, Tsinghua University-Peking University Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing100084, China
| | - Qing Jiang
- The Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, College of Life Sciences, Peking University, Beijing100871, China
| | - Chuanmao Zhang
- The Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, College of Life Sciences, Peking University, Beijing100871, China
- The Academy for Cell and Life Health, Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming650500, China
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Agrawal S, Luan J, Cummings BB, Weiss EJ, Wareham NJ, Khera AV. Relationship of Fat Mass Ratio, a Biomarker for Lipodystrophy, With Cardiometabolic Traits. Diabetes 2024; 73:1099-1111. [PMID: 38345889 PMCID: PMC11189835 DOI: 10.2337/db23-0575] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2023] [Accepted: 02/06/2024] [Indexed: 06/22/2024]
Abstract
Familial partial lipodystrophy (FPLD) is a heterogenous group of syndromes associated with a high prevalence of cardiometabolic diseases. Prior work has proposed DEXA-derived fat mass ratio (FMR), defined as trunk fat percentage divided by leg fat percentage, as a biomarker of FPLD, but this metric has not previously been characterized in large cohort studies. We set out to 1) understand the cardiometabolic burden of individuals with high FMR in up to 40,796 participants in the UK Biobank and 9,408 participants in the Fenland study, 2) characterize the common variant genetic underpinnings of FMR, and 3) build and test a polygenic predictor for FMR. Participants with high FMR were at higher risk for type 2 diabetes (odds ratio [OR] 2.30, P = 3.5 × 10-41) and metabolic dysfunction-associated liver disease or steatohepatitis (OR 2.55, P = 4.9 × 10-7) in UK Biobank and had higher fasting insulin (difference 19.8 pmol/L, P = 5.7 × 10-36) and fasting triglycerides (difference 36.1 mg/dL, P = 2.5 × 10-28) in the Fenland study. Across FMR and its component traits, 61 conditionally independent variant-trait pairs were discovered, including 13 newly identified pairs. A polygenic score for FMR was associated with an increased risk of cardiometabolic diseases. This work establishes the cardiometabolic significance of high FMR, a biomarker for FPLD, in two large cohort studies and may prove useful in increasing diagnosis rates of patients with metabolically unhealthy fat distribution to enable treatment or a preventive therapy. ARTICLE HIGHLIGHTS
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Affiliation(s)
- Saaket Agrawal
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA
- Department of Medicine, Massachusetts General Hospital, Boston, MA
- Department of Medicine, Harvard Medical School, Boston, MA
| | - Jian’an Luan
- MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge Biomedical Campus, Cambridge, U.K
| | | | | | - Nick J. Wareham
- MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge Biomedical Campus, Cambridge, U.K
| | - Amit V. Khera
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA
- Department of Medicine, Harvard Medical School, Boston, MA
- Division of Cardiology, Department of Medicine, Brigham and Women’s Hospital, Boston, MA
- Verve Therapeutics, Boston, MA
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Morguetti MJ, Neves PDMDM, Korkes I, Padilha WSC, Jorge LB, Watanabe A, Watanabe EH, Malheiros DMAC, Noronha IDL, Dib SA, Onuchic LF, Moisés RS. Podocytopathies associated with familial partial lipodystrophy due to LMNA variants: report of two cases. ARCHIVES OF ENDOCRINOLOGY AND METABOLISM 2024; 68:e230204. [PMID: 38739524 PMCID: PMC11156176 DOI: 10.20945/2359-4292-2023-0204] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Accepted: 11/29/2023] [Indexed: 05/16/2024]
Abstract
Lipodystrophies are characterized by complete or selective loss of adipose tissue and can be acquired or inherited. Familial partial lipodystrophy (FPLD) is a hereditary lipodystrophy commonly caused by mutations in the LMNA gene. Herein, we report two cases of FPLD associated with podocytopathies. Patient 1 was diagnosed with FPLD associated with the heterozygous p.Arg482Trp variant in LMNA and had normal glucose tolerance and hyperinsulinemia. During follow-up, she developed nephroticrange proteinuria. Renal biopsy was consistent with minimal change disease. Patient 2 was diagnosed with FPLD associated with a de novo heterozygous p.Arg349Trp variant in LMNA. Microalbuminuria progressed to macroalbuminuria within 6 years and tonephrotic range proteinuria in the last year. He remained without diabetes and with hyperinsulinemia. Renal biopsy revealed focal segmental glomerulosclerosis not otherwise specified. This report provides further evidence of variable features of lipodystrophy associated with LMNA variants and the importance of long-term follow-up with evaluation of kidney dysfunction.
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Affiliation(s)
- Maria Julia Morguetti
- Divisão de Endocrinologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP, Brasil
| | | | - Ilana Korkes
- Divisão de Endocrinologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP, Brasil
| | | | - Lectícia Barbosa Jorge
- Divisão de Nefrologia, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brasil
| | - Andreia Watanabe
- Divisões de Nefrologia Pediátrica e Medicina Molecular, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brasil
| | - Elieser Hitoshi Watanabe
- Divisões de Nefrologia e Medicina Molecular, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brasil
| | | | | | - Sergio Atala Dib
- Divisão de Endocrinologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP, Brasil
| | - Luiz Fernando Onuchic
- Departamento de Clínica Médica, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brasil
| | - Regina S Moisés
- Divisão de Endocrinologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP, Brasil,
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Mosbah H, Vatier C, Andriss B, Belalem I, Delemer B, Janmaat S, Jéru I, Le Collen L, Maiter D, Nobécourt E, Vantyghem MC, Vigouroux C, Dumas A. Patients' perspective on the medical pathway from first symptoms to diagnosis in genetic lipodystrophy. Eur J Endocrinol 2024; 190:23-33. [PMID: 38128113 DOI: 10.1093/ejendo/lvad169] [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: 09/21/2023] [Revised: 11/03/2023] [Accepted: 11/21/2023] [Indexed: 12/23/2023]
Abstract
OBJECTIVE Underdiagnosis is an important issue in genetic lipodystrophies, which are rare diseases with metabolic, cardiovascular, gynecological, and psychological complications. We aimed to characterize the diagnostic pathway in these diseases from the patients' perspective. DESIGN Cross-sectional study conducted through a self-reported patient questionnaire. METHODS Patients with genetic lipodystrophy were recruited throughout the French national reference network for rare diseases of insulin secretion and insulin sensitivity. Patients completed a self-reported questionnaire on disease symptoms, steps leading to the diagnosis, and healthcare professionals involved. Descriptive analyses were conducted. RESULTS Out of 175 eligible patients, 109 patients (84% women) were included; 93 had partial familial lipodystrophy and 16 congenital generalized lipodystrophy. Metabolic comorbidities (diabetes 68%, hypertriglyceridemia 66%, hepatic steatosis 57%), cardiovascular (hypertension 54%), and gynecologic complications (irregular menstruation 60%) were frequently reported. Median age at diagnosis was 30 years (interquartile range [IQR] 23-47). The overall diagnostic process was perceived as "very difficult" for many patients. It extended over 12 years (IQR 5-25) with more than five different physicians consulted by 36% of respondents, before diagnosis, for lipodystrophy-related symptoms. The endocrinologist made the diagnosis for 77% of the patients. Changes in morphotype were reported as the first symptoms by the majority of respondents. CONCLUSIONS Diagnostic pathway in patients with genetic lipodystrophy is rendered difficult by the multisystemic features of the disease and the lack of knowledge of non-specialized physicians. Training physicians to systematically include adipose tissue examination in routine clinical evaluation should improve diagnosis and management of lipodystrophy and lipodystrophy-associated comorbidities.
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Affiliation(s)
- Héléna Mosbah
- ECEVE UMR 1123, INSERM, Université Paris Cité, 75014 Paris, France
- Service Endocrinologie, Diabétologie, Nutrition, CHU La Milétrie, 86000 Poitiers, France
- Hôpital Saint-Antoine, Centre de Référence des Maladies Rares de l'Insulino-Sécrétion et de l'Insulino-Sensibilité (PRISIS), Service d'Endocrinologie, Assistance Publique-Hôpitaux de Paris (AP-HP), 75012 Paris, France
| | - Camille Vatier
- Hôpital Saint-Antoine, Centre de Référence des Maladies Rares de l'Insulino-Sécrétion et de l'Insulino-Sensibilité (PRISIS), Service d'Endocrinologie, Assistance Publique-Hôpitaux de Paris (AP-HP), 75012 Paris, France
- Inserm U938, Centre de Recherche Saint-Antoine et Institut de Cardio-Métabolisme et Nutrition (ICAN), Sorbonne Université, 75012 Paris, France
| | - Béatrice Andriss
- Unité d'Epidémiologie Clinique, APHP, Hôpital Universitaire Robert Debré, 75019 Paris, France
| | - Inès Belalem
- Hôpital Saint-Antoine, Centre de Référence des Maladies Rares de l'Insulino-Sécrétion et de l'Insulino-Sensibilité (PRISIS), Service d'Endocrinologie, Assistance Publique-Hôpitaux de Paris (AP-HP), 75012 Paris, France
| | - Brigitte Delemer
- Service d'endocrinologie diabète nutrition, CHU de Reims, Hôpital Robert-Debré, 51100 Reims, France
| | - Sonja Janmaat
- Hôpital Saint-Antoine, Centre de Référence des Maladies Rares de l'Insulino-Sécrétion et de l'Insulino-Sensibilité (PRISIS), Service d'Endocrinologie, Assistance Publique-Hôpitaux de Paris (AP-HP), 75012 Paris, France
- Inserm U938, Centre de Recherche Saint-Antoine et Institut de Cardio-Métabolisme et Nutrition (ICAN), Sorbonne Université, 75012 Paris, France
| | - Isabelle Jéru
- Inserm U938, Centre de Recherche Saint-Antoine et Institut de Cardio-Métabolisme et Nutrition (ICAN), Sorbonne Université, 75012 Paris, France
- Département de Génétique Médicale, DMU BioGeM, Hôpital Pitié-Salpêtrière, AP-HP, 75013 Paris, France
| | - Lauriane Le Collen
- Inserm/CNRS UMR 1283/8199, Institut Pasteur, EGID, Université Lille, 59000 Lille, France
- Service d'endocrinologie diabète nutrition, CHU de Reims, Hôpital Robert-Debré, 51100 Reims, France
- Service de Génétique clinique, Centre hospitalier de Reims, 51100 Reims, France
| | - Dominique Maiter
- Service d'Endocrinologie et Nutrition, Institut de Recherche Expérimentale et Clinique IREC, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, B-1348 Brussels, Belgique
| | - Estelle Nobécourt
- Service d'endocrinologie Diabétologie, Centre Hospitalier Universitaire Sud Réunion, 97410 Saint Pierre, France
| | - Marie-Christine Vantyghem
- Endocrinologie, diabétologie et métabolisme, CHU Lille, 59000 Lille, France
- Inserm U1190, Université Lille, Institut Pasteur, 59000 Lille, France
| | - Corinne Vigouroux
- Hôpital Saint-Antoine, Centre de Référence des Maladies Rares de l'Insulino-Sécrétion et de l'Insulino-Sensibilité (PRISIS), Service d'Endocrinologie, Assistance Publique-Hôpitaux de Paris (AP-HP), 75012 Paris, France
- Inserm U938, Centre de Recherche Saint-Antoine et Institut de Cardio-Métabolisme et Nutrition (ICAN), Sorbonne Université, 75012 Paris, France
| | - Agnes Dumas
- ECEVE UMR 1123, INSERM, Université Paris Cité, 75014 Paris, France
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Gagnon E, Paulin A, Mitchell PL, Arsenault BJ. Disentangling the impact of gluteofemoral versus visceral fat accumulation on cardiometabolic health using sex-stratified Mendelian randomization. Atherosclerosis 2023; 386:117371. [PMID: 38029505 DOI: 10.1016/j.atherosclerosis.2023.117371] [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: 06/19/2023] [Revised: 10/24/2023] [Accepted: 10/31/2023] [Indexed: 12/01/2023]
Abstract
BACKGROUND AND AIMS Individuals with a higher abdominal adipose tissue accumulation are at higher risk of developing cardiometabolic diseases. For a given body mass index (BMI), women typically present lower abdominal adipose tissue accumulation compared to men. Whether abdominal adiposity is a causal driver of cardiometabolic risk, or a mere marker of ectopic fat deposition is debated. METHODS We investigated the sex-specific and sex-combined impact of height and BMI-adjusted gluteofemoral adipose tissue (GFATadj) adjusted abdominal subcutaneous adipose tissue (ASATadj) and adjusted visceral adipose tissue (VATadj) on cardiometabolic traits and diseases using Mendelian randomization. RESULTS Leveraging genome-wide summary statistics on GFATadj, ASATadj and VATadj from 39,076 UK Biobank participants with full-body magnetic resonance imaging available, we found that GFATadj is associated with a more favourable cardiometabolic risk profile including lower low density lipoprotein (LDL) cholesterol, triglycerides, fasting glucose, fasting insulin, liver enzyme levels and blood pressure as well as higher high density lipoprotein (HDL) cholesterol levels. GFATadj also is negatively associated with ischemic stroke, coronary artery disease, type 2 diabetes, and non-alcoholic fatty liver disease (NAFLD). ASATadj is not associated with cardiometabolic traits and diseases, whereas VATadj is associated with liver fat accumulation but not with NAFLD or other cardiometabolic traits or diseases. Although the absolute effect sizes of GFATadj on LDL cholesterol were more pronounced in women compared to men, most associations did not differ by sex. CONCLUSIONS The inability of subcutaneous fat depots to efficiently store energy substrates could be the causal factor underlying the association of visceral lipid deposition with cardiometabolic health.
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Affiliation(s)
- Eloi Gagnon
- Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec, Québec, QC, Canada
| | - Audrey Paulin
- Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec, Québec, QC, Canada
| | - Patricia L Mitchell
- Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec, Québec, QC, Canada
| | - Benoit J Arsenault
- Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec, Québec, QC, Canada; Department of Medicine, Faculty of Medicine, Université Laval, Québec, QC, Canada.
