bims-obesme 2026-08-30 papers

bims-obesme

Biomed News

on Obesity metabolism

Issue of 2026–08–30
nine papers selected by
Xiong Weng, University of Edinburgh

β-cell FMO3-produced TMAO prevents NF-κB-mediated senescence and inflammation in ageing and diabetic conditions.
ASB3 limits adipocyte thermogenesis and energy expenditure through p62 ubiquitination.
Aberrant alternative splicing memorized in adipose tissue macrophages impedes efferocytosis during postobesity weight loss.
Activation of G12-type G proteins in pancreatic β cells protects against impaired glucose homeostasis.
Hepatic MED1 disruption ameliorates obesity-related fatty liver by attenuating SREBP1-driven lipogenesis.
Sex-specific aging clocks from a large-scale human phenome reveal distinct aging transitions and circulating signatures.
LMNA R527C pathogenic variant causes an inflammation-driven segmental progeroid syndrome via triggering DNA-sensing pathways.
Transcript-aware rare genetic variant association analyses of cardiopulmonary traits in participants from the All of Us Research Program.
Development of mitochondrial mutator pigs exhibiting increased mitochondrial DNA mutations and premature aging via prime editing.

Nat Commun. 2026 07 27. pii: 9112. [Epub ahead of print]17(1):

β-cell FMO3-produced TMAO prevents NF-κB-mediated senescence and inflammation in ageing and diabetic conditions.

Baomin Wang, Yumei Yang, Yuen Man Ho, Huige Lin, Juntao Yuan, Kekao Long, Kenneth King Yip Cheng, Xiaomu Li.

Human cells utilize gut microbiota-derived metabolites to control systemic metabolism. Trimethylamine N-oxide (TMAO) is traditionally considered a hepatocyte-derived metabolite from microbial trimethylamine. Here we show that pancreatic β-cells also produce TMAO as an autocrine and intracellular metabolite to maintain β-cell function. β-cells synthesize TMAO via flavin-containing monooxygenase 3 (FMO3), but this machinery deteriorates in humans and rodents under diabetic and ageing conditions. β-cell-specific deletion of FMO3 depletes intracellular TMAO, leading to senescence, inflammation, and defective glucose-stimulated insulin secretion, causing age-dependent glucose intolerance in mice. Loss of FMO3 triggers nuclear factor kappa-B (NF-κB) activation, promoting senescent and inflammatory responses. Mechanistically, TMAO binds to inhibitor of kappa B alpha (IκBα), which inhibits IκBα degradation and NF-κB nuclear translocation, thereby blocking NF-κB-mediated transcription of senescent and inflammatory programs. Replenishment of FMO3 reduces NF-κB activation and senescence in aged human islets. Our findings reveal a protective role of β-cell-derived TMAO against ageing-related β-cell dysfunction.

DOI: https://doi.org/10.1038/s41467-026-76075-5
Metabolism. 2026 Aug 28. pii: S0026-0495(26)00269-6. [Epub ahead of print] 156756

ASB3 limits adipocyte thermogenesis and energy expenditure through p62 ubiquitination.

Mengyu Shi, Haoye Liu, Zhihao Wu, Linlin Huang, Chunhua Song, Yuli Lin, Dongqin Yang.

   BACKGROUND: Adipose thermogenesis increases energy expenditure and protects against obesity. However, the endogenous mechanisms that restrain this process are not fully understood.
METHODS: Adipose tissue- and adipocyte-specific Asb3-deficient mice were exposed to cold or treated with the β3-adrenergic receptor agonist CL-316,243. Primary thermogenic adipocytes were used to assess adipogenic differentiation and β3-adrenergic/cAMP-PKA responses. Proteomic/phosphoproteomic profiling, co-immunoprecipitation, ubiquitination assays and domain mapping were performed to define the mechanism. Adipose p62 knockdown and high-fat-diet feeding were used to evaluate in vivo relevance.
RESULTS: The abundance of ASB3 protein increased in inguinal white adipose tissue (iWAT) following cold exposure or β3-adrenergic stimulation. Conversely, adipose-tissue- or adipocyte-specific deletion of Asb3 enhanced iWAT browning induced by cold exposure and b3-adrenergic receptor agonist CL-316,243, as well as brown adipose tissue activation and thermogenic gene expression. In primary beige adipocytes, ASB3 deficiency potentiated the thermogenic response to activation of the β3-adrenergic/cAMP-PKA pathway. Mechanistically, ASB3 interacted with p62 through its ankyrin-repeat region, promoting p62 ubiquitination involving both K48- and K63-linked ubiquitin chains. Loss of ASB3 was associated with increased p62 abundance and nuclear accumulation. Conversely, local p62 knockdown in iWAT attenuated ASB3 deficiency-induced beiging, thermogenic signaling and whole-body energy expenditure. Furthermore, adipose-tissue-specific ASB3 deficiency protected mice against weight gain, fat accumulation, hepatic steatosis, glucose intolerance and insulin resistance by a high-fat diet.
CONCLUSION: These findings indicate the critical role of the ASB3-p62 ubiquitin axis in restricting adipose tissue thermogenic plasticity and suggest that ASB3 may be a promising therapeutic target for obesity and related metabolic disorders.

