bims-obesme Biomed News
on Obesity metabolism
Issue of 2026–03–01
fifteen papers selected by
Xiong Weng, University of Edinburgh
  1. MEDAG functions as an A-kinase-anchoring protein in adipocytes.
  2. Male obesity causes adipose mitochondrial dysfunction in F1 mouse progeny via a let-7-DICER axis.
  3. Microbial-derived 3-phenylpropionic acid orchestrates immune-progenitor cell crosstalk to promote beige adipogenesis and energy expenditure.
  4. Modeling lipid homeostasis using stable isotope tracing and flux analysis.
  5. Fatty acids promote uncoupled respiration via ATP/ADP carriers in white adipocytes.
  6. OMICmAge quantifies biological age by integrating multi-omics with electronic medical records.
  7. Multi-ancestry GWAS of age-related hearing loss identifies 140 loci and key cellular mechanisms.
  8. Molecular evolution of animal aging.
  9. Nuclear Myosin 1 links genomic architecture to adipose tissue remodeling, metabolic inflammation and obesity in mice.
  10. CLCC1 governs ER bilayer equilibration to maintain lipid homeostasis.
  11. Chromatin dynamics shape aging across organs.
  12. CLCC1 promotes hepatic neutral lipid flux and nuclear pore complex assembly.
  13. Organism-wide cellular dynamics and epigenomic remodeling in mammalian aging.
  14. Obesity as a catalyst for neurodegeneration.
  15. Familial Generalized and Partial Lipodystrophies Due to Rare Biallelic Variants in LMNA.
  1. Mol Cell. 2026 Feb 25. pii: S1097-2765(26)00096-1. [Epub ahead of print]
    MEDAG functions as an A-kinase-anchoring protein in adipocytes.
    Fen Long, Adhideb Ghosh, Tianyu Xu, Lianggong Ding, Chunyan Wu, Radhika Khandelwal, Falko Noé, Wenfei Sun, Hua Dong, Tongtong Wang, Anne Hoffmann, Vincent Gardeux, Bart Deplancke, Laith Abu-Nawwas, Patrik Stefanicka, Lukas Varga, Jonatan R Ruiz, Matthias Blüher, Miroslav Balaz, Anand Kumar Sharma, Christian Wolfrum.
      Induction of catabolic adipocyte activity independent of mitochondrial uncoupling to induce energy expenditure has received increasing attention. In this study, we identified mesenteric estrogen-dependent adipogenesis gene (MEDAG), a poorly studied gene, as a promising therapeutic target for enhancing energy expenditure in adipocytes. We demonstrated that adipose MEDAG expression positively correlates with obesity and metabolic dysfunction in humans. Consistently, adipocyte-specific ablation of Medag in mice leads to increased energy expenditure, offering protection from diet-induced obesity. Mechanistically, we show that MEDAG functions as an A-kinase-anchoring protein (AKAP), which can directly regulate protein kinase A (PKA) activity through a negative feedback loop, involving direct interaction with PKA leading to MEDAG phosphorylation and consequent feedback fine-tuning of PKA activity. Specifically, the direct interaction of MEDAG with the PKA-RIIβ subunit regulates the stability of PKA-RIIβ to prevent PKA hyperactivation. These findings position MEDAG as a target for adipose energy expenditure and uncover its AKAP activity.
    Keywords:  AKAP; MEDAG; PKA; cAMP-PKA signaling; catabolic adipocytes; energy expenditure; glucose uptake and utilization; lipolysis; metabolic diseases; obesity
    DOI:  https://doi.org/10.1016/j.molcel.2026.02.001
  2. Nat Commun. 2026 Feb 24.
    Male obesity causes adipose mitochondrial dysfunction in F1 mouse progeny via a let-7-DICER axis.
    Chien Huang, Joo-Hyun Park, Ali Altıntaş, Natasa Stanic, Kristine Kyle de Leon, Signe Isacson, Panagiotis Kalogeropoulos, Hande Topel, Tobias Madsen, Sebastian Zanner, Phillip Mm Ruppert, Rocio Valdebenito, Jesper Havelund, Bjørk Ditlev Marcher Larsen, Yen-Ting Chien, Wen-Chi Huang, Yovita Permata Budi, Yi-Fan Jiang, Andréa Livia Rocha, Niedson Correia Lima-Junior, Karolina Szczepanowska, Jan-Wilm Lackmann, Aleksandra Trifunovic, Eva Kildall Hejbøl, Sönke Detlefsen, Ida Engberg Jepsen, Stefanie Hansborg Kolstrup, Ricardo Laguna-Barraza, Javier Martin-Gonzalez, Konstantin Khodosevich, Nils J Færgeman, Marcelo A Mori, Marc R Friedländer, Anita Öst, Romain Barrès, Jan-Wilhelm Kornfeld.