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9
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Schena E, Mattioli E, Peres C, Zanotti L, Morselli P, Iozzo P, Guzzardi MA, Bernardini C, Forni M, Nesci S, Caprio M, Cecchetti C, Pagotto U, Gabusi E, Cattini L, Lisignoli G, Blalock W, Gambineri A, Lattanzi G. Mineralocorticoid Receptor Antagonism Prevents Type 2 Familial Partial Lipodystrophy Brown Adipocyte Dysfunction. Cells 2023; 12:2586. [PMID: 37998321 PMCID: PMC10670260 DOI: 10.3390/cells12222586] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Revised: 10/29/2023] [Accepted: 11/02/2023] [Indexed: 11/25/2023] Open
Abstract
Type-2 Familial Partial Lipodystrophy (FPLD2), a rare lipodystrophy caused by LMNA mutations, is characterized by a loss of subcutaneous fat from the trunk and limbs and excess accumulation of adipose tissue in the neck and face. Several studies have reported that the mineralocorticoid receptor (MR) plays an essential role in adipose tissue differentiation and functionality. We previously showed that brown preadipocytes isolated from a FPLD2 patient's neck aberrantly differentiate towards the white lineage. As this condition may be related to MR activation, we suspected altered MR dynamics in FPLD2. Despite cytoplasmic MR localization in control brown adipocytes, retention of MR was observed in FPLD2 brown adipocyte nuclei. Moreover, overexpression of wild-type or mutated prelamin A caused GFP-MR recruitment to the nuclear envelope in HEK293 cells, while drug-induced prelamin A co-localized with endogenous MR in human preadipocytes. Based on in silico analysis and in situ protein ligation assays, we could suggest an interaction between prelamin A and MR, which appears to be inhibited by mineralocorticoid receptor antagonism. Importantly, the MR antagonist spironolactone redirected FPLD2 preadipocyte differentiation towards the brown lineage, avoiding the formation of enlarged and dysmorphic lipid droplets. Finally, beneficial effects on brown adipose tissue activity were observed in an FPLD2 patient undergoing spironolactone treatment. These findings identify MR as a new lamin A interactor and a new player in lamin A-linked lipodystrophies.
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Affiliation(s)
- Elisa Schena
- Unit of Bologna, CNR—National Research Council of Italy, Institute of Molecular Genetics “Luigi Luca Cavalli-Sforza”, 40136 Bologna, Italy; (E.S.); (E.M.); (C.P.); (W.B.)
- IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy
| | - Elisabetta Mattioli
- Unit of Bologna, CNR—National Research Council of Italy, Institute of Molecular Genetics “Luigi Luca Cavalli-Sforza”, 40136 Bologna, Italy; (E.S.); (E.M.); (C.P.); (W.B.)
- IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy
| | - Chiara Peres
- Unit of Bologna, CNR—National Research Council of Italy, Institute of Molecular Genetics “Luigi Luca Cavalli-Sforza”, 40136 Bologna, Italy; (E.S.); (E.M.); (C.P.); (W.B.)
- IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy
| | - Laura Zanotti
- Unit of Gynecology and Obstetrics, Division of Endocrinology and Diabetes Prevention and Care, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (L.Z.); (C.C.); (U.P.); (A.G.)
- Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum University of Bologna, 40126 Bologna, Italy;
| | - Paolo Morselli
- Plastic Surgery Unit, Department of Specialised, Experimental and Diagnostic Medicine, Alma Mater Studiorum University of Bologna, S. Orsola-Malpighi Hospital, 40126 Bologna, Italy;
| | - Patricia Iozzo
- CNR—National Research Council of Italy, Institute of Clinical Physiology, 56124 Pisa, Italy; (P.I.); (M.A.G.)
| | - Maria Angela Guzzardi
- CNR—National Research Council of Italy, Institute of Clinical Physiology, 56124 Pisa, Italy; (P.I.); (M.A.G.)
| | - Chiara Bernardini
- Department of Veterinary Medical Sciences, University of Bologna, 40064 Ozzano Emilia, Italy; (C.B.); (S.N.)
| | - Monica Forni
- Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum University of Bologna, 40126 Bologna, Italy;
| | - Salvatore Nesci
- Department of Veterinary Medical Sciences, University of Bologna, 40064 Ozzano Emilia, Italy; (C.B.); (S.N.)
| | - Massimiliano Caprio
- Laboratory of Cardiovascular Endocrinology, IRCCS San Raffaele, 00163 Rome, Italy;
- Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Roma Open University, 00166 Rome, Italy
| | - Carolina Cecchetti
- Unit of Gynecology and Obstetrics, Division of Endocrinology and Diabetes Prevention and Care, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (L.Z.); (C.C.); (U.P.); (A.G.)
- Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum University of Bologna, 40126 Bologna, Italy;
| | - Uberto Pagotto
- Unit of Gynecology and Obstetrics, Division of Endocrinology and Diabetes Prevention and Care, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (L.Z.); (C.C.); (U.P.); (A.G.)
- Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum University of Bologna, 40126 Bologna, Italy;
| | - Elena Gabusi
- SC Laboratorio di Immunoreumatologia e Rigenerazione Tissutale, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy; (E.G.); (L.C.); (G.L.)
| | - Luca Cattini
- SC Laboratorio di Immunoreumatologia e Rigenerazione Tissutale, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy; (E.G.); (L.C.); (G.L.)
| | - Gina Lisignoli
- SC Laboratorio di Immunoreumatologia e Rigenerazione Tissutale, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy; (E.G.); (L.C.); (G.L.)
| | - William Blalock
- Unit of Bologna, CNR—National Research Council of Italy, Institute of Molecular Genetics “Luigi Luca Cavalli-Sforza”, 40136 Bologna, Italy; (E.S.); (E.M.); (C.P.); (W.B.)
- IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy
| | - Alessandra Gambineri
- Unit of Gynecology and Obstetrics, Division of Endocrinology and Diabetes Prevention and Care, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (L.Z.); (C.C.); (U.P.); (A.G.)
- Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum University of Bologna, 40126 Bologna, Italy;
| | - Giovanna Lattanzi
- Unit of Bologna, CNR—National Research Council of Italy, Institute of Molecular Genetics “Luigi Luca Cavalli-Sforza”, 40136 Bologna, Italy; (E.S.); (E.M.); (C.P.); (W.B.)
- IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy
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10
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Upadhyay KK, Du X, Chen Y, Buscher B, Chen VL, Oliveri A, Zhao R, Speliotes EK, Brady GF. A common variant that alters SUN1 degradation associates with hepatic steatosis and metabolic traits in multiple cohorts. J Hepatol 2023; 79:1226-1235. [PMID: 37567366 PMCID: PMC10618955 DOI: 10.1016/j.jhep.2023.07.036] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Revised: 07/03/2023] [Accepted: 07/13/2023] [Indexed: 08/13/2023]
Abstract
BACKGROUND & AIMS Non-alcoholic fatty liver disease (NAFLD), and its progressive form steatohepatitis (NASH), represent a genetically and phenotypically diverse entity for which there is no approved therapy, making it imperative to define the spectrum of pathways contributing to its pathogenesis. Rare variants in genes encoding nuclear envelope proteins cause lipodystrophy with early-onset NAFLD/NASH; we hypothesized that common variants in nuclear envelope-related genes might also contribute to hepatic steatosis and NAFLD. METHODS Using hepatic steatosis as the outcome of interest, we performed an association meta-analysis of nuclear envelope-related coding variants in three large discovery cohorts (N >120,000 participants), followed by phenotype association studies in large validation cohorts (N >600,000) and functional testing of the top steatosis-associated variant in cell culture. RESULTS A common protein-coding variant, rs6461378 (SUN1 H118Y), was the top steatosis-associated variant in our association meta-analysis (p <0.001). In ancestrally distinct validation cohorts, rs6461378 associated with histologic NAFLD and with NAFLD-related metabolic traits including increased serum fatty acids, type 2 diabetes, hypertension, cardiovascular disease, and decreased HDL. SUN1 H118Y was subject to increased proteasomal degradation relative to wild-type SUN1 in cells, and SUN1 H118Y-expressing cells exhibited insulin resistance and increased lipid accumulation. CONCLUSIONS Collectively, these data support a potential causal role for the common SUN1 variant rs6461378 in NAFLD and metabolic disease. IMPACT AND IMPLICATIONS Non-alcoholic fatty liver disease (NAFLD), with an estimated global prevalence of nearly 30%, is a growing cause of morbidity and mortality for which there is no approved pharmacologic therapy. Our data provide a rationale for broadening current concepts of NAFLD genetics and pathophysiology to include the nuclear envelope, and particularly Sad1 and UNC84 domain containing 1 (SUN1), as novel contributors to this common liver disease. Furthermore, if future studies confirm causality of the common SUN1 H118Y variant, it has the potential to become a broadly relevant therapeutic target in NAFLD and metabolic disease.
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Affiliation(s)
- Kapil K Upadhyay
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Ann Arbor, Michigan, USA
| | - Xiaomeng Du
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Ann Arbor, Michigan, USA
| | - Yanhua Chen
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Ann Arbor, Michigan, USA
| | - Brandon Buscher
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Ann Arbor, Michigan, USA
| | - Vincent L Chen
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Ann Arbor, Michigan, USA
| | - Antonino Oliveri
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Ann Arbor, Michigan, USA
| | - Raymond Zhao
- University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Elizabeth K Speliotes
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Ann Arbor, Michigan, USA; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA
| | - Graham F Brady
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Ann Arbor, Michigan, USA.
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11
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Semple RK, Patel KA, Auh S, Brown RJ. Genotype-stratified treatment for monogenic insulin resistance: a systematic review. COMMUNICATIONS MEDICINE 2023; 3:134. [PMID: 37794082 PMCID: PMC10550936 DOI: 10.1038/s43856-023-00368-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Accepted: 09/20/2023] [Indexed: 10/06/2023] Open
Abstract
BACKGROUND Monogenic insulin resistance (IR) includes lipodystrophy and disorders of insulin signalling. We sought to assess the effects of interventions in monogenic IR, stratified by genetic aetiology. METHODS Systematic review using PubMed, MEDLINE and Embase (1 January 1987 to 23 June 2021). Studies reporting individual-level effects of pharmacologic and/or surgical interventions in monogenic IR were eligible. Individual data were extracted and duplicates were removed. Outcomes were analysed for each gene and intervention, and in aggregate for partial, generalised and all lipodystrophy. RESULTS 10 non-randomised experimental studies, 8 case series, and 23 case reports meet inclusion criteria, all rated as having moderate or serious risk of bias. Metreleptin use is associated with the lowering of triglycerides and haemoglobin A1c (HbA1c) in all lipodystrophy (n = 111), partial (n = 71) and generalised lipodystrophy (n = 41), and in LMNA, PPARG, AGPAT2 or BSCL2 subgroups (n = 72,13,21 and 21 respectively). Body Mass Index (BMI) is lowered in partial and generalised lipodystrophy, and in LMNA or BSCL2, but not PPARG or AGPAT2 subgroups. Thiazolidinediones are associated with improved HbA1c and triglycerides in all lipodystrophy (n = 13), improved HbA1c in PPARG (n = 5), and improved triglycerides in LMNA (n = 7). In INSR-related IR, rhIGF-1, alone or with IGFBP3, is associated with improved HbA1c (n = 17). The small size or absence of other genotype-treatment combinations preclude firm conclusions. CONCLUSIONS The evidence guiding genotype-specific treatment of monogenic IR is of low to very low quality. Metreleptin and Thiazolidinediones appear to improve metabolic markers in lipodystrophy, and rhIGF-1 appears to lower HbA1c in INSR-related IR. For other interventions, there is insufficient evidence to assess efficacy and risks in aggregated lipodystrophy or genetic subgroups.
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Affiliation(s)
- Robert K Semple
- Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
| | - Kashyap A Patel
- Department of Clinical and Biomedical Sciences, University of Exeter Medical School, Exeter, UK
- Department of Diabetes and Endocrinology, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK
| | - Sungyoung Auh
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Rebecca J Brown
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
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12
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Moreira MLM, de Araújo IM, Fukada SY, Venturini LGR, Guidorizzi NR, Garrido CE, Rosen CJ, de Paula FJA. Refining Evaluation of Bone Mass and Adipose Distribution in Dunnigan Syndrome. Int J Mol Sci 2023; 24:13118. [PMID: 37685926 PMCID: PMC10488191 DOI: 10.3390/ijms241713118] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2023] [Revised: 08/14/2023] [Accepted: 08/18/2023] [Indexed: 09/10/2023] Open
Abstract
Familial partial lipodystrophies (FPLD) are rare diseases characterized by selective loss of subcutaneous adipose tissue at different sites. This cross-sectional observational study aimed to estimate adipose tissue in the bone marrow (BMAT), intra (IMCL) and extra-myocyte lipids (EMCL), and define the bone phenotype in the context of FPLD2/Dunnigan syndrome (DS). The subjects comprised 23 controls (C) and 18 DS patients, matched by age, weight and height. Blood samples, dual-energy X-ray absorptiometry for bone mineral density (BMD) and trabecular bone score (TBS) and 1H-spectroscopy using magnetic resonance to estimate BMAT in the lumbar spine, IMCL, EMCL and osteoclastogenesis were assessed. The prevalence of diabetes mellitus was 78% in DS patients. Glucose, HbA1c, triglycerides, insulin and HOMA-IR levels were elevated in DS, whereas HDLc, 25(OH)D, PTH and osteocalcin levels were reduced. BMD was similar between groups at all sites, except 1/3 radius, which was lower in DS group. TBS was reduced in DS. DS presented increased osteoclastogenesis and elevated BMAT, with greater saturation levels and higher IMCL than the C group. HOMA-IR and EMCL were negatively associated with TBS; osteocalcin and EMCL were correlated negatively with BMD. This study contributes to refining the estimation of adipose tissue in DS by showing increased adiposity in the lumbar spine and muscle tissue. DXA detected lower TBS and BMD in the 1/3 radius, suggesting impairment in bone quality and that bone mass is mainly affected in the cortical bone.
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Affiliation(s)
- Mariana Lima Mascarenhas Moreira
- Department of Internal Medicine, Ribeirão Preto Medical School, University of Sao Paulo, Ribeirao Preto 14049-900, SP, Brazil; (M.L.M.M.); (I.M.d.A.); (N.R.G.)
| | - Iana Mizumukai de Araújo
- Department of Internal Medicine, Ribeirão Preto Medical School, University of Sao Paulo, Ribeirao Preto 14049-900, SP, Brazil; (M.L.M.M.); (I.M.d.A.); (N.R.G.)
| | - Sandra Yasuyo Fukada
- Department of Biomolecular Sciences, School of Pharmaceutical Sciences of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto 14040-900, SP, Brazil; (S.Y.F.); (L.G.R.V.)
| | - Lucas Gabriel R. Venturini
- Department of Biomolecular Sciences, School of Pharmaceutical Sciences of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto 14040-900, SP, Brazil; (S.Y.F.); (L.G.R.V.)
| | - Natalia Rossin Guidorizzi
- Department of Internal Medicine, Ribeirão Preto Medical School, University of Sao Paulo, Ribeirao Preto 14049-900, SP, Brazil; (M.L.M.M.); (I.M.d.A.); (N.R.G.)
| | - Carlos Ernesto Garrido
- Department of Physics, Faculty of Philosophy, Sciences and Letters of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto 14049-900, SP, Brazil;
| | | | - Francisco José Albuquerque de Paula
- Department of Internal Medicine, Ribeirão Preto Medical School, University of Sao Paulo, Ribeirao Preto 14049-900, SP, Brazil; (M.L.M.M.); (I.M.d.A.); (N.R.G.)