Keywords:  Adipose thermogenesis; Ankyrin repeat and SOCS box protein 3; Energy expenditure; Ubiquitination; p62

DOI:  https://doi.org/10.1016/j.metabol.2026.156756
Sci Transl Med. 2026 Aug 26. 18(864): eadv0221

Aberrant alternative splicing memorized in adipose tissue macrophages impedes efferocytosis during postobesity weight loss.

Takuro Miyazaki, Akira Shiraishi, Yuki Sugiura, Eisuke Shiozawa, Seiya Mizuno, Midori Yamaguchi, Ryota Nakano, Yuki Uchida, Akira Yoshikawa, Masahiro Hosonuma, Shogo Haraguchi, Daisuke Morito, Takeshi Aoki, Toshiko Yamochi, Shotaro Kamijo, Masahiko Izumizaki, Hiroshi Shitara, Yoshitaka Taketomi, Satoru Takahashi, Honoo Satake.

Obesity imprints an epigenetic memory in adipose tissue macrophages (ATMs), allowing proinflammatory traits to persist after weight loss. However, mechanisms by which ATMs sustain efferocytosis and influence adipose tissue mass remain unclear. Here, we demonstrate that aberrant messenger RNA splicing, caused by dysfunction of the CWC22/exon junction complex, limits efferocytosis in macrophages during postobesity weight loss. Multiomics and gene-targeting approaches revealed that 51.9% of the obesity-induced differentially spliced genes in ATMs remained altered after weight loss, identifying persistent splicing alterations as a prominent component of obesity memory, with one-quarter of these changes dependent on CWC22. Scarb1 exon skipping increased scavenger receptor class B type II (SR-BII) expression, promoting the formation of SR-BI/SR-BII heterodimers that were subsequently targeted for endoplasmic reticulum-associated degradation. This reduced surface SR-BI in macrophages, suppressed efferocytosis and inosine release from dead cells, and impaired inosine-induced lipolysis in white adipose tissue. Restoring Scarb1 splicing with an antisense oligonucleotide rescued SR-BI expression, efferocytosis, inosine availability, and fat loss in Cwc22-deficient mice. Immunohistochemical analysis of human adipose tissue specimens revealed predominant nuclear localization of CWC22 in ATMs from lean individuals, whereas this nuclear localization was markedly diminished in ATMs from obese individuals. These findings reveal that aberrant alternative splicing in macrophages underlies resistance to postobesity weight loss and suggest that splicing-targeted therapies may counteract obesity memory.

DOI: https://doi.org/10.1126/scitranslmed.adv0221
Sci Adv. 2026 Aug 28. 12(35): eaeh5504

Activation of G12-type G proteins in pancreatic β cells protects against impaired glucose homeostasis.

Srinivas Pittala, Liu Liu, Dhanush Haspula, Yinghong Cui, Gianluca Fulgenzi, Asuka Inoue, Jürgen Wess.

Impaired insulin secretion represents a key feature of type 2 diabetes (T2D), a major global health burden. Insulin release from pancreatic β cells is regulated by G protein-coupled receptors linked to different functional classes of G proteins. The potential metabolic role of β cell G12/13 (G12 hereafter) signaling remains unexplored. Thus, we studied the potential metabolic outcomes of β cell G12 activation by using a combination of mouse gene knockout technology and β cell-specific chemogenetic approaches. We found that selective activation of β cell G12 signaling strongly promoted insulin secretion, thus protecting mice against obesity-associated metabolic deficits and improving glycemic control in a mouse model of T2D. Mechanistic studies with perifused pancreatic mouse islets identified ROCK as a key downstream effector of G12 signaling and potent trigger of insulin secretion. Collectively, these findings suggest that G protein-coupled receptors linked to G12 in β cells represent potential targets for antidiabetic drugs.

DOI: https://doi.org/10.1126/sciadv.aeh5504
Metabolism. 2026 Aug 27. pii: S0026-0495(26)00270-2. [Epub ahead of print] 156757

Hepatic MED1 disruption ameliorates obesity-related fatty liver by attenuating SREBP1-driven lipogenesis.