      Male obesity negative affects gametic function and offspring metabolism. We here describe that (F0) obesity and weight loss in male mice reversibly alter metabolism and impair adipose mitochondrial function. These metabolic aberrations are transmitted to male offsprings (F1), which display reduced mitochondrial gene expression. Mechanistically, we identify microRNAs let-7d/e as epigenetic mediators induced in obese F0 sperm and in F0/F1 adipose tissue, where they silence the miRNA processor DICER1 and impair mitochondrial activity. Microinjecting let-7d/e into lean zygotes phenocopies the paternal obesity phenotype, inducing glucose intolerance and mitochondrial gene suppression in sired offspring. Single-cell RNA sequencing of blastomeres reveals that let-7d/e impair oxidative metabolism in early embryos. Furthermore, lifestyle-induced weight loss in males with obesity downregulates human HSA-LET-7D/E in semen, indicating a conserved role for let-7 in transmission of metabolic health. These findings demonstrate that microRNA let-7 in sperm reprograms offspring metabolism by modulating mitochondrial function during early development.
    DOI:  https://doi.org/10.1038/s41467-026-69686-5
  3. Cell Metab. 2026 Feb 24. pii: S1550-4131(26)00019-7. [Epub ahead of print]
    Microbial-derived 3-phenylpropionic acid orchestrates immune-progenitor cell crosstalk to promote beige adipogenesis and energy expenditure.
    Defu Li, Bo Xia, Ruoci Hu, Zhao Zhang, Cong Xu, Hanjian Zhou, Xiao Li, Yonglin Hua, Shusong Wu, Ke Zhang, Yuwei Jiang, Jiangwei Wu, Yexian Yuan.
      Cold exposure induces beige adipogenesis in white adipose tissue, enhancing thermogenesis and energy expenditure. While gut microbiota-derived metabolites influence host metabolism, their role in thermogenic adaptation remains poorly defined. Here, we identify P. copri as a key microbial mediator of cold-induced adipose remodeling. Cold exposure expands P. copri in the colon, which produces 3-phenylpropionic acid (3-PPA), a metabolite that promotes beige adipocyte formation and increases energy expenditure. Mechanistically, 3-PPA signals through free fatty acid receptor 1 in M2-like macrophages, inducing chemokine C-X-C motif chemokine 13 (CXCL13) secretion, which recruits T follicular helper cells to facilitate beige adipogenesis. Lineage-tracing analyses show that adipocyte progenitor cells generate new beige adipocytes in response to 3-PPA. Moreover, 3-PPA supplementation counteracts high-fat diet-induced obesity in mice and promotes thermogenesis in mouse, pig, and human adipose progenitor cells. These findings define a microbiota-immune-adipose progenitor axis regulating cold adaptation and highlight microbial metabolites as potential metabolic therapies.
    Keywords:  3-PPA; CXCL13; FFAR1; M2-like macrophages; Prevotella copri; UCP1; adipocyte progenitor cells; beige adipogenesis; obesity
    DOI:  https://doi.org/10.1016/j.cmet.2026.01.017
  4. Cell Metab. 2026 Feb 20. pii: S1550-4131(26)00020-3. [Epub ahead of print]
    Modeling lipid homeostasis using stable isotope tracing and flux analysis.
    Karl Wessendorf-Rodriguez, Maureen L Ruchhoeft, Christopher W Murray, Yale Huang, Ethan L Ashley, Hector M Galvez, Grace H McGregor, Shrikaar Kambhampati, Reuben J Shaw, Christian M Metallo.
      Lipids enable compartmentation and coordinate membrane-localized signaling events in cells, and dysregulation of lipid metabolism is linked to many disease states. However, limited tools are available for quantifying metabolic fluxes across the lipidome. To measure fluxes encompassing lipid homeostasis in cells and tissue slices, we apply stable isotope tracing, liquid chromatography-high-resolution mass spectrometry, and network-based isotopologue modeling to non-small cell lung cancer (NSCLC) models. Lipid metabolic flux analysis (Lipid-MFA) enables quantitation of fatty acid synthesis, elongation, headgroup assembly, and salvage reactions within virtually any biological system. Using Lipid-MFA, we observed decreased fatty acid synthase and very long-chain fatty acid (VLCFA) elongation fluxes, along with increased sphingolipid recycling, in p53-deficient versus liver kinase B1 (LKB1)-deficient NSCLC tumors using precision-cut lung slice culture. We also apply Lipid-MFA to demonstrate the unique trafficking of ceramides with distinct n-acyl chain lengths, highlighting the utility of this approach in elucidating molecular mechanisms in lipid homeostasis.