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13
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Upadhyay KK, Choi EYK, Foisner R, Omary MB, Brady GF. Hepatocyte-specific loss of LAP2α protects against diet-induced hepatic steatosis, steatohepatitis, and fibrosis in male mice. Am J Physiol Gastrointest Liver Physiol 2023; 325:G184-G195. [PMID: 37366543 PMCID: PMC10396226 DOI: 10.1152/ajpgi.00214.2022] [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: 09/02/2022] [Revised: 05/24/2023] [Accepted: 06/18/2023] [Indexed: 06/28/2023]
Abstract
There is increasing evidence for the importance of the nuclear envelope in lipid metabolism, nonalcoholic fatty liver disease (NAFLD), and nonalcoholic steatohepatitis (NASH). Human mutations in LMNA, encoding A-type nuclear lamins, cause early-onset insulin resistance and NASH, while hepatocyte-specific deletion of Lmna predisposes to NASH with fibrosis in male mice. Given that variants in the gene encoding LAP2α, a nuclear protein that regulates lamin A/C, were previously identified in patients with NAFLD, we sought to determine the role of LAP2α in NAFLD using a mouse genetic model. Hepatocyte-specific Lap2α-knockout (Lap2α(ΔHep)) mice and littermate controls were fed normal chow or high-fat diet (HFD) for 8 wk or 6 mo. Unexpectedly, male Lap2α(ΔHep) mice showed no increase in hepatic steatosis or NASH compared with controls. Rather, Lap2α(ΔHep) mice demonstrated reduced hepatic steatosis, with decreased NASH and fibrosis after long-term HFD. Accordingly, pro-steatotic genes including Cidea, Mogat1, and Cd36 were downregulated in Lap2α(ΔHep) mice, along with concomitant decreases in expression of pro-inflammatory and pro-fibrotic genes. These data indicate that hepatocyte-specific Lap2α deletion protects against hepatic steatosis and NASH in mice and raise the possibility that LAP2α could become a potential therapeutic target in human NASH.NEW & NOTEWORTHY The nuclear envelope and lamina regulate lipid metabolism and susceptibility to nonalcoholic steatohepatitis (NASH), but the role of the nuclear lamin-binding protein LAP2α in NASH has not been explored. Our data demonstrate that hepatocyte-specific loss of LAP2α protects against diet-induced hepatic steatosis, NASH, and fibrosis in male mice, with downregulation of pro-steatotic, pro-inflammatory, and pro-fibrotic lamin-regulated genes. These findings suggest that targeting LAP2α could have future potential as a novel therapeutic avenue in NASH.
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Affiliation(s)
- Kapil K Upadhyay
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States
| | - Eun-Young K Choi
- Department of Pathology, University of Michigan, Ann Arbor, Michigan, United States
| | - Roland Foisner
- Max Perutz Labs, Medical University of Vienna, Vienna Biocenter Campus, Vienna, Austria
| | - M Bishr Omary
- Robert Wood Johnson Medical School and the Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, New Jersey, United States
| | - Graham F Brady
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States
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14
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Pande S, Ghosh DK. Nuclear proteostasis imbalance in laminopathy-associated premature aging diseases. FASEB J 2023; 37:e23116. [PMID: 37498235 DOI: 10.1096/fj.202300878r] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Revised: 06/15/2023] [Accepted: 07/13/2023] [Indexed: 07/28/2023]
Abstract
Laminopathies are a group of rare genetic disorders with heterogeneous clinical phenotypes such as premature aging, cardiomyopathy, lipodystrophy, muscular dystrophy, microcephaly, epilepsy, and so on. The cellular phenomena associated with laminopathy invariably show disruption of nucleoskeleton of lamina due to deregulated expression, localization, function, and interaction of mutant lamin proteins. Impaired spatial and temporal tethering of lamin proteins to the lamina or nucleoplasmic aggregation of lamins are the primary molecular events that can trigger nuclear proteotoxicity by modulating differential protein-protein interactions, sequestering quality control proteins, and initiating a cascade of abnormal post-translational modifications. Clearly, laminopathic cells exhibit moderate to high nuclear proteotoxicity, raising the question of whether an imbalance in nuclear proteostasis is involved in laminopathic diseases, particularly in diseases of early aging such as HGPS and laminopathy-associated premature aging. Here, we review nuclear proteostasis and its deregulation in the context of lamin proteins and laminopathies.
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Affiliation(s)
- Shruti Pande
- Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
| | - Debasish Kumar Ghosh
- Enteric Disease Division, Department of Microbiology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
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15
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Semple RK, Patel KA, Auh S, Brown RJ. Systematic review of genotype-stratified treatment for monogenic insulin resistance. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2023:2023.04.17.23288671. [PMID: 37205502 PMCID: PMC10187355 DOI: 10.1101/2023.04.17.23288671] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/21/2023]
Abstract
Objective To assess the effects of pharmacologic and/or surgical interventions in monogenic insulin resistance (IR), stratified by genetic aetiology. Design Systematic review. Data sources PubMed, MEDLINE and Embase, from 1 January 1987 to 23 June 2021. Review methods Studies reporting individual-level effects of pharmacologic and/or surgical interventions in monogenic IR were eligible. Individual subject data were extracted and duplicate data removed. Outcomes were analyzed for each affected gene and intervention, and in aggregate for partial, generalised and all lipodystrophy. Results 10 non-randomised experimental studies, 8 case series, and 21 single case reports met inclusion criteria, all rated as having moderate or serious risk of bias. Metreleptin was associated with lower triglycerides and hemoglobin A1c in aggregated lipodystrophy (n=111), in partial lipodystrophy (n=71) and generalised lipodystrophy (n=41)), and in LMNA , PPARG , AGPAT2 or BSCL2 subgroups (n=72,13,21 and 21 respectively). Body Mass Index (BMI) was lower after treatment in partial and generalised lipodystrophy overall, and in LMNA or BSCL2 , but not PPARG or AGPAT2 subgroups. Thiazolidinedione use was associated with improved hemoglobin A1c and triglycerides in aggregated lipodystrophy (n=13), improved hemoglobin A1c only in the PPARG subgroup (n=5), and improved triglycerides only in the LMNA subgroup (n=7). In INSR -related IR, use of rhIGF-1, alone or with IGFBP3, was associated with improved hemoglobin A1c (n=15). The small size or absence of all other genotype-treatment combinations precluded firm conclusions. Conclusions The evidence guiding genotype-specific treatment of monogenic IR is of low to very low quality. Metreleptin and Thiazolidinediones appear to have beneficial metabolic effects in lipodystrophy, and rhIGF-1 appears to lower hemoglobin A1c in INSR-related IR. For other interventions there is insufficient evidence to assess efficacy and risks either in aggregated lipodystrophy or in genetic subgroups. There is a pressing need to improve the evidence base for management of monogenic IR.
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Affiliation(s)
- 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
| | - Kashyap A. Patel
- Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK
- Department of Diabetes and Endocrinology, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK
| | - Sungyoung Auh
- Office of the Clinical Director, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - ADA/EASD PMDI
- American Diabetes Association/European Association for the Study of Diabetes Precision Medicine in Diabetes Initiative
| | - Rebecca J. Brown
- National Institute of Diabetes and Digestive and Kidney Diseases. National Institutes of Health. Bethesda, MD, USA
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Treiber G, Guilleux A, Huynh K, Bonfanti O, Flaus-Furmaniuk A, Couret D, Mellet N, Bernard C, Le-Moullec N, Doray B, Jéru I, Maiza JC, Domun B, Cogne M, Meilhac O, Vigouroux C, Meikle PJ, Nobécourt E. Lipoatrophic diabetes in familial partial lipodystrophy type 2: From insulin resistance to diabetes. DIABETES & METABOLISM 2023; 49:101409. [PMID: 36400409 DOI: 10.1016/j.diabet.2022.101409] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Revised: 10/31/2022] [Accepted: 11/02/2022] [Indexed: 11/17/2022]
Abstract
AIM Subjects with Familial Partial Lipodystrophy type 2 (FPLD2) are at high risk to develop diabetes. To better understand the natural history and variability of this disease, we studied glucose tolerance, insulin response to an oral glucose load, and metabolic markers in the largest cohort to date of subjects with FPLD2 due to the same LMNA variant. METHODS A total of 102 patients aged > 18 years, with FPLD2 due to the LMNA 'Reunionese' variant p.(Thr655Asnfs*49) and 22 unaffected adult relatives with normal glucose tolerance (NGT) were enrolled. Oral Glucose Tolerance Tests (OGTT) with calculation of derived insulin sensitivity and secretion markers, and measurements of HbA1c, C-reactive protein, leptin, adiponectin and lipid profile were performed. RESULTS In patients with FPLD2: 65% had either diabetes (41%) or prediabetes (24%) despite their young age (median: 39.5 years IQR 29.0-50.8) and close-to-normal BMI (median: 25.5 kg/m2 IQR 23.1-29.4). Post-load OGTT values revealed insulin resistance and increased insulin secretion in patients with FPLD2 and NGT, whereas patients with diabetes were characterized by decreased insulin secretion. Impaired glucose tolerance with normal fasting glucose was present in 86% of patients with prediabetes. Adiponectin levels were decreased in all subjects with FPLD2 and correlated with insulin sensitivity markers. CONCLUSIONS OGTT reveals early alterations of glucose and insulin metabolism in patients with FPLD2, and should be systematically performed before excluding a diagnosis of prediabetes or diabetes to adapt medical care. Decreased adiponectin is an early marker of the disease. Adiponectin replacement therapy warrants further study in FPLD2.
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Affiliation(s)
- Guillaume Treiber
- Department of Endocrinology, Diabetes and Nutrition, GHSR, Centre Hospitalo-Universitaire de la Réunion, Saint-Pierre, La Réunion, France; University of La Réunion, INSERM, UMR 1188 Diabète Athérothrombose Thérapies Réunion Océan Indien (DéTROI), Plateforme CYROI, Saint-Denis de, La Réunion, France
| | - Alice Guilleux
- Centre d'Investigation Clinique - Epidémiologie Clinique (CIC-EC) U1410 INSERM, Centre Hospitalo-Universitaire de la Réunion, La Réunion, France
| | - Kevin Huynh
- Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
| | - Oriane Bonfanti
- Department of Endocrinology, Diabetes and Nutrition, GHSR, Centre Hospitalo-Universitaire de la Réunion, Saint-Pierre, La Réunion, France
| | - Ania Flaus-Furmaniuk
- Department of Endocrinology, Diabetes and Nutrition, Felix-Guyon, Centre Hospitalo-Universitaire de la Réunion, Saint-Denis, La Réunion, France
| | - David Couret
- University of La Réunion, INSERM, UMR 1188 Diabète Athérothrombose Thérapies Réunion Océan Indien (DéTROI), Plateforme CYROI, Saint-Denis de, La Réunion, France; Neurocritical Care Unit, Centre Hospitalo-Universitaire de la Réunion, University of La Réunion, BP 350, Saint Pierre, 97448, la Réunion, France
| | - Natalie Mellet
- Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
| | - Céline Bernard
- Department of Endocrinology, Diabetes and Nutrition, GHSR, Centre Hospitalo-Universitaire de la Réunion, Saint-Pierre, La Réunion, France
| | - Nathalie Le-Moullec
- Department of Endocrinology, Diabetes and Nutrition, GHSR, Centre Hospitalo-Universitaire de la Réunion, Saint-Pierre, La Réunion, France
| | - Berenice Doray
- Genetic Department, Felix-Guyon, Centre Hospitalo-Universitaire de la Réunion, Saint-Denis, La Réunion, France
| | - Isabelle Jéru
- Sorbonne Université, Inserm UMR S938, Saint-Antoine Research Centre, Institute of Cardiometabolism and Nutrition, AP-HP, Pitié-Salpêtrière Hospital, Department of Medical Genetics, DMU BioGeM, Paris, France
| | - Jean-Christophe Maiza
- Department of Endocrinology, Diabetes and Nutrition, GHSR, Centre Hospitalo-Universitaire de la Réunion, Saint-Pierre, La Réunion, France
| | - Bhoopendrasing Domun
- Department of Endocrinology, Diabetes and Nutrition, GHSR, Centre Hospitalo-Universitaire de la Réunion, Saint-Pierre, La Réunion, France
| | - Muriel Cogne
- Department of Endocrinology, Diabetes and Nutrition, GHSR, Centre Hospitalo-Universitaire de la Réunion, Saint-Pierre, La Réunion, France
| | - Olivier Meilhac
- University of La Réunion, INSERM, UMR 1188 Diabète Athérothrombose Thérapies Réunion Océan Indien (DéTROI), Plateforme CYROI, Saint-Denis de, La Réunion, France
| | - Corinne Vigouroux
- Sorbonne Université, Inserm UMR S938, Saint-Antoine Research Centre, Institute of Cardiometabolism and Nutrition, AP-HP, Saint-Antoine Hospital, Genetics, Molecular Biology and Endocrinology Departments, National Reference Centre for Rare Diseases of Insulin Secretion and Insulin Sensitivity (PRISIS), Paris, France
| | - Peter J Meikle
- Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia; Baker Department of Cardiometabolic Health, University of Melbourne, Melbourne, Victoria, Australia; Baker Department of Cardiovascular Research Translation and Implementation, La Trobe University, Bundoora, Victoria, Australia
| | - Estelle Nobécourt
- Department of Endocrinology, Diabetes and Nutrition, GHSR, Centre Hospitalo-Universitaire de la Réunion, Saint-Pierre, La Réunion, France; University of La Réunion, INSERM, UMR 1188 Diabète Athérothrombose Thérapies Réunion Océan Indien (DéTROI), Plateforme CYROI, Saint-Denis de, La Réunion, France; Centre d'Investigation Clinique - Epidémiologie Clinique (CIC-EC) U1410 INSERM, Centre Hospitalo-Universitaire de la Réunion, La Réunion, France.
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17
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Agrawal S, Klarqvist MDR, Diamant N, Stanley TL, Ellinor PT, Mehta NN, Philippakis A, Ng K, Claussnitzer M, Grinspoon SK, Batra P, Khera AV. BMI-adjusted adipose tissue volumes exhibit depot-specific and divergent associations with cardiometabolic diseases. Nat Commun 2023; 14:266. [PMID: 36650173 PMCID: PMC9844175 DOI: 10.1038/s41467-022-35704-5] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2022] [Accepted: 12/20/2022] [Indexed: 01/18/2023] Open
Abstract
For any given body mass index (BMI), individuals vary substantially in fat distribution, and this variation may have important implications for cardiometabolic risk. Here, we study disease associations with BMI-independent variation in visceral (VAT), abdominal subcutaneous (ASAT), and gluteofemoral (GFAT) fat depots in 40,032 individuals of the UK Biobank with body MRI. We apply deep learning models based on two-dimensional body MRI projections to enable near-perfect estimation of fat depot volumes (R2 in heldout dataset = 0.978-0.991 for VAT, ASAT, and GFAT). Next, we derive BMI-adjusted metrics for each fat depot (e.g. VAT adjusted for BMI, VATadjBMI) to quantify local adiposity burden. VATadjBMI is associated with increased risk of type 2 diabetes and coronary artery disease, ASATadjBMI is largely neutral, and GFATadjBMI is associated with reduced risk. These results - describing three metabolically distinct fat depots at scale - clarify the cardiometabolic impact of BMI-independent differences in body fat distribution.
