bims-obesme 2025-11-02 papers

bims-obesme

Biomed News

on Obesity metabolism

Issue of 2025–11–02
eleven papers selected by
Xiong Weng, University of Edinburgh

Discovery of obesity genes through cross-ancestry analysis.
Chaperone-mediated autophagy controls brown adipose tissue thermogenic activity.
Brown adipose tissue and skeletal muscle coordinately contribute to thermogenesis in mice.
Lysine potentiates insulin secretion via AASS-dependent catabolism and regulation of GABA content and signaling.
Cardiomyocyte Nucleoporin 35 regulates pathological cardiac remodeling through Wif1.
Piezo1 activation suppresses bone marrow adipogenesis to prevent osteoporosis by inhibiting a mechanoinflammatory autocrine loop.
Protein restriction reprograms the multi-organ proteomic landscape of mouse aging.
Exploring penetrance of clinically relevant variants in over 800,000 humans from the Genome Aggregation Database.
DNA topoisomerase II promotes N6-adenosine mRNA methylation.
Distinct senotypes in p16- and p21-positive cells across human and mouse aging tissues.
Epigenetic dysregulation in aged muscle stem cells drives mesenchymal progenitor expansion via IL-6 and Spp1 signaling.

Nat Commun. 2025 Oct 30. 16(1): 9319

Discovery of obesity genes through cross-ancestry analysis.

Deepro Banerjee, Santhosh Girirajan.

Gene discoveries in obesity have largely relied on homogeneous populations, limiting their generalizability across ancestries. Here, we conduct a gene-based rare variant association study of BMI on 839,110 individuals from six ancestries across two population-scale biobanks. A cross-ancestry meta-analysis identifies 13 genes, including YLPM1, RIF1, GIGYF1, SLC5A3, and GRM7, that confer about three-fold risk for severe obesity, are expressed in the brain and adipose tissue, and are linked to obesity traits such as body-fat percentage. While YLPM1, MC4R, and SLTM show consistent effects, GRM7 and APBA1 show significant ancestral heterogeneity. Polygenic risk additively increases obesity penetrance, and phenome-wide studies reveal additional associations, including YLPM1 with altered mental status. These genes also influence cardiometabolic comorbidities, including GIGYF1 and SLTM towards type 2 diabetes with or without BMI as a mediator, and altered levels of plasma proteins, such as LECT2 and NCAN, which in turn affect BMI. Our findings provide insights into the genetic basis of obesity and its related comorbidities across ancestries and ascertainments.

DOI: https://doi.org/10.1038/s41467-025-64933-7
Sci Adv. 2025 Oct 31. 11(44): eady0415

Chaperone-mediated autophagy controls brown adipose tissue thermogenic activity.

Alberto Mestres-Arenas, Tania Quesada-López, Albert Blasco-Roset, Aleix Gavaldà-Navarro, Francisco J Godoy-Nieto, Rubén Cereijo, Susmita Kaushik, Antonio Diaz, Marta Giralt, Francesc Villarroya, Ana Maria Cuervo, Joan Villarroya.

Brown adipose tissue (BAT) protects against obesity, diabetes, and cardiovascular disease. During BAT activation, macroautophagy is inhibited, while chaperone-mediated autophagy (CMA) is induced, promoting thermogenic gene expression, adipokine release, oxidative activity, and lipolysis. Aging reduces BAT function and lowers levels of LAMP2A, the rate-limiting CMA component. Pharmacological CMA activation restores BAT activity in aged mice. To explore the CMA's role in BAT, we generated LAMP2A-deficient brown adipocytes and found that CMA regulates proteins essential for thermogenesis and metabolism. Blocking CMA in BAT reduced energy expenditure, raised blood triglycerides, impaired secretion, and led to an increase of thermogenesis repressors. These findings show that CMA is essential for maintaining BAT function, especially during adaptive thermogenesis. By degrading repressors of thermogenesis, CMA supports BAT activity under cold or metabolic stress. This work highlights CMA as a key regulator of BAT plasticity and a promising therapeutic target for treating age-related metabolic disorders.