    Keywords:  ELOVL1; LKB1; TP53; ceramide; lipid homeostasis; metabolic flux analysis; non-small cell lung cancer; precision-cut lung slice culture; sphingolipids; very long-chain fatty acids
    DOI:  https://doi.org/10.1016/j.cmet.2026.01.020
  5. Nat Metab. 2026 Feb 23.
    Fatty acids promote uncoupled respiration via ATP/ADP carriers in white adipocytes.
    Maryam Ahmadian, A Melisa Aksu, Preetveer Dhillon, Zane J Zerbel, Yosip Kelemen, Oluwafemi Gbayisomore, Nicolás Gómez-Banoy, Serena J Chen, Shannon M Reilly.
      Energy stored in adipocytes as triglycerides is mobilized via lipolysis, releasing fatty acids and glycerol into the circulation. Re-esterification of fatty acids that remain within the adipose tissue is the primary driver of adipocyte ATP consumption. Paradoxically, re-esterification suppresses respiration in lipolytic adipocytes. We previously found that STAT3 drives respiration by inhibiting re-esterification via GPAT3. Here we show that free fatty acids drive uncoupled respiration in complex with the ATP/ADP carriers. The impacts of lipolysis and re-esterification on uncoupled respiration correspond with fatty acids, not fatty acyl-CoAs or beta-oxidation. Under standard housing conditions, brown adipocyte uncoupling via uncoupling protein 1 is the dominant thermogenic pathway. However, in obese thermoneutral-adapted mice, uncoupled respiration in white adipocytes contributes to thermogenesis and cold tolerance, independent of brown adipose tissue or muscle activity. Our results suggest that uncoupled respiration in white adipocytes contributes to whole-body energy expenditure and could be a promising target for obesity treatment.
    DOI:  https://doi.org/10.1038/s42255-026-01467-2
  6. Nat Aging. 2026 Feb 25.
    OMICmAge quantifies biological age by integrating multi-omics with electronic medical records.
    Qingwen Chen, Varun B Dwaraka, Natàlia Carreras-Gallo, Jenel F Armstrong, Raghav Sehgal, M Austin Argentieri, Anne Richmond, Andrea Aparicio, Kevin Mendez, Yulu Chen, Sofina Begum, Priyadarshini Kachroo, Nicole Prince, Tao Guo, Hannah Went, Tavis Mendez, Aaron Lin, Logan Turner, Mahdi Moqri, Su H Chu, Rachel S Kelly, Scott T Weiss, Nicholas J W Rattray, Vadim N Gladyshev, Elizabeth Karlson, Craig E Wheelock, Ewy A Mathé, Amber Dahlin, Michael J McGeachie, Riccardo E Marioni, Albert T Higgins-Chen, Ryan Smith, Jessica Lasky-Su.
      Biological aging reflects complex cellular and biochemical processes that can be measured across multiple omic layers. Using routine clinical laboratory data from ~31,000 participants in the Mass General Brigham Biobank, we developed EMRAge, a biomarker of mortality risk that can be broadly recapitulated across electronic medical records. Here we show that EMRAge can be modeled using elastic net regression with DNA methylation and multi-omics to generate DNAmEMRAge and OMICmAge, respectively. Both biomarkers are strongly associated with incident and prevalent chronic diseases and mortality, performing comparably or better than current biomarkers across discovery (Massachusetts General Brigham Aging Biobank Cohort, n = 3,451) and validation cohorts (TruDiagnostic, n = 14,213; Generation Scotland, n = 18,672). Importantly, OMICmAge leverages epigenetic biomarker proxies to integrate proteomic, metabolomic and clinical domains while remaining quantifiable from DNA methylation alone. This framework establishes an accessible, scalable measure of biological aging with potential to reveal molecular interconnections that shape healthspan and disease risk.
    DOI:  https://doi.org/10.1038/s43587-026-01073-7
  7. Nat Commun. 2026 Feb 21.
    Multi-ancestry GWAS of age-related hearing loss identifies 140 loci and key cellular mechanisms.