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Affiliation(s)
- Saaket Agrawal
- Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Center for Genomic Medicine, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
| | | | - Nathaniel Diamant
- Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Takara L Stanley
- Metabolism Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Patrick T Ellinor
- Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Nehal N Mehta
- National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA
| | - Anthony Philippakis
- Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Eric and Wendy Schmidt Center, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Kenney Ng
- Center for Computational Health, IBM Research, Cambridge, MA, USA
| | - Melina Claussnitzer
- Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Center for Genomic Medicine, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Steven K Grinspoon
- Metabolism Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Puneet Batra
- Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Amit V Khera
- Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
- Center for Genomic Medicine, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
- Department of Medicine, Harvard Medical School, Boston, MA, USA.
- Verve Therapeutics, Cambridge, MA, USA.
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18
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Loss of Mature Lamin A/C Triggers a Shift in Intracellular Metabolic Homeostasis via AMPKα Activation. Cells 2022; 11:cells11243988. [PMID: 36552752 PMCID: PMC9777081 DOI: 10.3390/cells11243988] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2022] [Revised: 12/06/2022] [Accepted: 12/06/2022] [Indexed: 12/14/2022] Open
Abstract
The roles of lamin A/C in adipocyte differentiation and skeletal muscle lipid metabolism are associated with familial partial lipodystrophy of Dunnigan (FPLD). We confirmed that LMNA knockdown (KD) in mouse adipose-derived mesenchymal stem cells (AD-MSCs) prevented adipocyte maturation. Importantly, in in vitro experiments, we discovered a significant increase in phosphorylated lamin A/C levels at serine 22 or 392 sites (pLamin A/C-S22/392) accompanying increased lipid synthesis in a liver cell line (7701 cells) and two hepatocellular carcinoma (HCC) cell lines (HepG2 and MHCC97-H cells). Moreover, HCC cells did not survive after LMNA knockout (KO) or even KD. Evidently, the functions of lamin A/C differ between the liver and adipose tissue. To date, the mechanism of hepatocyte lipid metabolism mediated by nuclear lamin A/C remains unclear. Our in-depth study aimed to identify the molecular connection between lamin A/C and pLamin A/C, hepatic lipid metabolism and liver cancer. Gain- and loss-of-function experiments were performed to investigate functional changes and the related molecular pathways in 7701 cells. Adenosine 5' monophosphate-activated protein kinase α (AMPKα) was activated when abnormalities in functional lamin A/C were observed following lamin A/C depletion or farnesyltransferase inhibitor (FTI) treatment. Active AMPKα directly phosphorylated acetyl-CoA-carboxylase 1 (ACC1) and subsequently inhibited lipid synthesis but induced glycolysis in both HCC cells and normal cells. According to the mass spectrometry analysis, lamin A/C potentially regulated AMPKα activation through its chaperone proteins, ATPase or ADP/ATP transporter 2. Lonafarnib (an FTI) combined with low-glucose conditions significantly decreased the proliferation of the two HCC cell lines more efficiently than lonafarnib alone by inhibiting glycolysis or the maturation of prelamin A.
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19
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Kono Y, Adam SA, Sato Y, Reddy KL, Zheng Y, Medalia O, Goldman RD, Kimura H, Shimi T. Nucleoplasmic lamin C rapidly accumulates at sites of nuclear envelope rupture with BAF and cGAS. J Cell Biol 2022; 221:e202201024. [PMID: 36301259 PMCID: PMC9617480 DOI: 10.1083/jcb.202201024] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Revised: 07/14/2022] [Accepted: 09/06/2022] [Indexed: 12/13/2022] Open
Abstract
In mammalian cell nuclei, the nuclear lamina (NL) underlies the nuclear envelope (NE) to maintain nuclear structure. The nuclear lamins, the major structural components of the NL, are involved in the protection against NE rupture induced by mechanical stress. However, the specific role of the lamins in repair of NE ruptures has not been fully determined. Our analyses using immunofluorescence and live-cell imaging revealed that the nucleoplasmic pool of lamin C rapidly accumulated at sites of NE rupture induced by laser microirradiation in mouse embryonic fibroblasts. The accumulation of lamin C at the rupture sites required both the immunoglobulin-like fold domain that binds to barrier-to-autointegration factor (BAF) and a nuclear localization signal. The accumulation of nuclear BAF and cytoplasmic cyclic GMP-AMP synthase (cGAS) at the rupture sites was in part dependent on lamin A/C. These results suggest that nucleoplasmic lamin C, BAF, and cGAS concertedly accumulate at sites of NE rupture for rapid repair.
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Affiliation(s)
- Yohei Kono
- Cell Biology Center, Institute of Innovative Research, Tokyo Institute of Technology, Yokohama, Japan
| | - Stephen A. Adam
- Department of Cell and Developmental Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL
| | - Yuko Sato
- Cell Biology Center, Institute of Innovative Research, Tokyo Institute of Technology, Yokohama, Japan
- School of Life Science and Technology, Tokyo Institute of Technology, Yokohama, Japan
| | - Karen L. Reddy
- Department of Biological Chemistry, Johns Hopkins University, Baltimore, MD
| | - Yixian Zheng
- Department of Embryology, Carnegie Institution for Science, Baltimore, MD
| | - Ohad Medalia
- Department of Biochemistry, University of Zurich, Zurich, Switzerland
| | - Robert D. Goldman
- Department of Cell and Developmental Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL
| | - Hiroshi Kimura
- Cell Biology Center, Institute of Innovative Research, Tokyo Institute of Technology, Yokohama, Japan
- School of Life Science and Technology, Tokyo Institute of Technology, Yokohama, Japan
- World Research Hub Initiative, Institute of Innovative Research, Tokyo Institute of Technology, Yokohama, Japan
| | - Takeshi Shimi
- Cell Biology Center, Institute of Innovative Research, Tokyo Institute of Technology, Yokohama, Japan
- World Research Hub Initiative, Institute of Innovative Research, Tokyo Institute of Technology, Yokohama, Japan
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20
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Zhong ZX, Harris J, Wilber E, Gorman S, Savage DB, O'Rahilly S, Stears A, Williams RM. Describing the natural history of clinical, biochemical and radiological outcomes of children with familial partial lipodystrophy type 2 (FPLD2) from the United Kingdom: A retrospective case series. Clin Endocrinol (Oxf) 2022; 97:755-762. [PMID: 35920656 PMCID: PMC9804585 DOI: 10.1111/cen.14806] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 07/10/2022] [Accepted: 07/12/2022] [Indexed: 01/07/2023]
Abstract
CONTEXT Familial partial lipodystrophy type 2 (FPLD2) results from autosomal dominant mutations in the LMNA gene, causing lack of subcutaneous fat deposition and excess ectopic fat accumulation, leading to metabolic complications and reduced life expectancy. The rarity of the condition means that the natural history of FPLD2 throughout childhood is not well understood. We report outcomes in a cohort of 12 (5M) children with a genetic diagnosis of FPLD2, under the care of the UK National Severe Insulin Resistance Service (NSIRS) which offers multidisciplinary input including dietetic, in addition to screening for comorbidities. OBJECTIVE To describe the natural history of clinical, biochemical and radiological outcomes of children with FPLD2. DESIGN A retrospective case note review of children with a genetic diagnosis of FPLD2 who had been seen in the paediatric NSIRS was performed. PATIENTS Twelve (5M) individuals diagnosed with FPLD2 via genetic testing before age 18 and who attended the NSIRS clinic were included. MEASUREMENTS Relationships between metabolic variables (HbA1c, triglycerides, fasting insulin, fasting glucose and alanine transaminase [ALT]) across time, from first visit to most recent, were explored using a multivariate model, adjusted for age and gender. The age of development of comorbidities was recorded. RESULTS Three patients (all female) developed diabetes between 12 and 19 years and were treated with Metformin. One female has hypertrophic cardiomyopathy and four (1M) patients developed mild hepatic steatosis at a median [range] age of 14(12-15) years. Three (1M) patients reported mental health problems related to lipodystrophy. There was no relationship between biochemical results and age. Patients with diabetes had higher concentrations of ALT than patients who did not have diabetes, adjusted for age, gender and body mass index standard deviation scores. CONCLUSIONS Despite dietetic input, some patients, more commonly females, developed comorbidities after the age of 10. The absence of relationships between biochemical results and age likely reflects a small cohort size. We propose that, while clinical review and dietetic support are beneficial for children with FPLD2, formal screening for comorbidities before age 10 may not be of benefit. Clinical input from an multidisciplinary team including dietician, psychologist and clinician should be offered after diagnosis.
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Affiliation(s)
| | | | - Ellen Wilber
- Cambridge University Hospitals NHS TrustCambridgeUK
| | | | - David B. Savage
- Institute of Metabolic ScienceUniversity of CambridgeCambridgeUK
| | | | - Anna Stears
- Cambridge University Hospitals NHS TrustCambridgeUK
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21
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Anand D, Chaudhuri A. Grease in the Nucleus: Insights into the Dynamic Life of Nuclear Membranes. J Membr Biol 2022; 256:137-145. [PMID: 36331589 PMCID: PMC10082704 DOI: 10.1007/s00232-022-00272-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Accepted: 09/20/2022] [Indexed: 11/06/2022]
Abstract
AbstractNucleus is at the center stage of cellular drama orchestrated in the life of a cell and the nucleoplasm is surrounded by a double membranous compartment constituting the Nuclear membrane/envelope (NE) that separates it from the cytoplasm in nucleated cells. The initial understanding of the NE was that of a border security entity between the nucleus and the cytoplasm, separating gene regulation and transcription in the nucleus from translation in the cytoplasm. However, the discovery of a wide array of inherited diseases caused by mutations in genes encoding proteins that reside or interact with NE diverted the interest into deciphering the lipid-protein-rich environment of the NE. Today, the NE is considered a dynamic organelle which forms a functional linkage between the nucleus and the rest of the cell. The exposure of NE to constant mechanical constraints by its connectivity to the large polymer network of the lamina and chromatin on one side, and to the cytoskeleton on the other side results, in a variety of shape changes. We discuss two such deformation, the formation of nuclear blebs and nucleoplasmic reticulum (NER). Although the protein and the lipid composition of NE comprises a small fraction of the total lipid-protein load of the cell, the ability to define the lipid-protein composition of Inner nuclear membrane (INM) and Outer nuclear membrane (ONM) with precision is crucial for obtaining a deeper mechanistic understanding of their lipid-protein interaction and the various signaling pathways that are triggered by them. In addition, this allows us to further understand the direct and indirect roles of NE machinery in the chromosomal organization and gene regulation.
Graphical Abstract
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Affiliation(s)
- Deepak Anand
- The Microbiology Group, Department of Biology, Biology Building, Lund University, Sölvegatan 35, 223 62, Lund, Sweden
| | - Arunima Chaudhuri
- Department of Microbiology, Immunology and Glycobiology, Institute of Laboratory Medicine, Lund University, Sölvegatan 19, 223 62, Lund, Sweden.
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22
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Wei X, Murphy MA, Reddy NA, Hao Y, Eggertsen TG, Saucerman JJ, Bochkis IM. Redistribution of lamina-associated domains reshapes binding of pioneer factor FOXA2 in development of nonalcoholic fatty liver disease. Genome Res 2022; 32:1981-1992. [PMID: 36522168 PMCID: PMC9808618 DOI: 10.1101/gr.277149.122] [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: 07/25/2022] [Accepted: 11/16/2022] [Indexed: 12/23/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is highly prevalent in type 2 diabetes mellitus and the elderly, impacting 40% of individuals over 70. Regulation of heterochromatin at the nuclear lamina has been associated with aging and age-dependent metabolic changes. We previously showed that changes at the lamina in aged hepatocytes and laminopathy models lead to redistribution of lamina-associated domains (LADs), opening of repressed chromatin, and up-regulation of genes regulating lipid synthesis and storage, culminating in fatty liver. Here, we test the hypothesis that change in the expression of lamina-associated proteins and nuclear shape leads to redistribution of LADs, followed by altered binding of pioneer factor FOXA2 and by up-regulation of lipid synthesis and storage, culminating in steatosis in younger NAFLD patients (aged 21-51). Changes in nuclear morphology alter LAD partitioning and reduced lamin B1 signal correlate with increased FOXA2 binding before severe steatosis in young mice placed on a western diet. Nuclear shape is also changed in younger NAFLD patients. LADs are redistrubted and lamin B1 signal decreases similarly in mild and severe steatosis. In contrast, FOXA2 binding is similar in normal and NAFLD patients with moderate steatosis and is repositioned only in NAFLD patients with more severe lipid accumulation. Hence, changes at the nuclear lamina reshape FOXA2 binding with progression of the disease. Our results suggest a role for nuclear lamina in etiology of NAFLD, irrespective of aging, with potential for improved stratification of patients and novel treatments aimed at restoring nuclear lamina function.
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Affiliation(s)
- Xiaolong Wei
- Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908, USA
| | - Megan A Murphy
- Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908, USA
| | - Nihal A Reddy
- Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908, USA
| | - Yi Hao
- Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908, USA
| | - Taylor G Eggertsen
- Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia 22908, USA
| | - Jeffrey J Saucerman
- Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia 22908, USA
| | - Irina M Bochkis
- Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908, USA
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23
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Bonnefond A, Semple RK. Achievements, prospects and challenges in precision care for monogenic insulin-deficient and insulin-resistant diabetes. Diabetologia 2022; 65:1782-1795. [PMID: 35618782 PMCID: PMC9522735 DOI: 10.1007/s00125-022-05720-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Accepted: 02/01/2022] [Indexed: 01/19/2023]
Abstract
Integration of genomic and other data has begun to stratify type 2 diabetes in prognostically meaningful ways, but this has yet to impact on mainstream diabetes practice. The subgroup of diabetes caused by single gene defects thus provides the best example to date of the vision of 'precision diabetes'. Monogenic diabetes may be divided into primary pancreatic beta cell failure, and primary insulin resistance. In both groups, clear examples of genotype-selective responses to therapy have been advanced. The benign trajectory of diabetes due to pathogenic GCK mutations, and the sulfonylurea-hyperresponsiveness conferred by activating KCNJ11 or ABCC8 mutations, or loss-of-function HNF1A or HNF4A mutations, often decisively guide clinical management. In monogenic insulin-resistant diabetes, subcutaneous leptin therapy is beneficial in some severe lipodystrophy. Increasing evidence also supports use of 'obesity therapies' in lipodystrophic people even without obesity. In beta cell diabetes the main challenge is now implementation of the precision diabetes vision at scale. In monogenic insulin-resistant diabetes genotype-specific benefits are proven in far fewer patients to date, although further genotype-targeted therapies are being evaluated. The conceptual paradigm established by the insulin-resistant subgroup with 'adipose failure' may have a wider influence on precision therapy for common type 2 diabetes, however. For all forms of monogenic diabetes, population-wide genome sequencing is currently forcing reappraisal of the importance assigned to pathogenic mutations when gene sequencing is uncoupled from prior suspicion of monogenic diabetes.