Xulei Dai, Ziyue Wang, Xiangzhu Xiao, Jie Gao, Yuanming Xing, Qian Gao, Mengru Wang, Fangzhou He, Yanru Zhang, Pengxiang Qu, Liangshuo Hu, Rong Wang, Weirong Wang, Sihai Zhao, Yuzhi Jia, Enqi Liu, Liang Bai.

   BACKGROUND & AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major global health concern, with obesity serving as a primary risk factor. Although Mediator subunit 1 (MED1) plays an important role in lipid metabolism, its specific contribution to obesity-related hepatic steatosis remains unclear. This study aims to elucidate the involvement of MED1 in the pathogenesis of MASLD during obesity.
APPROACH & RESULTS: Herein, we found that MED1 expression was upregulated in fatty livers from obese patients with MASLD, a primate MASLD model, genetically obese (ob/ob) mice, and in palmitate-treated HepG2 cells. Hepatocyte-specific knockout of MED1 on an ob/ob background under both chow and high-fat diet feeding ameliorated hepatic steatosis, glucose intolerance, obesity and inflammation of visceral white adipose tissue. Mechanistically, MED1 regulates hepatic lipid metabolism primarily through direct interaction with SREBP1, thereby mediating the expression of key SREBP1 target genes, including ACC, FASN and SCD1. Importantly, therapeutic delivery of AAV8-shMED1 attenuated MASLD progression in ob/ob mice.
CONCLUSIONS: These findings establish MED1 as a critical activator of SREBP1-driven lipogenesis and identify hepatic MED1 inhibition as a promising therapeutic strategy for MASLD.

Keywords:  Mediator 1; Metabolic dysfunction-associated steatotic liver disease; Obesity; Sterol regulatory element binding transcription factor 1; Transcriptional regulation

DOI:  https://doi.org/10.1016/j.metabol.2026.156757
Nat Aging. 2026 Aug 25.

Sex-specific aging clocks from a large-scale human phenome reveal distinct aging transitions and circulating signatures.

Jiaming Li, Dan-Dan Gao, Jing Li, Lei Cao, Yuanyuan Du, Muzhao Xiong, Xi Chu, Wan Lei, Wei-Dong Ye, Gang Xu, Lina Ma, Jiazhen Tang, Qing Fu, Zikai Zheng, Hongkai Zhao, Ming Yi, Chunyu Lan, Liu-Jun Xu, Yanling Fan, Guohua Zhu, Liwen Xiao, Quan Zheng, Sicong Si, Huabiao Cheng, Beier Jiang, Shuhui Sun, Wenjian Jiang, Shuai Ma, Hongjia Zhang, Si Wang, Yun-Gui Yang, Jiayin Yang, Jing Qu, Feng Zhang, Zhili Liu, Guoguang Zhao, Guang-Hui Liu, Weiqi Zhang.

Aging is a primary risk factor for chronic diseases, yet its progression varies among individuals and between sexes. Here, under the X-Age Project, we profiled the clinical aging phenome of the Multicentric Chinese Aging Study (mCAS) through a cross-sectional analysis of 172 clinical measures from more than 100,000 participants aged 18-98 years across three centers. These profiles enabled sex-specific clinical aging clocks that revealed divergent aging trajectories between women and men during midlife that converged in later life. Phenome-wide analyses revealed age-related accumulation of metabolic factors, including low-density lipoprotein, triglycerides, glucose and uric acid, and tumor markers, such as carcinoembryonic antigen and human epithelial protein 4. These age-accumulating factors induced senescence-related phenotypes in human endothelial cells. Furthermore, a high-fat diet mouse model with dietary reversal supported the modifiability of metabolic burden-induced aging. Together, this work establishes metabolic and tumor marker accumulation as actionable drivers of human aging, paving the way for personalized, sex-stratified geroprotective interventions.

DOI: https://doi.org/10.1038/s43587-026-01180-5
Protein Cell. 2026 Aug 25. pii: pwag061. [Epub ahead of print]

LMNA R527C pathogenic variant causes an inflammation-driven segmental progeroid syndrome via triggering DNA-sensing pathways.

Yingchi Zhao, Tianyi Liu, Wei Shu, Dandan Wang, Haocheng Wang, Xiaoyu Liu, Xuyao Jiao, Jianshuang Li, Tao Liu, Ming Kuang, Ridong Li, Hongqiang Du, Zeming Zhang, Zhe Zhou, Xuefei Guo, Xuemei Wei, Tongtong Liu, Yunfei Li, Shengde Liu, Jingxuan Chen, Yujie Luo, Huawei Xia, Lili Cao, Wenmin Tian, Xue Sun, Wei Dong, Guangqian Zhou, Xiang Gao, Yongzhi Li, Shize Liu, Xinran Liu, Dan Lu, Qinghua Zhou, Pingsen Zhao, Fuping You.