    Lulu Shi, Haibin He, Junpeng Li, Kai Gai, Wenjian Li, Yu Zhao, Huijun Yuan, Yang Wu.
      Age-related hearing loss is a prevalent and growing public health issue among the elderly. Here, we perform a multi-ancestry genome-wide association study comprising 456,613 cases and 1,053,834 controls, identifying 140 independent loci associated with age-related hearing loss, including 44 novel signals. We further fine-map 9 likely causal missense variants for age-related hearing loss and provide evidence of purifying selection for age-related hearing loss-associated variants. Notably, genetic risk for age-related hearing loss is strongly correlated with behavior traits such as neuroticism score and irritability. Integration of molecular phenotypes identifies 22 genes and 85 DNA methylation sites significantly associated with age-related hearing loss. Moreover, analyses incorporating spatial and single-cell transcriptomic identify the inner ear as a crucial site of age-related hearing loss, emphasizing the importance of hair cells, supporting cells, basal and root cells of the stria vascularis to its pathogenesis. Our study provides genetic and cellular insights into age-related hearing loss and advance our understanding of its genetics architecture.
    DOI:  https://doi.org/10.1038/s41467-026-69894-z
  8. EMBO J. 2026 Feb 27.
    Molecular evolution of animal aging.
    Daniel H Nussey, Fabrizio d'Adda di Fagagna, Allison J Bardin, Helen Blau, Anne Brunet, Dmitry V Bulavin, Longhua Guo, Eiji Hara, Jan Philipp Junker, Vera Gorbunova, Maria Mittelbrunn, Michael Rera, Jane Reznick, Andrei Seluanov, Björn Schumacher, Emma C Teeling, Dario Riccardo Valenzano, Jing Ye, Maximina H Yun, George A Garinis, Eric Gilson.
      Comparative biology plays a crucial role in uncovering fundamental biological mechanisms and providing evolutionary models for their variation. This approach is particularly valuable for studying aging, given the remarkable diversity in aging trajectories across the tree of life. Many evolutionary theories of aging were proposed well before the discovery of the molecular mechanisms involved, and they remain largely theoretical. Moreover, the growing number of model organisms and the expanding array of experimental and theoretical approaches used to study aging have often remained compartmentalized. As a result, integrating these diverse insights into a unified framework has become increasingly important. As a step toward this goal, this field perspective outlines general biological mechanisms that help explain the variability in aging patterns and longevity across the animal kingdom.
    Keywords:  Aging; Development; Environment; Evolution; Senescence
    DOI:  https://doi.org/10.1038/s44318-026-00725-z
  9. Cell Death Dis. 2026 Feb 26.
    Nuclear Myosin 1 links genomic architecture to adipose tissue remodeling, metabolic inflammation and obesity in mice.
    Samira Khalaji, Tomas Venit, Zuzana Lukáčová, Valentina Fambri, Rahul Shrestha, Sachin Kaluarachchi, Maylis Boitet, Maud Fagny, Giuseppe Saldi, Piergiorgio Percipalle.
      Adipocyte differentiation involves a metabolic transition from oxidative phosphorylation (OXPHOS) to aerobic glycolysis, allowing preadipocytes to meet the biosynthetic and energetic demands of maturation. Here, we show that nuclear myosin 1 (NM1), a chromatin-associated actomyosin motor, known to control transcription and chromatin accessibility, is required for metabolic homeostasis during adipocyte differentiation. Integrated ATAC-seq and RNA-seq profiling of NM1-deficient mouse embryonic fibroblasts (MEFs) revealed coordinated downregulation of key adipogenic and lipid-droplet machinery genes like Cebpa, Plin2, Abhd5, Agpat2, Pink1, and altered enhancer accessibility near adipogenesis-linked transcription factors (TFs) such as Klf6, Foxo3, Smad5, and Gata4. NM1 knockout (KO) mesenchymal stem cells (MSCs) exhibited impaired differentiation potential despite enlarged adipocyte morphology. In vivo, NM1-deficient mice developed progressive visceral obesity, accompanied by transcriptional reprogramming in epididymal white adipose tissue (eWAT), including repression of mitochondrial and adipogenic pathways and activation of inflammatory networks driven by IFNG, IL33, and TNF. Cross-species network analysis highlighted conserved regulatory architecture centered on MYO1C, implicating NM1/MYO1C as key chromatin-level regulators of adipose remodeling.
    DOI:  https://doi.org/10.1038/s41419-026-08525-3
  10. Nature. 2026 Feb 25.
    CLCC1 governs ER bilayer equilibration to maintain lipid homeostasis.