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Affiliation(s)
- Amélie Bonnefond
- Inserm UMR1283, CNRS UMR8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, Lille University Hospital, Lille, France.
- Université de Lille, Lille, France.
- Department of Metabolism, Imperial College London, London, 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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24
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Vasandani C, Li X, Sekizkardes H, Brown RJ, Garg A. Phenotypic Differences Among Familial Partial Lipodystrophy Due to LMNA or PPARG Variants. J Endocr Soc 2022; 6:bvac155. [PMID: 36397776 PMCID: PMC9664976 DOI: 10.1210/jendso/bvac155] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Indexed: 11/19/2022] Open
Abstract
Context Despite several reports of familial partial lipodystrophy (FPLD) type 2 (FPLD2) due to heterozygous LMNA variants and FPLD3 due to PPARG variants, the phenotypic differences among them remain unclear. Objective To compare the body fat distribution, metabolic parameters, and prevalence of metabolic complications between FPLD3 and FPLD2. Methods A retrospective, cross-sectional comparison of patients from 2 tertiary referral centers-UT Southwestern Medical Center and the National Institute of Diabetes and Digestive and Kidney Diseases. A total of 196 females and 59 males with FPLD2 (age 2-86 years) and 28 females and 4 males with FPLD3 (age 9-72 years) were included. The main outcome measures were skinfold thickness, regional body fat by dual-energy X-ray absorptiometry (DXA), metabolic variables, and prevalence of diabetes mellitus and hypertriglyceridemia. Results Compared with subjects with FPLD2, subjects with FPLD3 had significantly increased prevalence of hypertriglyceridemia (66% vs 84%) and diabetes (44% vs 72%); and had higher median fasting serum triglycerides (208 vs 255 mg/dL), and mean hemoglobin A1c (6.4% vs 7.5%). Compared with subjects with FPLD2, subjects with FPLD3 also had significantly higher mean upper limb fat (21% vs 27%) and lower limb fat (16% vs 21%) on DXA and increased median skinfold thickness at the anterior thigh (5.8 vs 11.3 mm), calf (4 vs 6 mm), triceps (5.5 vs 7.5 mm), and biceps (4.3 vs 6.8 mm). Conclusion Compared with subjects with FPLD2, subjects with FPLD3 have milder lipodystrophy but develop more severe metabolic complications, suggesting that the remaining adipose tissue in subjects with FPLD3 may be dysfunctional or those with mild metabolic disease are underrecognized.
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Affiliation(s)
- Chandna Vasandani
- Division of Nutrition and Metabolic Diseases and the Center for Human Nutrition, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX 75390, USA
| | - Xilong Li
- Department of Population and Data Sciences, UT Southwestern Medical Center, Dallas, TX 75390, USA
| | - Hilal Sekizkardes
- National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA
| | - Rebecca J Brown
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Abhimanyu Garg
- Division of Nutrition and Metabolic Diseases and the Center for Human Nutrition, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX 75390, USA
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25
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Primmer SR, Liao CY, Kummert OMP, Kennedy BK. Lamin A to Z in normal aging. Aging (Albany NY) 2022; 14:8150-8166. [PMID: 36260869 DOI: 10.18632/aging.204342] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Accepted: 08/31/2022] [Indexed: 11/25/2022]
Abstract
Almost since the discovery that mutations in the LMNA gene, encoding the nuclear structure components lamin A and C, lead to Hutchinson-Gilford progeria syndrome, people have speculated that lamins may have a role in normal aging. The most common HPGS mutation creates a splice variant of lamin A, progerin, which promotes accelerated aging pathology. While some evidence exists that progerin accumulates with normal aging, an increasing body of work indicates that prelamin A, a precursor of lamin A prior to C-terminal proteolytic processing, accumulates with age and may be a driver of normal aging. Prelamin A shares properties with progerin and is also linked to a rare progeroid disease, restrictive dermopathy. Here, we describe mechanisms underlying changes in prelamin A with aging and lay out the case that this unprocessed protein impacts normative aging. This is important since intervention strategies can be developed to modify this pathway as a means to extend healthspan and lifespan.
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Affiliation(s)
| | - Chen-Yu Liao
- The Buck Institute for Research on Aging, Novato, CA 94945, USA
| | | | - Brian K Kennedy
- Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.,Centre for Healthy Longevity, National University Health System, Singapore.,Departments of Biochemistry and Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
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Östlund C, Hernandez-Ono A, Turk SJ, Dauer WT, Ginsberg HN, Worman HJ, Shin JY. Hepatocytes Deficient in Nuclear Envelope Protein Lamina-associated Polypeptide 1 are an Ideal Mammalian System to Study Intranuclear Lipid Droplets. J Lipid Res 2022; 63:100277. [PMID: 36100089 PMCID: PMC9587410 DOI: 10.1016/j.jlr.2022.100277] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 09/06/2022] [Accepted: 09/07/2022] [Indexed: 01/21/2023] Open
Abstract
Lipid droplets (LDs) are generally considered to be synthesized in the ER and utilized in the cytoplasm. However, LDs have been observed inside nuclei in some cells, although recent research on nuclear LDs has focused on cultured cell lines. To better understand nuclear LDs that occur in vivo, here we examined LDs in primary hepatocytes from mice following depletion of the nuclear envelope protein lamina-associated polypeptide 1 (LAP1). Microscopic image analysis showed that LAP1-depleted hepatocytes contain frequent nuclear LDs, which differ from cytoplasmic LDs in their associated proteins. We found type 1 nucleoplasmic reticula, which are invaginations of the inner nuclear membrane, are often associated with nuclear LDs in these hepatocytes. Furthermore, in vivo depletion of the nuclear envelope proteins lamin A and C from mouse hepatocytes led to severely abnormal nuclear morphology, but significantly fewer nuclear LDs than were observed upon depletion of LAP1. In addition, we show both high-fat diet feeding and fasting of mice increased cytoplasmic lipids in LAP1-depleted hepatocytes but reduced nuclear LDs, demonstrating a relationship of LD formation with nutritional state. Finally, depletion of microsomal triglyceride transfer protein did not change the frequency of nuclear LDs in LAP1-depleted hepatocytes, suggesting that it is not required for the biogenesis of nuclear LDs in these cells. Together, these data show that LAP1-depleted hepatocytes represent an ideal mammalian system to investigate the biogenesis of nuclear LDs and their partitioning between the nucleus and cytoplasm in response to changes in nutritional state and cellular metabolism in vivo.
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Affiliation(s)
- Cecilia Östlund
- Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA,Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA
| | - Antonio Hernandez-Ono
- Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA
| | - Samantha J. Turk
- Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA,Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA
| | - William T. Dauer
- Peter O’Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA,Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX, USA,Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Henry N. Ginsberg
- Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA
| | - Howard J. Worman
- Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA,Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA
| | - Ji-Yeon Shin
- Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA,For correspondence: Ji-Yeon Shin
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Abstract
PURPOSE OF REVIEW Genetic or acquired lipodystrophies are characterized by selective loss of body fat along with predisposition towards metabolic complications of insulin resistance, such as diabetes mellitus, hypertriglyceridemia, hepatic steatosis, polycystic ovarian syndrome, and acanthosis nigricans. In this review, we discuss the various subtypes and when to suspect and how to diagnose lipodystrophy. RECENT FINDINGS The four major subtypes are autosomal recessive, congenital generalized lipodystrophy (CGL); acquired generalized lipodystrophy (AGL), mostly an autoimmune disorder; autosomal dominant or recessive familial partial lipodystrophy (FPLD); and acquired partial lipodystrophy (APL), an autoimmune disorder. Diagnosis of lipodystrophy is mainly based upon physical examination findings of loss of body fat and can be supported by body composition analysis by skinfold measurements, dual-energy x-ray absorptiometry, and whole-body magnetic resonance imaging. Confirmatory genetic testing is helpful in the proband and at-risk family members with suspected genetic lipodystrophies. The treatment is directed towards the specific comorbidities and metabolic complications, and there is no treatment to reverse body fat loss. Metreleptin should be considered as the first-line therapy for metabolic complications in patients with generalized lipodystrophy and for prevention of comorbidities in children. Metformin and insulin therapy are the best options for treating hyperglycemia and fibrates and/or fish oil for hypertriglyceridemia. Lipodystrophy should be suspected in lean and muscular subjects presenting with diabetes mellitus, hypertriglyceridemia, non-alcoholic fatty liver disease, polycystic ovarian syndrome, or amenorrhea. Diabetologists should be aware of lipodystrophies and consider genetic varieties as an important subtype of monogenic diabetes.
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Affiliation(s)
- Nivedita Patni
- Division of Pediatric Endocrinology, Department of Pediatrics, UT Southwestern Medical Center, Dallas, TX, USA
| | - Abhimanyu Garg
- Division of Nutrition and Metabolic Diseases, Department of Internal Medicine and the Center for Human Nutrition, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX, 75390-8537, USA.
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28
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Silhouette images enable estimation of body fat distribution and associated cardiometabolic risk. NPJ Digit Med 2022; 5:105. [PMID: 35896726 PMCID: PMC9329470 DOI: 10.1038/s41746-022-00654-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Accepted: 07/06/2022] [Indexed: 11/09/2022] Open
Abstract
Inter-individual variation in fat distribution is increasingly recognized as clinically important but is not routinely assessed in clinical practice, in part because medical imaging has not been practical to deploy at scale for this task. Here, we report a deep learning model trained on an individual’s body shape outline—or “silhouette” —that enables accurate estimation of specific fat depots of interest, including visceral (VAT), abdominal subcutaneous (ASAT), and gluteofemoral (GFAT) adipose tissue volumes, and VAT/ASAT ratio. Two-dimensional coronal and sagittal silhouettes are constructed from whole-body magnetic resonance images in 40,032 participants of the UK Biobank and used as inputs for a convolutional neural network to predict each of these quantities. Mean age of the study participants is 65 years and 51% are female. A cross-validated deep learning model trained on silhouettes enables accurate estimation of VAT, ASAT, and GFAT volumes (R2: 0.88, 0.93, and 0.93, respectively), outperforming a comparator model combining anthropometric and bioimpedance measures (ΔR2 = 0.05–0.13). Next, we study VAT/ASAT ratio, a nearly body-mass index (BMI)—and waist circumference-independent marker of metabolically unhealthy fat distribution. While the comparator model poorly predicts VAT/ASAT ratio (R2: 0.17–0.26), a silhouette-based model enables significant improvement (R2: 0.50–0.55). Increased silhouette-predicted VAT/ASAT ratio is associated with increased risk of prevalent and incident type 2 diabetes and coronary artery disease independent of BMI and waist circumference. These results demonstrate that body silhouette images can estimate important measures of fat distribution, laying the scientific foundation for scalable population-based assessment.
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Agrawal S, Wang M, Klarqvist MDR, Smith K, Shin J, Dashti H, Diamant N, Choi SH, Jurgens SJ, Ellinor PT, Philippakis A, Claussnitzer M, Ng K, Udler MS, Batra P, Khera AV. Inherited basis of visceral, abdominal subcutaneous and gluteofemoral fat depots. Nat Commun 2022; 13:3771. [PMID: 35773277 PMCID: PMC9247093 DOI: 10.1038/s41467-022-30931-2] [Citation(s) in RCA: 65] [Impact Index Per Article: 21.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Accepted: 05/25/2022] [Indexed: 12/11/2022] Open
Abstract
For any given level of overall adiposity, individuals vary considerably in fat distribution. The inherited basis of fat distribution in the general population is not fully understood. Here, we study up to 38,965 UK Biobank participants with MRI-derived visceral (VAT), abdominal subcutaneous (ASAT), and gluteofemoral (GFAT) adipose tissue volumes. Because these fat depot volumes are highly correlated with BMI, we additionally study six local adiposity traits: VAT adjusted for BMI and height (VATadj), ASATadj, GFATadj, VAT/ASAT, VAT/GFAT, and ASAT/GFAT. We identify 250 independent common variants (39 newly-identified) associated with at least one trait, with many associations more pronounced in female participants. Rare variant association studies extend prior evidence for PDE3B as an important modulator of fat distribution. Local adiposity traits (1) highlight depot-specific genetic architecture and (2) enable construction of depot-specific polygenic scores that have divergent associations with type 2 diabetes and coronary artery disease. These results - using MRI-derived, BMI-independent measures of local adiposity - confirm fat distribution as a highly heritable trait with important implications for cardiometabolic health outcomes.
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Affiliation(s)
- Saaket Agrawal
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Center for Genomic Medicine, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Minxian Wang
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Center for Genomic Medicine, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
- CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China
| | | | - Kirk Smith
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Center for Genomic Medicine, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Joseph Shin
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Center for Genomic Medicine, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Hesam Dashti
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Nathaniel Diamant
- Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Seung Hoan Choi
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Center for Genomic Medicine, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Sean J Jurgens
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Center for Genomic Medicine, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
- Department of Experimental Cardiology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Patrick T Ellinor
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Center for Genomic Medicine, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Anthony Philippakis
- Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Eric and Wendy Schmidt Center, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Melina Claussnitzer
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Center for Genomic Medicine, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Kenney Ng
- Center for Computational Health, IBM Research, Cambridge, MA, USA
| | - Miriam S Udler
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Center for Genomic Medicine, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Puneet Batra
- Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Amit V Khera
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
- Center for Genomic Medicine, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
- Department of Medicine, Harvard Medical School, Boston, MA, USA.
- Verve Therapeutics, Cambridge, MA, USA.
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30
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Genetic Insights into Primary Restrictive Cardiomyopathy. J Clin Med 2022; 11:jcm11082094. [PMID: 35456187 PMCID: PMC9027761 DOI: 10.3390/jcm11082094] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Revised: 04/05/2022] [Accepted: 04/06/2022] [Indexed: 12/04/2022] Open
Abstract
Restrictive cardiomyopathy is a rare cardiac disease causing severe diastolic dysfunction, ventricular stiffness and dilated atria. In consequence, it induces heart failure often with preserved ejection fraction and is associated with a high mortality. Since it is a poor clinical prognosis, patients with restrictive cardiomyopathy frequently require heart transplantation. Genetic as well as non-genetic factors contribute to restrictive cardiomyopathy and a significant portion of cases are of unknown etiology. However, the genetic forms of restrictive cardiomyopathy and the involved molecular pathomechanisms are only partially understood. In this review, we summarize the current knowledge about primary genetic restrictive cardiomyopathy and describe its genetic landscape, which might be of interest for geneticists as well as for cardiologists.