DOI: https://doi.org/10.1126/sciadv.ady0415
Elife. 2025 Oct 27. pii: RP99982. [Epub ahead of print]13

Brown adipose tissue and skeletal muscle coordinately contribute to thermogenesis in mice.

Yuna Izumi-Mishima, Rie Tsutsumi, Tetsuya Shiuchi, Saori Fujimoto, Momoka Taniguchi, Mizuki Sugiuchi, Manaka Tsutsumi, Yuko Okamatsu-Ogura, Takeshi Yoneshiro, Masashi Kuroda, Kazuhiro Nomura, Hiroshi Sakaue.

  Endotherms increase the rate of metabolism in metabolic organs as one strategy to cope with a decline in the temperature of the external environment. However, an additional major contributor to maintenance of body temperature in a cold environment is contraction-based thermogenesis in skeletal muscle. Here, we show that impairment of hind limb muscle contraction by cast immobilization induced a loss of function of skeletal muscle and activated brown adipose tissue (BAT) thermogenesis as a compensatory mechanism. BAT utilizes free branched-chain amino acids (BCAAs) derived from skeletal muscle as an energy substrate for thermogenesis, and interleukin-6 released by skeletal muscle stimulates BCAAs production in muscle for support of BAT thermogenesis. Additionally, this thermoregulatory system between BAT and skeletal muscle may also play an important role in response to cold temperatures or acute stress. Our findings suggest that BAT and skeletal muscle cooperate to maintain body temperature in endotherms.

Keywords:  amino acids; biochemistry; brown adipose tissue; chemical biology; inter-organ metabolic network; mouse; skeletal muscle; thermogenesis

DOI:  https://doi.org/10.7554/eLife.99982
Metabolism. 2025 Oct 28. pii: S0026-0495(25)00292-6. [Epub ahead of print] 156423

Lysine potentiates insulin secretion via AASS-dependent catabolism and regulation of GABA content and signaling.

Felipe Munoz, Qian Gao, Matthias Mattanovich, Kajetan Trost, Ondřej Hodek, Andreas Lindqvist, Nils Wierup, Malin Fex, Thomas Moritz, Hindrik Mulder, Luis Rodrigo Cataldo.

  Lysine is an essential amino acid with insulinotropic effects in humans. In vitro, it enhances glucose-stimulated insulin secretion (GSIS) in β-cell lines and rodent islets. While lysine is thought to act via membrane depolarization similar to arginine, the role of its intracellular metabolism in β-cell function remains unexplored. Here, we show that lysine acutely potentiates GSIS and that genes encoding enzymes in the lysine degradation pathway, including Aminoadipate-semialdehyde synthase (AASS), a key mitochondrial enzyme catalysing the first two steps of lysine catabolism, were present in human pancreatic islets and INS1 832/13 β cells. Some of these genes including AASS, ALDH7A1, DHTKD1, and HADH, were downregulated in pancreatic islets from type 2 diabetes (T2D) versus non-diabetic (ND) donors. Silencing AASS in human islets and INS1 832/13 β cells led to reduced GSIS. Integrated transcriptomics and metabolomics revealed altered expression of GABA metabolism genes, reduced GABA content and accumulation of glutamate in Aass-KD cells. Mitochondrial TCA cycle and OXPHOS function was impaired, evidenced by decreased ATP/ADP ratio, diminished glucose-stimulated mitochondrial respiration, and elevated lactate/pyruvate ratio. Cytosolic calcium responses to glucose and GABA were also disrupted. Pharmacological analyses demonstrated that inhibition of GABA synthesis or degradation did not account for the reduced GSIS, but providing substrates and activation of GDH partially restored insulin secretion, pointing to a diminished glutamate supply as a contributing factor. Remarkably, exogenous GABA restored insulin secretion in β cells and human islets with suppressed AASS-dependent lysine catabolism, supporting a role for GABA as both a metabolic substrate and signaling effector. Together, these findings identify AASS-mediated lysine catabolism as a critical regulator of β-cell metabolic integrity, linking impaired lysine metabolism to GABA depletion, mitochondrial dysfunction, and secretory failure in T2D islets. They also underscore the nutritional importance of essential amino acids such as lysine in sustaining GSIS and glucose homeostasis, and support therapeutic strategies aimed at restoring lysine catabolism or GABA/glutamate balance to maintain β-cell function.