    Lingzhi Wu, Jianqin Wang, Yawei Wang, Junhan Yang, Yuanhang Yao, Yonglun Wang, Dong Huang, Yating Hu, Xinxuan Xu, Renqian Wang, Wenjing Du, Yiting Shi, Quan Li, Lu Liu, Yuangang Zhu, Shijie Li, Feng-Jung Chen, Xiuqin Zhang, Xiao Wang, Qiang Guo, Li Xu, Peng Li, Xiao-Wei Chen.
      Orchestration of lipid production, storage and mobilization is vital for cellular and systemic homeostasis1,2. Dysfunctional plasma lipid control represents the major risk factor for cardiometabolic diseases-the leading cause of human mortality3,4. Within the cellular landscape, the endoplasmic reticulum (ER) is the central hub of lipid synthesis and secretion, particularly in metabolically active hepatocytes in the liver or enterocytes in the gut5,6. Initially assembled in the ER lumen, lipid-ferrying lipoproteins necessitate the cross-membrane transfer of both neutral and phospholipids onto the lumenal apolipoprotein B (APOB), in a poorly defined process7-10. Here we show that the ER protein CLCC1 regulates cellular lipid partition and, consequently, systemic lipid homeostasis by participating in trans-bilayer equilibration of phospholipids. CLCC1 partners with the phospholipid scramblase TMEM41B11,12 to recognize imbalanced bilayers and promote lipid scrambling, thereby supporting lipoprotein biogenesis and the subsequent bulk lipid transport. Loss of CLCC1 or TMEM41B leads to the emergence of giant lumenal lipid droplets enclosed by imbalanced ER bilayers and, consequently, accelerated pathogenesis of metabolic-dysfunction-associated liver steatohepatitis. The results reveal that phospholipid scrambling at the ER is essential for establishing a dynamic equilibrium. Considering the requirement of trans-bilayer phospholipid equilibration in numerous biological processes, ranging from catabolic autophagy to viral infection13-16, we anticipate that future work will elucidate a homeostatic control mechanism intrinsic to ER function in lipid biogenesis and distribution.
    DOI:  https://doi.org/10.1038/s41586-026-10161-y
  11. Science. 2026 Feb 26. 391(6788): 869-870
    Chromatin dynamics shape aging across organs.
    Sam N Barnett, Michela Noseda.
      Age-related chromatin remodeling includes shared and specific signatures across cell types, sex, and organs.
    DOI:  https://doi.org/10.1126/science.aef5650
  12. Nature. 2026 Feb 25.
    CLCC1 promotes hepatic neutral lipid flux and nuclear pore complex assembly.
    Alyssa J Mathiowetz, Emily S Meymand, Güneş Parlakgül, Niek van Hilten, Emily F Torres, Leonardo L Artico, Kirandeep K Deol, Mike Lange, Stephany P Pang, Cody E Doubravsky, Melissa A Roberts, Danielle M Jorgens, Reena Zalpuri, Misun Kang, Casadora Boone, Brian W Parks, Yaohuan Zhang, David W Morgens, Emily Tso Newman, Yingjiang Zhou, Saswata Talukdar, Michael Grabe, Gregory Ku, Tim P Levine, Ana Paula Arruda, James A Olzmann.
      Imbalances in lipid storage and secretion lead to hepatic steatosis, the accumulation of lipid droplets in hepatocytes1,2. Our understanding of the mechanisms that govern the channelling of neutral lipids in hepatocytes towards cytosolic lipid droplets or secreted lipoproteins remains incomplete3,4. Here we performed a series of CRISPR-Cas9 screens under different metabolic states that led to the identification of CLCC1 as a critical regulator of neutral lipid storage and secretion in hepatocytes. Loss of CLCC1 resulted in the buildup of large lipid droplets in hepatoma cells and Clcc1 knockout in mice caused liver steatosis. Lipid droplets were present in the lumen of the endoplasmic reticulum of the Clcc1-knockout hepatocytes and exhibited properties of lipoproteins, indicating a profound shift in neutral lipid flux. The loss of CLCC1 also led to the accumulation of nuclear membrane herniations accompanied by a reduction in nuclear pores. Remote homology searches identified a domain in CLCC1 that is homologous to yeast Brl1 and Brr6, factors that promote nuclear envelope fusion during nuclear pore complex assembly. Molecular dynamics simulations and mutagenesis studies support a model in which CLCC1 mediates membrane bending and fusion. We propose that CLCC1 mediates membrane fusion to promote hepatic neutral lipid flux and nuclear pore complex assembly.