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31
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Abstract
The nuclear envelope is composed of the nuclear membranes, nuclear lamina, and nuclear pore complexes. Laminopathies are diseases caused by mutations in genes encoding protein components of the lamina and these other nuclear envelope substructures. Mutations in the single gene encoding lamin A and C, which are expressed in most differentiated somatic cells, cause diseases affecting striated muscle, adipose tissue, peripheral nerve, and multiple systems with features of accelerated aging. Mutations in genes encoding other nuclear envelope proteins also cause an array of diseases that selectively affect different tissues or organs. In some instances, the molecular and cellular consequences of laminopathy-causing mutations are known. However, even when these are understood, mechanisms explaining specific tissue or organ pathology remain enigmatic. Current mechanistic hypotheses focus on how alterations in the nuclear envelope may affect gene expression, including via the regulation of signaling pathways, or cellular mechanics, including responses to mechanical stress.
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Affiliation(s)
- Ji-Yeon Shin
- Department of Medicine and Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
| | - Howard J. Worman
- Department of Medicine and Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
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32
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Czapiewski R, Batrakou DG, de Las Heras JI, Carter RN, Sivakumar A, Sliwinska M, Dixon CR, Webb S, Lattanzi G, Morton NM, Schirmer EC. Genomic loci mispositioning in Tmem120a knockout mice yields latent lipodystrophy. Nat Commun 2022; 13:321. [PMID: 35027552 PMCID: PMC8758788 DOI: 10.1038/s41467-021-27869-2] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Accepted: 12/19/2021] [Indexed: 12/13/2022] Open
Abstract
Little is known about how the observed fat-specific pattern of 3D-spatial genome organisation is established. Here we report that adipocyte-specific knockout of the gene encoding nuclear envelope transmembrane protein Tmem120a disrupts fat genome organisation, thus causing a lipodystrophy syndrome. Tmem120a deficiency broadly suppresses lipid metabolism pathway gene expression and induces myogenic gene expression by repositioning genes, enhancers and miRNA-encoding loci between the nuclear periphery and interior. Tmem120a-/- mice, particularly females, exhibit a lipodystrophy syndrome similar to human familial partial lipodystrophy FPLD2, with profound insulin resistance and metabolic defects that manifest upon exposure to an obesogenic diet. Interestingly, similar genome organisation defects occurred in cells from FPLD2 patients that harbour nuclear envelope protein encoding LMNA mutations. Our data indicate TMEM120A genome organisation functions affect many adipose functions and its loss may yield adiposity spectrum disorders, including a miRNA-based mechanism that could explain muscle hypertrophy in human lipodystrophy.
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Affiliation(s)
- Rafal Czapiewski
- Institute of Cell Biology, University of Edinburgh, Edinburgh, EH9 3BF, UK
| | - Dzmitry G Batrakou
- Institute of Cell Biology, University of Edinburgh, Edinburgh, EH9 3BF, UK
| | | | - Roderick N Carter
- Molecular Metabolism Group, University/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, EH16 4TJ, UK
| | | | | | - Charles R Dixon
- Institute of Cell Biology, University of Edinburgh, Edinburgh, EH9 3BF, UK
- Wellcome Centre for Cell Biology, University of Edinburgh, Edinburgh, EH9 3BF, UK
| | - Shaun Webb
- Wellcome Centre for Cell Biology, University of Edinburgh, Edinburgh, EH9 3BF, UK
| | - Giovanna Lattanzi
- CNR - National Research Council of Italy, Institute of Molecular Genetics "Luigi Luca Cavalli-Sforza", Unit of Bologna, Bologna, 40136, Italy
- IRCCS, Istituto Ortopedico Rizzoli, Bologna, 40136, Italy
| | - Nicholas M Morton
- Molecular Metabolism Group, University/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, EH16 4TJ, UK
| | - Eric C Schirmer
- Institute of Cell Biology, University of Edinburgh, Edinburgh, EH9 3BF, UK.
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Przybylski R, Abrams DJ. Clinical and genetic features of arrhythmogenic cardiomyopathy: the electrophysiology perspective. PROGRESS IN PEDIATRIC CARDIOLOGY 2021. [DOI: 10.1016/j.ppedcard.2021.101463] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
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Preclinical Advances of Therapies for Laminopathies. J Clin Med 2021; 10:jcm10214834. [PMID: 34768351 PMCID: PMC8584472 DOI: 10.3390/jcm10214834] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Revised: 10/19/2021] [Accepted: 10/19/2021] [Indexed: 11/29/2022] Open
Abstract
Laminopathies are a group of rare disorders due to mutation in LMNA gene. Depending on the mutation, they may affect striated muscles, adipose tissues, nerves or are multisystemic with various accelerated ageing syndromes. Although the diverse pathomechanisms responsible for laminopathies are not fully understood, several therapeutic approaches have been evaluated in patient cells or animal models, ranging from gene therapies to cell and drug therapies. This review is focused on these therapies with a strong focus on striated muscle laminopathies and premature ageing syndromes.
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35
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The Role of Emerin in Cancer Progression and Metastasis. Int J Mol Sci 2021; 22:ijms222011289. [PMID: 34681951 PMCID: PMC8537873 DOI: 10.3390/ijms222011289] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Revised: 10/14/2021] [Accepted: 10/15/2021] [Indexed: 12/27/2022] Open
Abstract
It is commonly recognized in the field that cancer cells exhibit changes in the size and shape of their nuclei. These features often serve as important biomarkers in the diagnosis and prognosis of cancer patients. Nuclear size can significantly impact cell migration due to its incredibly large size. Nuclear structural changes are predicted to regulate cancer cell migration. Nuclear abnormalities are common across a vast spectrum of cancer types, regardless of tissue source, mutational spectrum, and signaling dependencies. The pervasiveness of nuclear alterations suggests that changes in nuclear structure may be crucially linked to the transformation process. The factors driving these nuclear abnormalities, and the functional consequences, are not completely understood. Nuclear envelope proteins play an important role in regulating nuclear size and structure in cancer. Altered expression of nuclear lamina proteins, including emerin, is found in many cancers and this expression is correlated with better clinical outcomes. A model is emerging whereby emerin, as well as other nuclear lamina proteins, binding to the nucleoskeleton regulates the nuclear structure to impact metastasis. In this model, emerin and lamins play a central role in metastatic transformation, since decreased emerin expression during transformation causes the nuclear structural defects required for increased cell migration, intravasation, and extravasation. Herein, we discuss the cellular functions of nuclear lamina proteins, with a particular focus on emerin, and how these functions impact cancer progression and metastasis.
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36
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Fernández-Pombo A, Sánchez-Iglesias S, Cobelo-Gómez S, Hermida-Ameijeiras Á, Araújo-Vilar D. Familial partial lipodystrophy syndromes. Presse Med 2021; 50:104071. [PMID: 34610417 DOI: 10.1016/j.lpm.2021.104071] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Accepted: 08/18/2021] [Indexed: 12/14/2022] Open
Abstract
Lipodystrophies are a heterogeneous group of rare conditions characterised by the loss of adipose tissue. The most common forms are the familial partial lipodystrophy (FPLD) syndromes, which include a set of disorders, usually autosomal dominant, due to different pathogenetic mechanisms leading to improper fat distribution (loss of fat in the limbs and gluteal region and variable regional fat accumulation). Affected patients are prone to suffering serious morbidity via the development of metabolic complications associated to insulin resistance and an inability to properly store lipids. Although no well-defined diagnostic criteria have been established for lipodystrophy, there are certain clues related to medical history, physical examination and body composition evaluation that may suggest FPLD prior to confirmatory genetic analysis. Its treatment must be fundamentally oriented towards the control of the metabolic abnormalities. In this sense, metreleptin therapy, the newer classes of hypoglycaemic agents and other investigational drugs are showing promising results. This review aims to summarise the current knowledge of FPLD syndromes and to describe their clinical and molecular picture, diagnostic approaches and recent treatment modalities.
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Affiliation(s)
- Antía Fernández-Pombo
- UETeM-Molecular Pathology of Rare Diseases Group, Department of Psychiatry, Radiology, Public Health, Nursing and Medicine, IDIS-CiMUS, University of Santiago de Compostela, Santiago de Compostela 15782, Spain; Division of Endocrinology and Nutrition, University Clinical Hospital of Santiago de Compostela, 15706, Spain
| | - Sofía Sánchez-Iglesias
- UETeM-Molecular Pathology of Rare Diseases Group, Department of Psychiatry, Radiology, Public Health, Nursing and Medicine, IDIS-CiMUS, University of Santiago de Compostela, Santiago de Compostela 15782, Spain
| | - Silvia Cobelo-Gómez
- UETeM-Molecular Pathology of Rare Diseases Group, Department of Psychiatry, Radiology, Public Health, Nursing and Medicine, IDIS-CiMUS, University of Santiago de Compostela, Santiago de Compostela 15782, Spain
| | - Álvaro Hermida-Ameijeiras
- UETeM-Molecular Pathology of Rare Diseases Group, Department of Psychiatry, Radiology, Public Health, Nursing and Medicine, IDIS-CiMUS, University of Santiago de Compostela, Santiago de Compostela 15782, Spain; Division of Internal Medicine, University Clinical Hospital of Santiago de Compostela, 15706, Spain
| | - David Araújo-Vilar
- UETeM-Molecular Pathology of Rare Diseases Group, Department of Psychiatry, Radiology, Public Health, Nursing and Medicine, IDIS-CiMUS, University of Santiago de Compostela, Santiago de Compostela 15782, Spain; Division of Endocrinology and Nutrition, University Clinical Hospital of Santiago de Compostela, 15706, Spain.
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37
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Jéru I. Genetics of lipodystrophy syndromes. Presse Med 2021; 50:104074. [PMID: 34562561 DOI: 10.1016/j.lpm.2021.104074] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Revised: 08/24/2021] [Accepted: 09/15/2021] [Indexed: 12/11/2022] Open
Abstract
Lipodystrophic syndromes (LS) constitute a clinically and genetically heterogeneous group of diseases characterized by a loss of adipose tissue. These syndromes are usually associated with metabolic complications, which are determinant for morbidity and mortality. The classical forms of LS include partial, generalized, and progeroid lipodystrophies. They are usually due to defects in proteins playing a key role in adipogenesis and adipocyte functions. More recently, systemic disorders combining lipodystrophy and multiple organ dysfunction have been described, including autoinflammatory syndromes, mitochondrial disorders, as well as other complex entities. To date, more than thirty genes have been implicated in the monogenic forms of LS, but the majority of them remain genetically-unexplained. The associated pathophysiological mechanisms also remain to be clarified in many instances. Next generation sequencing-based approaches allow simultaneous testing of multiple genes and have become crucial to speed up the identification of new disease-causing genes. The challenge for geneticists is now the interpretation of the amount of available genetic data, generated especially by exome and whole-genome sequencing. International recommendations on the interpretation and classification of variants have been set up and are regularly reassessed. Very close collaboration between geneticists, clinicians, and researchers will be necessary to make rapid progress in understanding the molecular and cellular basis of these diseases, and to promote personalized medicine.
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Affiliation(s)
- Isabelle Jéru
- Laboratoire commun de Biologie et Génétique Moléculaires, Hôpital Saint-Antoine, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France; Sorbonne Université-Inserm UMRS_938, Centre de Recherche Saint-Antoine (CRSA), Paris 75012, France.
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38
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Corsa CAS, Walsh CM, Bagchi DP, Foss Freitas MC, Li Z, Hardij J, Granger K, Mori H, Schill RL, Lewis KT, Maung JN, Azaria RD, Rothberg AE, Oral EA, MacDougald OA. Adipocyte-Specific Deletion of Lamin A/C Largely Models Human Familial Partial Lipodystrophy Type 2. Diabetes 2021; 70:1970-1984. [PMID: 34088712 PMCID: PMC8576431 DOI: 10.2337/db20-1001] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Accepted: 05/25/2021] [Indexed: 11/13/2022]
Abstract
Mechanisms by which autosomal recessive mutations in Lmna cause familial partial lipodystrophy type 2 (FPLD2) are poorly understood. To investigate the function of lamin A/C in adipose tissue, we created mice with an adipocyte-specific loss of Lmna (Lmna ADKO). Although Lmna ADKO mice develop and maintain adipose tissues in early postnatal life, they show a striking and progressive loss of white and brown adipose tissues as they approach sexual maturity. Lmna ADKO mice exhibit surprisingly mild metabolic dysfunction on a chow diet, but on a high-fat diet they share many characteristics of FPLD2 including hyperglycemia, hepatic steatosis, hyperinsulinemia, and almost undetectable circulating adiponectin and leptin. Whereas Lmna ADKO mice have reduced regulated and constitutive bone marrow adipose tissue with a concomitant increase in cortical bone, FPLD2 patients have reduced bone mass and bone mineral density compared with controls. In cell culture models of Lmna deficiency, mesenchymal precursors undergo adipogenesis without impairment, whereas fully differentiated adipocytes have increased lipolytic responses to adrenergic stimuli. Lmna ADKO mice faithfully reproduce many characteristics of FPLD2 and thus provide a unique animal model to investigate mechanisms underlying Lmna-dependent loss of adipose tissues.
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Affiliation(s)
- Callie A S Corsa
- Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI
| | - Carolyn M Walsh
- Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI
| | - Devika P Bagchi
- Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI
| | - Maria C Foss Freitas
- Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, MI
| | - Ziru Li
- Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI
| | - Julie Hardij
- Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI
| | - Katrina Granger
- Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI
| | - Hiroyuki Mori
- Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI
| | - Rebecca L Schill
- Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI
| | - Kenneth T Lewis
- Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI
| | - Jessica N Maung
- Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI
| | - Ruth D Azaria
- Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI
| | - Amy E Rothberg
- Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, MI
| | - Elif A Oral
- Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, MI
| | - Ormond A MacDougald
- Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI
- Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, MI
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Abaj F, Saeedy SAG, Mirzaei K. Mediation role of body fat distribution (FD) on the relationship between CAV1 rs3807992 polymorphism and metabolic syndrome in overweight and obese women. BMC Med Genomics 2021; 14:202. [PMID: 34384444 PMCID: PMC8359537 DOI: 10.1186/s12920-021-01050-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Accepted: 08/03/2021] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Metabolic syndrome (MetS) is associated with an increased risk of morbidity and mortality in almost all chronic diseases. The most frequent methods for the calculation of a continuous MetS (cMetS) score have used the standardized residuals in linear regression (z-score). Recently, emerging data suggest that one of the main genetic targets is the CAV1, which plays a crucial role in regulating body fat distribution. This study is designed to investigate the relationship between CAV1 rs3807992 genotypes and cMetS, and to determine whether body fat distribution plays a mediating role in this regard. METHODS The current cross-sectional study was conducted on 386 overweight and obese females. The CAV1 rs3807992 and body composition were measured by the PCR-RFLP method and bioelectrical impedance analysis, respectively. Serum profile of HDL-C, TGs, FPG, and Insulin were measured by standard protocols. RESULTS GG allele carriers had significantly lowered Z-MAP (p = 0.02), total cMetS (p = 0.03) and higher Z-HDL (p = 0.001) compared with (A) allele carriers. There was a significant specific indirect effect (standardized coefficient = 0.19; 95% CI 0.01-0.4) of Visceral fat level (VFL). Although, total body fat was significantly associated with CAV1 rs3807992 and cMetS, the specific indirect effect was not significant (standardized coefficient = 0.21; 95% CI - 0.006, 0.44). VFL contributed to significant indirect effects of 35% on the relationship between CAV1 and cMetS. CONCLUSION Higher visceral adipose tissue may affect the relationship between CAV1 and cMetS. Although CAV1 rs3807992 is linked to VFL in our study, the influence of this polymorphism on MetS is not via total fat.