  Homozygous pathogenic variants in Ig-like domain of LMNA cause severe segmental progeroid syndromes. Unlike typical HGPS, it remains elusive how these pathogenic variants cause segmental progeroid syndromes. We here reported that affected individuals with LMNAR527C/R527C pathogenic variant developed an atypical segmental progeroid syndrome characterized by autoimmune features. Mesenchymal stem cells (MSCs) derived from these affected individuals exhibited significant inflammation and cellular senescence. In mice, LmnaR527C/R527C pathogenic variant triggered chronic interferon signaling, exacerbated aging-related pathologies, and even induced thymic lymphomas following ionizing radiation. In addition, this pathogenic variant increased susceptibility to inflammation induced by a high-fat diet or LCMV infection. R527C pathogenic variant disrupted the interaction between Lamin A and DNA-binding proteins, causing abnormal protein aggregation and hyperactivation of the cGAS-STING. Importantly, blocking DNA sensing pathways suppressed inflammation, rescued senescence in affected individual-derived MSCs, and alleviated premature aging in LmnaR527C/R527C mice. These findings establish a homozygous LMNA pathogenic variant as a key driver of inflammation-driven segmental progeroid syndrome and highlight DNA sensing pathways as promising therapeutic targets.

Keywords:  DNA-sensing pathways; LMNA; inflammation; segmental progeroid syndrome; senescence

DOI:  https://doi.org/10.1093/procel/pwag061
Nat Commun. 2026 Jul 24. pii: 9038. [Epub ahead of print]17(1):

Transcript-aware rare genetic variant association analyses of cardiopulmonary traits in participants from the All of Us Research Program.

Jingwen Zhang, So-Hyeon Hong, Xin Wang, Sean J Jurgens, Ching-Ti Liu, Josée Dupuis, Patrick T Ellinor, George T O'Connor, Quanshun Mei, Seung Hoan Choi.

Gene-based rare variant analyses often lack statistical power and may overlook transcript-specific effects. Here, we present a transcript-aware aggregation framework. In simulation studies, the framework maintains appropriate false-positive rates and shows competitive power relative to standard single-transcript analyses, approaching the performance of the ideal case of knowing the most informative transcript in advance. We then apply the approach to 129 cardiopulmonary traits in over 240,000 whole-genome-sequenced All of Us participants. By leveraging transcript-specific annotations, we identify 11 novel associations and recover 47 reported associations, including potentially pleiotropic genes linked to plasma lipid traits (PPARG) and body habitus (TCF12). Notably, for TTN, a gene known for its transcript-specific effects in cardiomyopathy, our framework strengthens the association signal and pinpoints the N2B isoform, which shows a stronger association with cardiomyopathy than other transcripts. These findings highlight the value of a transcript-aware framework for improving rare variant association studies.

DOI: https://doi.org/10.1038/s41467-026-75569-6
Sci Adv. 2026 Aug 28. 12(35): eadu0632

Development of mitochondrial mutator pigs exhibiting increased mitochondrial DNA mutations and premature aging via prime editing.

Fangbing Chen, Yanhui Liang, Wei Zheng, Aobo Yao, Ning Wang, Huangyao Chen, Zhenpeng Zhuang, Meng Lian, Yu Zhao, Zhen Ouyang, Zhaohai Zhou, Weikai Ge, Qishuai Liu, Yinghua Ye, Liangxue Lai, Kepin Wang.

The accumulation of mitochondrial DNA (mtDNA) mutations is a primary driver of mitochondrial dysfunction, which is intrinsically linked to aging and various pathologies. POLG, the catalytic subunit of DNA polymerase gamma, is essential for mtDNA replication; notably, a deficiency in its proofreading function precipitates the accumulation of mtDNA mutations. In this study, by combining prime editing with somatic cell nuclear transfer technology, we successfully generated a mitochondrial mutator pig model expressing proofreading-deficient POLG. These pigs exhibited elevated somatic mtDNA mutation loads and recapitulated key premature aging phenotypes, including weight loss, rough hair coat, anemia, structural alterations in the skin and testicular interstitium, increased apoptosis, and the up-regulation of senescence-associated markers, culminating in shortened life span. Given the physiological and metabolic similarities between pigs and humans, this mitochondrial mutator pig model represents an ideal preclinical tool for dissecting the mechanistic role of mtDNA mutations in aging and age-related pathologies and for accelerating the translation of therapeutic strategies.

DOI: https://doi.org/10.1126/sciadv.adu0632