    DOI:  https://doi.org/10.1038/s41586-025-10064-4
  13. Science. 2026 Feb 26. 391(6788): eadw6273
    Organism-wide cellular dynamics and epigenomic remodeling in mammalian aging.
    Ziyu Lu, Zehao Zhang, Zihan Xu, Abdulraouf Abdulraouf, Wei Zhou, Junyue Cao.
      To investigate organism-wide cellular alterations and epigenomic dynamics during aging, we constructed a single-cell chromatin accessibility atlas spanning 21 mouse tissues across three age groups and both sexes. We found that around one-quarter of 536 organ-specific cell types and 1828 finer-grained subtypes exhibited considerable age-related population shifts. Cellular states from broadly distributed lineages displayed synchronized dynamics with age, indicating systemic signals that coordinate these changes. Molecular analyses identified both intrinsic regulators (chromatin peaks, transcription factor activity) and extrinsic factors (cytokine programs) underlying these shifts. Moreover, ~40% of aging-associated population dynamics were sex-dependent, with tens of thousands of peaks altered exclusively in one sex. Together, these findings present a comprehensive framework for how aging reshapes the chromatin landscape and cellular composition across diverse tissues.
    DOI:  https://doi.org/10.1126/science.adw6273
  14. Nat Metab. 2026 Feb 27.
    Obesity as a catalyst for neurodegeneration.
    Bandy Chen, Amanda Rodríguez-Díaz, Marc Schneeberger, Eric Topol.
      The parallel rise in obesity and neurological disorders suggests a potential mechanistic link between these two conditions. Midlife obesity is a well-established risk factor for cognitive decline and neurological disorders; however, the underlying mechanisms and cause-and-effect relationship remain poorly defined, in part owing to limited spatiotemporal resolution in existing studies and the absence of a unifying framework. Recent studies have begun to uncover pathways linking obesity to neurodegenerative vulnerability. First, we discuss how obesity induces brain-wide reprogramming across neural, metabolic and vascular systems including neurovascular coupling, blood-brain barrier integrity, cerebrospinal fluid dynamics and myelination. By systematically examining the disparate mechanisms for each condition, a more cohesive picture emerges, revealing progressive neurodegeneration driven by chronic metabolic overload. Lastly, we propose a framework that integrates these different mechanisms with both spatial and temporal specificity.
    DOI:  https://doi.org/10.1038/s42255-026-01477-0
  15. Int J Mol Sci. 2026 Feb 11. pii: 1724. [Epub ahead of print]27(4):
    Familial Generalized and Partial Lipodystrophies Due to Rare Biallelic Variants in LMNA.
    Michael Hwang, Charlita Worthy, Elaine Cochran, Megan Startzell, Ranganath Muniyappa, Chao Xing, Abhimanyu Garg, Rebecca J Brown.
      Genetic lipodystrophies are a heterogeneous group of autosomal dominant and recessive disorders characterized by generalized or partial loss of body fat. Most patients with familial partial lipodystrophy (FPLD) have dominant inheritance with heterozygous pathogenic missense variants in LMNA. Here, we report two females with rare biallelic variants in LMNA presenting with divergent lipodystrophic phenotypes. Proband 1, a 32-year-old female, has near-generalized lipodystrophy (body fat 12.7%) due to compound heterozygous c.1745G>T (p.R582L) and c.1750C>T (p.R584C) LMNA variants. She was diagnosed with diabetes at age 17, hypertriglyceridemia at age 18, and metabolic dysfunction-associated steatotic liver disease (MASLD) at age 20. She was treated with metreleptin with only partial improvement in metabolic parameters. Her parents, heterozygous carriers of these variants, did not have lipodystrophy. Proband 2, a 35-year-old female, has partial lipodystrophy (body fat 21.2%) due to a homozygous c.1750C>T (p.R584C) LMNA variant. She was diagnosed with diabetes at age 19 and had a history of hypertriglyceridemia and mild hepatic steatosis. Her parents reportedly did not have lipodystrophy. These cases highlight the expression of LMNA variants in the homozygous or compound heterozygous state, manifesting in near-generalized and partial loss of body fat with distinct phenotypic heterogeneity.
    Keywords:  LMNA; biallelic; compound heterozygous; generalized lipodystrophy; homozygous; lamin A; partial lipodystrophy
    DOI:  https://doi.org/10.3390/ijms27041724
This page is being maintained by Thomas Krichel. It was last updated on 2026‒03‒02 at 15:32.