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Affiliation(s)
- Faezeh Abaj
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences (TUMS), P.O. Box 14155-6117, Tehran, Iran
| | | | - Khadijeh Mirzaei
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences (TUMS), P.O. Box 14155-6117, Tehran, Iran
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Srinivasa S, Garcia-Martin R, Torriani M, Fitch KV, Carlson AR, Kahn CR, Grinspoon SK. Altered pattern of circulating miRNAs in HIV lipodystrophy perturb key adipose differentiation and inflammation pathways. JCI Insight 2021; 6:e150399. [PMID: 34383714 PMCID: PMC8492307 DOI: 10.1172/jci.insight.150399] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Accepted: 08/11/2021] [Indexed: 11/17/2022] Open
Abstract
We identified a microRNA (miRNA) profile characterizing HIV lipodystrophy and explored the downstream mechanistic implications with respect to adipocyte biology and the associated clinical phenotype. miRNA profiles were extracted from small extracellular vesicles (sEVs) of HIV-infected individuals with and without lipodystrophic changes and individuals without HIV, among whom we previously showed significant reductions in adipose Dicer expression related to HIV. miR-20a-3p was increased and miR-324-5p and miR-186 were reduced in sEVs from HIV lipodystrophic individuals. Changes in these miRNAs correlated with adipose Dicer expression and clinical markers of lipodystrophy, including fat redistribution, insulin resistance, and hypertriglyceridemia. Human preadipocytes transfected with mimic miR-20a-3p, anti–miR-324-5p, or anti–miR-186 induced consistent changes in latent transforming growth factor beta binding protein 2 (Ltbp2), Wisp2, and Nebl expression. Knockdown of Ltbp2 downregulated markers of adipocyte differentiation (Fabp4, Pparγ, C/ebpa, Fasn, adiponectin, Glut4, CD36), and Lamin C, and increased expression of genes involved in inflammation (IL1β, IL6, and Ccl20). Our studies suggest a likely unique sEV miRNA signature related to dysregulation of Dicer in adipose tissue in HIV. Enhanced miR-20a-3p or depletion of miR-186 and miR-324-5p may downregulate Ltbp2 in HIV, leading to dysregulation in adipose differentiation and inflammation, which could contribute to acquired HIV lipodystrophy and associated metabolic and inflammatory perturbations.
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Affiliation(s)
- Suman Srinivasa
- Metabolic Unit, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America
| | - Ruben Garcia-Martin
- Section on Integrative Physiology and Metabolism, Joslin Diabetes Center and Harvard Medical School, boston, United States of America
| | - Martin Torriani
- Division of Musculoskeletal Imaging and Intervention, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America
| | - Kathleen V Fitch
- Metabolic Unit, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America
| | - Anna R Carlson
- Metabolic Unit, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America
| | - C Ronald Kahn
- Section on Integrative Physiology and Metabolism, Joslin Diabetes Center and Harvard Medical School, boston, United States of America
| | - Steven K Grinspoon
- Metabolic Unit, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America
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Eldin AJ, Akinci B, da Rocha AM, Meral R, Simsir IY, Adiyaman SC, Ozpelit E, Bhave N, Gen R, Yurekli B, Kutbay NO, Siklar Z, Neidert AH, Hench R, Tayeh MK, Innis JW, Jalife J, Oral H, Oral EA. Cardiac phenotype in familial partial lipodystrophy. Clin Endocrinol (Oxf) 2021; 94:1043-1053. [PMID: 33502018 PMCID: PMC9003538 DOI: 10.1111/cen.14426] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Revised: 01/21/2021] [Accepted: 01/22/2021] [Indexed: 12/16/2022]
Abstract
OBJECTIVES LMNA variants have been previously associated with cardiac abnormalities independent of lipodystrophy. We aimed to assess cardiac impact of familial partial lipodystrophy (FPLD) to understand the role of laminopathy in cardiac manifestations. STUDY DESIGN Retrospective cohort study. METHODS Clinical data from 122 patients (age range: 13-77, 101 females) with FPLD were analysed. Mature human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from a patient with an LMNA variant were studied as proof-of-concept for future studies. RESULTS Subjects with LMNA variants had a higher prevalence of overall cardiac events than others. The likelihood of having an arrhythmia was significantly higher in patients with LMNA variants (OR: 3.77, 95% CI: 1.45-9.83). These patients were at higher risk for atrial fibrillation or flutter (OR: 5.78, 95% CI: 1.04-32.16). The time to the first arrhythmia was significantly shorter in the LMNA group, with a higher HR of 3.52 (95% CI: 1.34-9.27). Non-codon 482 LMNA variants were more likely to be associated with cardiac events (vs. 482 LMNA: OR: 4.74, 95% CI: 1.41-15.98 for arrhythmia; OR: 17.67, 95% CI: 2.45-127.68 for atrial fibrillation or flutter; OR: 5.71, 95% CI: 1.37-23.76 for conduction disease). LMNA mutant hiPSC-CMs showed a higher frequency of spontaneous activity and shorter action potential duration. Functional syncytia of hiPSC-CMs displayed several rhythm alterations such as early afterdepolarizations, spontaneous quiescence and spontaneous tachyarrhythmia, and significantly slower recovery in chronotropic changes induced by isoproterenol exposure. CONCLUSIONS Our results highlight the need for vigilant cardiac monitoring in FPLD, especially in patients with LMNA variants who have an increased risk of developing cardiac arrhythmias. In addition, hiPSC-CMs can be studied to understand the basic mechanisms for the arrhythmias in patients with lipodystrophy to understand the impact of specific mutations.
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Affiliation(s)
- Abdelwahab Jalal Eldin
- Division of Metabolism, Endocrinology and Diabetes (MEND), Department of Internal Medicine, Michigan Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Baris Akinci
- Division of Metabolism, Endocrinology and Diabetes (MEND), Department of Internal Medicine, Michigan Medicine, University of Michigan, Ann Arbor, MI, USA
- Division of Endocrinology, Department of Internal Medicine, Dokuz Eylul University, Izmir, Turkey
| | - Andre Monteiro da Rocha
- Center for Arrhythmia Research, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Rasimcan Meral
- Division of Metabolism, Endocrinology and Diabetes (MEND), Department of Internal Medicine, Michigan Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Ilgin Yildirim Simsir
- Division of Endocrinology, Department of Internal Medicine, Ege University, Izmir, Turkey
| | - Suleyman Cem Adiyaman
- Division of Endocrinology, Department of Internal Medicine, Dokuz Eylul University, Izmir, Turkey
| | - Ebru Ozpelit
- Division of Cardiology, Department of Internal Medicine, Dokuz Eylul University, Izmir, Turkey
| | - Nicole Bhave
- Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Ramazan Gen
- Division of Endocrinology, Department of Internal Medicine, Mersin University, Mersin, Turkey
| | - Banu Yurekli
- Division of Endocrinology, Department of Internal Medicine, Ege University, Izmir, Turkey
| | - Nilufer Ozdemir Kutbay
- Division of Endocrinology, Department of Internal Medicine, Celal Bayar University, Manisa, Turkey
| | - Zeynep Siklar
- Division of Endocrinology, Department of Pediatrics, Ankara University, Ankara, Turkey
| | - Adam H. Neidert
- Division of Metabolism, Endocrinology and Diabetes (MEND), Department of Internal Medicine, Michigan Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Rita Hench
- Division of Metabolism, Endocrinology and Diabetes (MEND), Department of Internal Medicine, Michigan Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Marwan K. Tayeh
- Departments of Pediatrics, University of Michigan, Ann Arbor, MI, USA
| | - Jeffrey W. Innis
- Departments of Pediatrics, University of Michigan, Ann Arbor, MI, USA
- Human Genetics, University of Michigan, Ann Arbor, MI, USA
| | - Jose Jalife
- Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
- Cardiac Arrhythmia Section, Centro Nacional de Investigaciones Cardiovasculares (CNIC) Carlos III, Madrid, Spain
| | - Hakan Oral
- Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Elif A. Oral
- Division of Metabolism, Endocrinology and Diabetes (MEND), Department of Internal Medicine, Michigan Medicine, University of Michigan, Ann Arbor, MI, USA
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Hughes AE, Hattersley AT, Flanagan SE, Freathy RM. Two decades since the fetal insulin hypothesis: what have we learned from genetics? Diabetologia 2021; 64:717-726. [PMID: 33569631 PMCID: PMC7940336 DOI: 10.1007/s00125-021-05386-7] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Accepted: 11/25/2020] [Indexed: 12/16/2022]
Abstract
In 1998 the fetal insulin hypothesis proposed that lower birthweight and adult-onset type 2 diabetes are two phenotypes of the same genotype. Since then, advances in research investigating the role of genetics affecting insulin secretion and action have furthered knowledge of fetal insulin-mediated growth and the biology of type 2 diabetes. In this review, we discuss the historical research context from which the fetal insulin hypothesis originated and consider the position of the hypothesis in light of recent evidence. In summary, there is now ample evidence to support the idea that variants of certain genes which result in impaired pancreatic beta cell function and reduced insulin secretion contribute to both lower birthweight and higher type 2 diabetes risk in later life when inherited by the fetus. There is also evidence to support genetic links between type 2 diabetes secondary to reduced insulin action and lower birthweight but this applies only to loci implicated in body fat distribution and not those influencing insulin resistance via obesity or lipid metabolism by the liver. Finally, we also consider how advances in genetics are being used to explore alternative hypotheses, namely the role of the maternal intrauterine environment, in the relationship between lower birthweight and adult cardiometabolic disease.
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Affiliation(s)
- Alice E Hughes
- Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK
| | - Andrew T Hattersley
- Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK
| | - Sarah E Flanagan
- Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK
| | - Rachel M Freathy
- Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK.
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Araújo-Vilar D, Sánchez-Iglesias S, Castro AI, Cobelo-Gómez S, Hermida-Ameijeiras Á, Rodríguez-Carnero G, Casanueva FF, Fernández-Pombo A. Variable Expressivity in Type 2 Familial Partial Lipodystrophy Related to R482 and N466 Variants in the LMNA Gene. J Clin Med 2021; 10:jcm10061259. [PMID: 33803652 PMCID: PMC8002937 DOI: 10.3390/jcm10061259] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 03/09/2021] [Accepted: 03/15/2021] [Indexed: 12/11/2022] Open
Abstract
Patients with Dunnigan disease (FPLD2) with a pathogenic variant affecting exon 8 of the LMNA gene are considered to have the classic disease, whereas those with variants in other exons manifest the "atypical" disease. The aim of this study was to investigate the degree of variable expressivity when comparing patients carrying the R482 and N466 variants in exon 8. Thus, 47 subjects with FPLD2 were studied: one group of 15 patients carrying the N466 variant and the other group of 32 patients with the R482 variant. Clinical, metabolic, and body composition data were compared between both groups. The thigh skinfold thickness was significantly decreased in the R482 group in comparison with the N466 group (4.2 ± 1.8 and 5.6 ± 2.0 mm, respectively, p = 0.002), with no other differences in body composition. Patients with the N466 variant showed higher triglyceride levels (177.5 [56-1937] vs. 130.0 [55-505] mg/dL, p = 0.029) and acute pancreatitis was only present in these subjects (20%). Other classic metabolic abnormalities related with the disease were present regardless of the pathogenic variant. Thus, although FPLD2 patients with the R482 and N466 variants share most of the classic characteristics, some phenotypic and metabolic differences suggest possible heterogeneity even within exon 8 of the LMNA gene.
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Affiliation(s)
- David Araújo-Vilar
- UETeM-Molecular Pathology Group, Department of Psychiatry, Radiology, Public Health, Nursing and Medicine, IDIS-CIMUS, University of Santiago de Compostela, 15706 Santiago de Compostela, Spain; (D.A.-V.); (S.S.-I.); (S.C.-G.); (Á.H.-A.)
- Division of Endocrinology and Nutrition, University Clinical Hospital of Santiago de Compostela, 15706 Santiago de Compostela, Spain; (A.I.C.); (G.R.-C.); (F.F.C.)
| | - Sofía Sánchez-Iglesias
- UETeM-Molecular Pathology Group, Department of Psychiatry, Radiology, Public Health, Nursing and Medicine, IDIS-CIMUS, University of Santiago de Compostela, 15706 Santiago de Compostela, Spain; (D.A.-V.); (S.S.-I.); (S.C.-G.); (Á.H.-A.)
| | - Ana I. Castro
- Division of Endocrinology and Nutrition, University Clinical Hospital of Santiago de Compostela, 15706 Santiago de Compostela, Spain; (A.I.C.); (G.R.-C.); (F.F.C.)
- CIBER Fisiopatología de la Obesidad y la Nutrición (CIBERobn), 28029 Madrid, Spain
| | - Silvia Cobelo-Gómez
- UETeM-Molecular Pathology Group, Department of Psychiatry, Radiology, Public Health, Nursing and Medicine, IDIS-CIMUS, University of Santiago de Compostela, 15706 Santiago de Compostela, Spain; (D.A.-V.); (S.S.-I.); (S.C.-G.); (Á.H.-A.)
| | - Álvaro Hermida-Ameijeiras
- UETeM-Molecular Pathology Group, Department of Psychiatry, Radiology, Public Health, Nursing and Medicine, IDIS-CIMUS, University of Santiago de Compostela, 15706 Santiago de Compostela, Spain; (D.A.-V.); (S.S.-I.); (S.C.-G.); (Á.H.-A.)
- Division of Internal Medicine, University Clinical Hospital of Santiago de Compostela, 15706 Santiago de Compostela, Spain
| | - Gemma Rodríguez-Carnero
- Division of Endocrinology and Nutrition, University Clinical Hospital of Santiago de Compostela, 15706 Santiago de Compostela, Spain; (A.I.C.); (G.R.-C.); (F.F.C.)
- Epigenomics in Endocrinology and Nutrition Group, Epigenomics Unit, Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), University Clinical Hospital of Santiago de Compostela, 15706 Santiago de Compostela, Spain
| | - Felipe F. Casanueva
- Division of Endocrinology and Nutrition, University Clinical Hospital of Santiago de Compostela, 15706 Santiago de Compostela, Spain; (A.I.C.); (G.R.-C.); (F.F.C.)
- CIBER Fisiopatología de la Obesidad y la Nutrición (CIBERobn), 28029 Madrid, Spain
| | - Antía Fernández-Pombo
- UETeM-Molecular Pathology Group, Department of Psychiatry, Radiology, Public Health, Nursing and Medicine, IDIS-CIMUS, University of Santiago de Compostela, 15706 Santiago de Compostela, Spain; (D.A.-V.); (S.S.-I.); (S.C.-G.); (Á.H.-A.)