Keywords:  AASS; Amino acids; GABA; GABA shunt; GDH; Glutamate; Insulin secretion; Lysine; Mitochondrial metabolism; TCA cycle; Type 2 diabetes

DOI:  https://doi.org/10.1016/j.metabol.2025.156423
Cardiovasc Res. 2025 Oct 27. pii: cvaf204. [Epub ahead of print]

Cardiomyocyte Nucleoporin 35 regulates pathological cardiac remodeling through Wif1.

Lei Pan, Tao Zhuang, Yi-Xiu Liang, Xi-De Hu, Tong Zhang, Ting Meng, Xiao-Dong Shi, Jun-Bo Ge.

   AIMS: Nucleoporin 35, a member of nucleoporins in nuclear pore complex, is involved in vitro cultured cardiomyocyte pHi homeostasis. The in vivo roles of cardiomyocyte Nup35 in pathological cardiac remodeling has not been determined.
METHODS AND RESULTS: Cardiac Nup35 expression is significantly down-regulated during Angiotensin II- and transverse aortic constriction- induced pathological cardiac remodeling. Cardiac-specific Nup35 knockout mice display severe cardiac fibrosis, hypertrophy and cardiac dysfunction. Conversely, Nup35 overexpression in cardiomyocytes exhibits the opposite protective phenotypes. Mechanistically, Nup35 directly bound to WNT inhibitory factor 1 (Wif1) mRNA assessed by RNA immunoprecipitation sequencing, resulting in the increased localization of pre-mRNA of Wif1 in nucleus and decreased Wif1 protein level in Nup35 deficient cardiomyocytes. Finally, the deteriorated pathological hypertrophy, cardiac fibrosis and dysfunction in Nup35 deficient cardiomyocytes were suppressed by cardiac specific adeno-associated virus subtype 9 (AAV9) target delivery of Wif1 mRNA.
CONCLUSION: Cardiomyocyte Nup35, via its regulation of Wif1 mRNA transport in cardiomyocytes, alleviates pathological cardiac remodeling. Our study highlights potential therapeutic target in cardiac pathological remodeling.

Keywords:  Nup35; Wif1; angiotensin II; cardiac dysfunction; cardiac pathological remodeling; cardiomyocyte hypertrophy; fibrosis

DOI:  https://doi.org/10.1093/cvr/cvaf204
Signal Transduct Target Ther. 2025 Oct 28. 10(1): 357

Piezo1 activation suppresses bone marrow adipogenesis to prevent osteoporosis by inhibiting a mechanoinflammatory autocrine loop.

Baile Wang, Jie Liu, Qin Wang, Malika Arhatte, Lai Yee Cheong, Edyta Glogowska, Xue Jiang, Sookja Kim Chung, Leigang Jin, Qianxing Hu, Yu Wang, Eric Honoré, Aimin Xu.

With aging or osteoporosis, bone marrow adipogenesis is increased and inversely correlates with the loss of bone mass. Bone marrow adipocytes are derived from multipotent bone marrow mesenchymal stem cells (BMMSCs), which can differentiate into either fat or bone. BMMSCs are mechanosensitive cells, but how mechanical loading is implicated in the in vivo regulation of bone marrow adipogenesis and its impact on bone remodeling remain poorly understood. Here, we identify the mechanosensitive cationic channel Piezo1 in BMMSCs as a key suppressor of bone marrow adipogenesis by preventing local inflammation, thereby enhancing osteoblast differentiation and bone formation. Mice with a specific Piezo1 invalidation in BMMSCs exhibit osteoporosis and marrow adiposity, together with resistance to the beneficial effects of exercise on bone health. Accordingly, Piezo1-deficient BMMSCs in vitro preferentially differentiate into adipocytes rather than osteoblasts. Invalidation of Piezo1 in BMMSCs enhances the autocrine activation of CCR2 by Ccl2, which further induces lipocalin-2 (Lcn2) production via NF-κB activation, thereby promoting adipocyte differentiation. Conversely, Piezo1 opening induces Klf2 expression through CaMKII, preventing c-Jun activation, Ccl2 production and bone marrow adipogenesis. These findings demonstrate that Piezo1 activation in BMMSCs suppresses bone marrow adipogenesis to maintain bone strength by preventing the Ccl2-Lcn2 inflammatory autocrine loop, thus uncovering a previously unrecognized link between mechanotransduction, inflammation, and cell fate determination.