- Division of Endocrinology and Nutrition, University Clinical Hospital of Santiago de Compostela, 15706 Santiago de Compostela, Spain; (A.I.C.); (G.R.-C.); (F.F.C.)
- Correspondence: ; Tel.: +34-981-951-611
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Araújo de Melo Campos JT, Dantas de Medeiros JL, Cardoso de Melo ME, Alvares da Silva M, Oliveira de Sena M, Sales Craveiro Sarmento A, Fassarella Agnez Lima L, de Freitas Fregonezi GA, Gomes Lima J. Endoplasmic reticulum stress and muscle dysfunction in congenital lipodystrophies. Biochim Biophys Acta Mol Basis Dis 2021; 1867:166120. [PMID: 33713793 DOI: 10.1016/j.bbadis.2021.166120] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 03/05/2021] [Accepted: 03/08/2021] [Indexed: 01/17/2023]
Abstract
Lipodystrophy syndromes are a group of rare diseases related to the pathological impairment of adipose tissue and metabolic comorbidities, including dyslipidemia, diabetes, insulin resistance, hypoleptinemia, and hypoadiponectinemia. They can be categorized as partial or generalized according to the degree of fat loss, and inherited or acquired disorders, if they are associated with genetic mutations or are related to autoimmunity, respectively. Some types of lipodystrophies have been associated with changes in both redox and endoplasmic reticulum (ER) homeostasis as well as muscle dysfunction (MD). Although ER stress (ERS) has been related to muscle dysfunction (MD) in many diseases, there is no data concerning its role in lipodystrophies' muscle physiopathology. Here we focused on congenital lipodystrophies associated with ERS and MD. We also described recent advances in our understanding of the relationships among ERS, MD, and genetic lipodystrophies, highlighting the adiponectin-protective roles.
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Affiliation(s)
- Julliane Tamara Araújo de Melo Campos
- Laboratório de Biologia Molecular e Genômica, Departamento de Biologia Celular e Genética, Centro de Biociências, Universidade Federal do Rio Grande do Norte, Natal, RN, Brazil.
| | - Jorge Luiz Dantas de Medeiros
- PneumoCardioVascular Lab/HUOL, Hospital Universitário Onofre Lopes, Empresa Brasileira de Serviços Hospitalares and Departamento de Fisioterapia, Universidade Federal do Rio Grande do Norte, Natal, RN, Brazil.
| | - Maria Eduarda Cardoso de Melo
- Laboratório de Biologia Molecular e Genômica, Departamento de Biologia Celular e Genética, Centro de Biociências, Universidade Federal do Rio Grande do Norte, Natal, RN, Brazil
| | - Monique Alvares da Silva
- Laboratório de Biologia Molecular e Genômica, Departamento de Biologia Celular e Genética, Centro de Biociências, Universidade Federal do Rio Grande do Norte, Natal, RN, Brazil
| | - Matheus Oliveira de Sena
- Laboratório de Biologia Molecular e Genômica, Departamento de Biologia Celular e Genética, Centro de Biociências, Universidade Federal do Rio Grande do Norte, Natal, RN, Brazil
| | - Aquiles Sales Craveiro Sarmento
- Unidade de Laboratório de Análises Clínicas e Anatomia Patológica, Hospital Universitário de Lagarto (HUL)/UFS, Lagarto, SE, Brazil
| | - Lucymara Fassarella Agnez Lima
- Laboratório de Biologia Molecular e Genômica, Departamento de Biologia Celular e Genética, Centro de Biociências, Universidade Federal do Rio Grande do Norte, Natal, RN, Brazil
| | - Guilherme Augusto de Freitas Fregonezi
- PneumoCardioVascular Lab/HUOL, Hospital Universitário Onofre Lopes, Empresa Brasileira de Serviços Hospitalares and Departamento de Fisioterapia, Universidade Federal do Rio Grande do Norte, Natal, RN, Brazil; Laboratório de Inovação Tecnológica em Reabilitação, Departamento de Fisioterapia, Universidade Federal do Rio Grande do Norte, Natal, RN, Brazil
| | - Josivan Gomes Lima
- Departamento de Medicina Clínica, Hospital Universitário Onofre Lopes (HUOL)/UFRN, Natal, RN, Brazil
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Lipták N, Gál Z, Biró B, Hiripi L, Hoffmann OI. Rescuing lethal phenotypes induced by disruption of genes in mice: a review of novel strategies. Physiol Res 2021; 70:3-12. [PMID: 33453719 DOI: 10.33549/physiolres.934543] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Approximately 35 % of the mouse genes are indispensable for life, thus, global knock-out (KO) of those genes may result in embryonic or early postnatal lethality due to developmental abnormalities. Several KO mouse lines are valuable human disease models, but viable homozygous mutant mice are frequently required to mirror most symptoms of a human disease. The site-specific gene editing systems, the transcription activator-like effector nucleases (TALENs), Zinc-finger nucleases (ZFNs) and the clustered regularly interspaced short palindrome repeat-associated Cas9 nuclease (CRISPR/Cas9) made the generation of KO mice more efficient than before, but the homozygous lethality is still an undesired side-effect in case of many genes. The literature search was conducted using PubMed and Web of Science databases until June 30th, 2020. The following terms were combined to find relevant studies: "lethality", "mice", "knock-out", "deficient", "embryonic", "perinatal", "rescue". Additional manual search was also performed to find the related human diseases in the Online Mendelian Inheritance in Man (OMIM) database and to check the citations of the selected studies for rescuing methods. In this review, the possible solutions for rescuing human disease-relevant homozygous KO mice lethal phenotypes were summarized.
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Affiliation(s)
- N Lipták
- NARIC-Agricultural Biotechnology Institute, Animal Biotechnology Department, Gödöllő, Hungary.
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O'Rahilly S. "Treasure Your Exceptions"-Studying Human Extreme Phenotypes to Illuminate Metabolic Health and Disease: The 2019 Banting Medal for Scientific Achievement Lecture. Diabetes 2021; 70:29-38. [PMID: 33355307 PMCID: PMC7881844 DOI: 10.2337/dbi19-0037] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
The study of humans with genetic mutations which lead to a substantial disturbance of physiological processes has made a contribution to biomedical science that is disproportionate to the rarity of affected individuals. In this lecture, I discuss examples of where such studies have helped to illuminate two areas of human metabolism. First, the control of insulin sensitivity and its disruption in states of insulin resistance and second, the regulation of energy balance and its disturbances in obesity.
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Affiliation(s)
- Stephen O'Rahilly
- MRC Metabolic Diseases Unit, Wellcome-MRC Institute of Metabolic Science, Addenbrooke's Treatment Centre, University of Cambridge, Cambridge, U.K.
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Lim K, Haider A, Adams C, Sleigh A, Savage DB. Lipodistrophy: a paradigm for understanding the consequences of "overloading" adipose tissue. Physiol Rev 2020; 101:907-993. [PMID: 33356916 DOI: 10.1152/physrev.00032.2020] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Lipodystrophies have been recognized since at least the nineteenth century and, despite their rarity, tended to attract considerable medical attention because of the severity and somewhat paradoxical nature of the associated metabolic disease that so closely mimics that of obesity. Within the last 20 yr most of the monogenic subtypes have been characterized, facilitating family genetic screening and earlier disease detection as well as providing important insights into adipocyte biology and the systemic consequences of impaired adipocyte function. Even more recently, compelling genetic studies have suggested that subtle partial lipodystrophy is likely to be a major factor in prevalent insulin-resistant type 2 diabetes mellitus (T2DM), justifying the longstanding interest in these disorders. This progress has also underpinned novel approaches to treatment that, in at least some patients, can be of considerable therapeutic benefit.
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Affiliation(s)
- Koini Lim
- Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom
| | - Afreen Haider
- Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom
| | - Claire Adams
- Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom
| | - Alison Sleigh
- Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom
| | - David B Savage
- Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom
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Knebel B, Müller-Wieland D, Kotzka J. Lipodystrophies-Disorders of the Fatty Tissue. Int J Mol Sci 2020; 21:ijms21228778. [PMID: 33233602 PMCID: PMC7699751 DOI: 10.3390/ijms21228778] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Revised: 11/18/2020] [Accepted: 11/18/2020] [Indexed: 02/07/2023] Open
Abstract
Lipodystrophies are a heterogeneous group of physiological changes characterized by a selective loss of fatty tissue. Here, no fat cells are present, either through lack of differentiation, loss of function or premature apoptosis. As a consequence, lipids can only be stored ectopically in non-adipocytes with the major health consequences as fatty liver and insulin resistance. This is a crucial difference to being slim where the fat cells are present and store lipids if needed. A simple clinical classification of lipodystrophies is based on congenital vs. acquired and generalized vs. partial disturbance of fat distribution. Complications in patients with lipodystrophy depend on the clinical manifestations. For example, in diabetes mellitus microangiopathic complications such as nephropathy, retinopathy and neuropathy may develop. In addition, due to ectopic lipid accumulation in the liver, fatty liver hepatitis may also develop, possibly with cirrhosis. The consequences of extreme hypertriglyceridemia are typically acute pancreatitis or eruptive xanthomas. The combination of severe hyperglycemia with dyslipidemia and signs of insulin resistance can lead to premature atherosclerosis with its associated complications of coronary heart disease, peripheral vascular disease and cerebrovascular changes. Overall, lipodystrophy is rare with an estimated incidence for congenital (<1/1.000.000) and acquired (1-9/100.000) forms. Due to the rarity of the syndrome and the phenotypic range of metabolic complications, only studies with limited patient numbers can be considered. Experimental animal models are therefore useful to understand the molecular mechanisms in lipodystrophy and to identify possible therapeutic approaches.
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Affiliation(s)
- Birgit Knebel
- German Diabetes-Center, Leibniz Center for Diabetes Research at Heinrich-Heine-University Düsseldorf, 40225 Düsseldorf, Germany;
- Institute for Clinical Biochemistry and Pathobiochemistry, 40225 Düsseldorf, Germany
- German Center for Diabetes Research (DZD), 85764 München-Neuherberg, Germany
| | - Dirk Müller-Wieland
- Clinical Research Center, Department of Internal Medicine I, University Hospital Aachen, 52074 Aachen, Germany;
| | - Jorg Kotzka
- German Diabetes-Center, Leibniz Center for Diabetes Research at Heinrich-Heine-University Düsseldorf, 40225 Düsseldorf, Germany;
- German Center for Diabetes Research (DZD), 85764 München-Neuherberg, Germany
- Correspondence: ; Tel.: +49-221-3382537
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Loss of MTX2 causes mandibuloacral dysplasia and links mitochondrial dysfunction to altered nuclear morphology. Nat Commun 2020; 11:4589. [PMID: 32917887 PMCID: PMC7486921 DOI: 10.1038/s41467-020-18146-9] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2019] [Accepted: 07/27/2020] [Indexed: 11/08/2022] Open
Abstract
Mandibuloacral dysplasia syndromes are mainly due to recessive LMNA or ZMPSTE24 mutations, with cardinal nuclear morphological abnormalities and dysfunction. We report five homozygous null mutations in MTX2, encoding Metaxin-2 (MTX2), an outer mitochondrial membrane protein, in patients presenting with a severe laminopathy-like mandibuloacral dysplasia characterized by growth retardation, bone resorption, arterial calcification, renal glomerulosclerosis and severe hypertension. Loss of MTX2 in patients' primary fibroblasts leads to loss of Metaxin-1 (MTX1) and mitochondrial dysfunction, including network fragmentation and oxidative phosphorylation impairment. Furthermore, patients' fibroblasts are resistant to induced apoptosis, leading to increased cell senescence and mitophagy and reduced proliferation. Interestingly, secondary nuclear morphological defects are observed in both MTX2-mutant fibroblasts and mtx-2-depleted C. elegans. We thus report the identification of a severe premature aging syndrome revealing an unsuspected link between mitochondrial composition and function and nuclear morphology, establishing a pathophysiological link with premature aging laminopathies and likely explaining common clinical features.
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Vasandani C, Li X, Sekizkardes H, Adams-Huet B, Brown RJ, Garg A. Diagnostic Value of Anthropometric Measurements for Familial Partial Lipodystrophy, Dunnigan Variety. J Clin Endocrinol Metab 2020; 105:5810271. [PMID: 32193531 PMCID: PMC7202860 DOI: 10.1210/clinem/dgaa137] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Accepted: 03/18/2020] [Indexed: 01/17/2023]
Abstract
CONTEXT Familial partial lipodystrophy, Dunnigan variety (FPLD2) is a rare autosomal dominant disorder resulting from LMNA causal variants, which is characterized by loss of subcutaneous fat from the extremities and predisposition to metabolic complications. The diagnostic value of various anthropometric measurements for FPLD2 remains unknown. OBJECTIVE To determine specificity and sensitivity of anthropometric measurements for the diagnosis of FPLD2. METHODS We measured skinfold thickness and regional body fat by dual energy X-ray absorptiometry (DXA) in 50 adult females and 6 males with FPLD2 at UT Southwestern and compared their data with the sex- and age-matched controls from the National Health and Nutrition Examination Survey (NHANES) 1999-2010. We further compared data from 1652 unaffected females from the Dallas Heart Study and 23 females with FPLD2 from the National Institutes of Health with the NHANES data. RESULTS The DXA-derived lower limb fat (%) had the best specificity (0.995) and sensitivity (1.0) compared with the upper limb fat, truncal fat, the ratio of lower limb to truncal fat, and triceps skinfold thickness for adult females with FPLD2. The lower limb fat below 1st percentile of NHANES females had a false-positive rate of 0.0054 and a false negative rate of 0. The diagnostic value of anthropometric parameters could not be determined for males with FPLD2 due to small sample size. CONCLUSIONS The lower limb fat (%) is the best objective anthropometric measure for diagnosing FPLD2 in females. Women with below the 1st percentile lower limb fat should undergo genetic testing for FPLD2, especially if they have metabolic complications.
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Affiliation(s)
- Chandna Vasandani
- The Division of Nutrition and Metabolic Diseases and the Center for Human Nutrition, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas
| | - Xilong Li
- Department of Population and Data Sciences, UT Southwestern Medical Center, Dallas, Texas
| | - Hilal Sekizkardes
- National Institute of Child Health and Human Development, National Institutes of Health, Bathesda, Maryland
| | - Beverley Adams-Huet
- Department of Population and Data Sciences, UT Southwestern Medical Center, Dallas, Texas
| | - Rebecca J Brown
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
| | - Abhimanyu Garg
- The Division of Nutrition and Metabolic Diseases and the Center for Human Nutrition, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas
- Correspondence: Abhimanyu Garg, M.D., Division of Nutrition and Metabolic Diseases, Department of Internal Medicine and the Center for Human Nutrition, 5323 Harry Hines Boulevard, Dallas, TX 75390-8537. E-mail:
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