DOI: https://doi.org/10.1038/s41392-025-02455-w
Cell. 2025 Oct 24. pii: S0092-8674(25)01133-X. [Epub ahead of print]

Protein restriction reprograms the multi-organ proteomic landscape of mouse aging.

Tian Lu, Yuting Xie, Yingrui Wang, Xiling Lin, Xue Cai, Yuqi Zhang, Zongxiang Nie, Chang Su, Wanglong Gou, Hong Zhang, Jing Wang, Yan Zhong, Zeyin Lai, Jingjing Xiang, Peng-Fei Shan, Ju-Sheng Zheng, Huijun Wang, Yi Zhu, Tiannan Guo.

  Population aging is accelerating, yet the multi-organ aging process and the geroprotective effects of dietary protein restriction (PR) remain poorly understood. Here, we conducted comprehensive proteomic analyses on 41 mouse tissues during male mouse aging and PR. Our findings identified tissue-specific aging hallmarks, including widespread changes in immunoglobulins and serine protease inhibitors across multiple tissues. PR mitigated age-related tissue-specific protein expression, epigenomic states, and protein phosphorylation patterns, and it significantly improved adipose tissue functions. These findings were supported by independent reduced representation bisulfite sequencing (RRBS), phosphoproteomics, and pathological analyses. Furthermore, analysis of plasma samples from mice and humans confirmed the cardiovascular benefits of PR. We identified sexual and temporal variations in the impact of PR, with middle age being the optimal intervention period. Overall, our study depicts the multi-organ aging process and provides valuable insights into the geroprotective potential of PR.

Keywords:  aging; epigenomics; geroprotective; human; mouse; multi-organ; protein restriction; proteomics; thermogenesis

DOI:  https://doi.org/10.1016/j.cell.2025.10.004
Nat Commun. 2025 Oct 31. 16(1): 9623

Exploring penetrance of clinically relevant variants in over 800,000 humans from the Genome Aggregation Database.

Genome Aggregation Database Consortium

Incomplete penetrance, or absence of disease phenotype in an individual with a disease-associated variant, is a major challenge in variant interpretation. Studying individuals with apparent incomplete penetrance can shed light on underlying drivers of altered phenotype penetrance. Here, we investigate clinically relevant variants from ClinVar in 807,162 individuals from the Genome Aggregation Database (gnomAD), demonstrating improved representation in gnomAD version 4. We then conduct a comprehensive case-by-case assessment of 734 predicted loss of function variants in 77 genes associated with severe, early-onset, highly penetrant haploinsufficient disease. Here, we identify explanations for the presumed lack of disease manifestation in 701 of 734 variants (95%). Individuals with unexplained lack of disease manifestation in this set of disorders are rare, underscoring the need and power of deep case-by-case assessment presented here to minimize false assignments of disease risk, particularly in unaffected individuals with higher rates of secondary properties that result in rescue.

DOI: https://doi.org/10.1038/s41467-025-61698-x
Cell Rep. 2025 Oct 29. pii: S2211-1247(25)01239-2. [Epub ahead of print]44(11): 116468

DNA topoisomerase II promotes N6-adenosine mRNA methylation.

Clara Megías-Fernández, Irene Delgado-Sainz, Alberto León-Halcón, Valentina Buglioni, Federica Bruno, Cristina González-Aguilera, Magdalena M Maslon, Silvia Jimeno-González.

  DNA topoisomerase II (TOP2) is an enzyme that regulates DNA topology, primarily by removing DNA supercoiling. This function is crucial during transcription, as the movement of RNA polymerase II (RNAPII) generates torsional stress. However, the specific role of TOP2 in the regulation of gene expression remains to be fully elucidated, as both TOP2 inhibitors and poisons have been shown to upregulate specific genes. In this study, we show that TOP2 poisoning negatively affects transcription elongation of genes repressed at the level of promoter-proximal pausing. Importantly, this effect is counteracted by defective mRNA N6-adenosine methylation (m6A), which results in altered RNA turnover and pre-mRNA splicing. We propose that TOP2 serves a dual function, supporting the maintenance of basal transcription elongation while simultaneously promoting m6A modification in pre-mRNAs to reduce the overall gene expression output.

Keywords:  CP: Molecular biology; DNA topoisomerases; DNA topology; METTL3; RNA metabolism; RNA polymerase II; RNA stability; epitranscriptomics; gene expression; m6A modification; transcription elongation

DOI:  https://doi.org/10.1016/j.celrep.2025.116468
EMBO J. 2025 Oct 29.

Distinct senotypes in p16- and p21-positive cells across human and mouse aging tissues.

Dominik Saul, Diana Jurk, Madison L Doolittle, Robyn Laura Kosinsky, Yeaeun Han, Xu Zhang, Ana Catarina Franco, Sung Y Kim, Saranya P Wyles, Y S Prakash, David G Monroe, Luigi Ferrucci, Nathan K LeBrasseur, Paul D Robbins, Laura J Niedernhofer, Sundeep Khosla, João F Passos.

  Senescent cells drive age-related tissue dysfunction via the induction of a chronic senescence-associated secretory phenotype (SASP). The cyclin-dependent kinase inhibitors p21Cip1 and p16Ink4a have long served as markers of cellular senescence. However, their individual roles remain incompletely elucidated, particularly in vivo. Thus, we conducted a comprehensive examination of multiple single-cell RNA sequencing datasets spanning both murine and human tissues during aging. Our analysis revealed that p21Cip1 and p16Ink4a transcripts demonstrate significant heterogeneity across distinct cell types and tissues, frequently exhibiting a lack of co-expression. Moreover, we identified tissue-specific variations in SASP profiles linked to p21Cip1 or p16Ink4a expression. Using RNA velocity and pseudotime analyses, we discovered that p21+ and p16+ cells follow independent trajectory dynamics, with no evidence of direct transitions between these two states. Despite this heterogeneity, we identified a limited set of shared "core" SASP factors that may drive common senescence-related functions. Our study underscores the substantial diversity of cellular senescence and the SASP, emphasizing that these phenomena are inherently cell- and tissue-dependent.

Keywords:  Aging; Cellular Senescence; Heterogeneity; Senescence-Associated Secretory Phenotype (SASP); Single-Cell Mapping

DOI:  https://doi.org/10.1038/s44318-025-00601-2
Nat Aging. 2025 Oct 29.

Epigenetic dysregulation in aged muscle stem cells drives mesenchymal progenitor expansion via IL-6 and Spp1 signaling.

Giulia Riparini, Morgan Mackenzie, Faiza Naz, Stephen Brooks, Kan Jiang, Anshu Deewan, Brittany Dulek, Shamima Islam, Kyung Dae Ko, Wanxia L Tsai, Massimo Gadina, Stefania Dell'Orso, Vittorio Sartorelli.

Sarcopenia, the age-related decline in muscle mass, strength and function, is characterized by impaired muscle homeostasis, reduced regenerative potential of muscle stem cells (MuSCs) and increased fibrosis. Here we report that aged MuSCs can autonomously instruct fibro-adipogenic progenitors (FAPs) to proliferate and acquire a fibrogenic phenotype, independent of other cell types. Both the polycomb-deficient Ezh2-/- mouse model and aged mice exhibited defective regeneration, FAP expansion, fibrosis and elevated secretion of interleukin 6 (IL-6) and secreted phosphoprotein 1 (Spp1; osteopontin) by MuSCs. In aged MuSCs, reduction of the histone H3K27me3 repressive mark at the Nfbk1 gene correlated with its increased expression and enhanced chromatin recruitment to the IL6 and Spp1 genes, leading to their activation. Pharmacological inhibition of IL-6 and Spp1 signaling in co-culture systems or in aged mice reduced FAP proliferation and muscle fibrosis. These findings indicate that epigenetic dysregulation of aged MuSCs contributes to aged-related muscle fibrosis.

DOI: https://doi.org/10.1038/s43587-025-01002-0