bims-obesme 2026-02-15 papers

bims-obesme

Biomed News

on Obesity metabolism

Issue of 2026–02–15
nine papers selected by
Xiong Weng, University of Edinburgh

Serum Response Factor (SRF) promotes actin cytoskeletal organization in adipocytes to support adaptive hypertrophic expansion and tissue remodeling during obesity in mice.
A selective Cullin 3 RING E3 ligase inhibitor attenuates hyperglycemia via dual insulin sensitizing and insulinotropic action.
M1-linked ubiquitination by LUBAC regulates AMPK signalling and the response to energetic stress.
Hypothalamic malate dehydrogenase 2 modulates systemic glucose metabolism through oxytocin-mediated thermogenesis.
Semaglutide ameliorates osteoarthritis progression through a weight loss-independent metabolic restoration mechanism.
ANKRD53 is downregulated in human obesity and coordinates lipolysis with mitochondrial oxidative metabolism in adipocytes.
Interleukin-10 expressing B lineage cells in visceral adipose tissue protect against aging-related insulin resistance and extend lifespan.
Genetic regulation of methylation across East Asian and European populations.
Compartmentalized branched-chain amino acid metabolism orchestrates colorectal cancer dissemination via an UMP-vimentin axis.

Metabolism. 2026 Feb 06. pii: S0026-0495(26)00057-0. [Epub ahead of print]178 156548

Serum Response Factor (SRF) promotes actin cytoskeletal organization in adipocytes to support adaptive hypertrophic expansion and tissue remodeling during obesity in mice.

Jisun So, Jamie Wann, Kyungchan Kim, Solaema Taleb, Hyeong-Geug Kim, Manju Kumari, Alexander S Banks, X Charlie Dong, Hyun Cheol Roh.

   BACKGROUND: Adipocyte hypertrophy, the unique capacity of adipocytes to enlarge in response to energy surplus, is a crucial determinant of metabolic health during obesity. Nonetheless, the molecular mechanisms governing this adaptive growth remain incompletely characterized.
METHODS: Super-enhancer landscapes in adipocytes were mapped via H3K27ac chromatin immunoprecipitation sequencing analysis of adipocyte nuclei from mice fed either a standard chow diet or high-fat diet (HFD) to identify transcriptional regulators activated under obesogenic conditions. Functional validation was conducted through both in vitro and in vivo experiments, including adipocyte-specific gene deletion mouse models, followed by single-nucleus RNA sequencing.
RESULTS: Super-enhancer profiling identified Serum Response Factor (SRF) as a critical driver of actin cytoskeletal remodeling in adipocytes during obesity. SRF was shown to be both necessary and sufficient for regulation of actin cytoskeletal gene expression in 3T3-L1 adipocytes. Adipocyte-specific SRF ablation in mice led to reduced expression of actin cytoskeletal genes, disruption of actin filament organization, and impaired adipocyte enlargement under HFD feeding. Despite comparable body weight, SRF-deficient mice developed exacerbated insulin resistance and ectopic lipid accumulation in the liver and brown adipose tissue, indicative of compromised lipid storage within adipocytes. Single-nucleus RNA-seq further revealed that cell-intrinsic actin cytoskeletal defects in adipocytes propagated to tissue-level dysfunction, impairing vascularization and increasing inflammation.
CONCLUSION: These findings establish SRF as a central regulator of actin cytoskeletal organization that promotes healthy adipocyte hypertrophy and adipose tissue remodeling. Enhancing SRF-dependent cytoskeletal remodeling in adipocytes may offer a therapeutic strategy to preserve metabolic health in obesity.

Keywords:  Actin cytoskeleton; Adipocyte hypertrophy; Obesity; Serum Response Factor (SRF); Single-nucleus RNA sequencing; Super-enhancer; Tissue remodeling

DOI:  https://doi.org/10.1016/j.metabol.2026.156548
bioRxiv. 2026 Feb 01. pii: 2026.01.28.702366. [Epub ahead of print]

A selective Cullin 3 RING E3 ligase inhibitor attenuates hyperglycemia via dual insulin sensitizing and insulinotropic action.

Lijie Gu, Lei Xiong, Mohammad Nazmul Hasan, Yanhong Du, Timothy Wu, Tiangang Li.

Hyperglycemia is a hallmark of type-2 diabetes and a key pathogenic driver of diabetic complications. Cullin RING E3 ligases (CRLs) are multi-subunit E3 ubiquitin ligases that mediate cellular protein turnover. The activity of CRLs requires cullin neddylation, a post-translational modification that can be pharmacologically targeted with therapeutic potentials. By using hyperinsulinemic-euglycemic clamp analysis, we discover that pan neddylation inhibitor exerts both insulin sensitization effect in liver and muscle and insulinotropic effect in pancreatic β cells. This dual action is mediated by Cullin 3 (Cul3), a member of the 7 canonical cullin family proteins. DI-1859, a selective Cul3 neddylation inhibitor, effectively protects against hyperglycemia in obese mice. DI-1859 enhances insulin signaling by preventing Cul3-mediated insulin receptor substrate degradation in liver and muscle cells. DI-1859 increases insulin secretion in a glucagon-like peptide-1-independent manner in mice and directly potentiates glucose-stimulated insulin secretion in INS-1 832/13 β cells and human islets. Mechanistic studies reveal that DI-1859 does not promote glycolytic flux or bioenergetics function but potentiates glucose-stimulated insulin secretion via mechanisms involving RhoA activation and cytoskeleton remodeling in β cells. This study shows that a single agent targeting Cul3 neddylation simultaneously promotes insulin sensitization and insulin secretion to attenuate hyperglycemia in mice.
Article Highlights: a. Pan cullin neddylation inhibitors exhibit potent hypoglycemic effect.b. The target organs and mechanisms underlying the hypoglycemia effect of cullin pan neddylation inhibitors are incompletely understood.c. We found that inhibition of Cul3 leads to a dual insulin sensitization and insulinotropic effect.d. Selective inhibition of Cul3 neddylation is a feasible approach to lower hyperglycemia.

DOI: https://doi.org/10.64898/2026.01.28.702366
Cell Death Differ. 2026 Feb 13.

M1-linked ubiquitination by LUBAC regulates AMPK signalling and the response to energetic stress.

Camilla Reiter Elbæk, Sophie Gradinaru, Anna M Dahlström, Alexander Frueh, Akhee S Jahan, Joyceline Cuenco, Anna L Aalto, John Rizk, Simon A Hawley, Sarah N J Franks, Michael Stumpe, Srinivasa Prasad Kolapalli, Chris Kedong Wang, Cara J Ellison, Ximena Hildebrandt, Klara Nielsen, Dominik Priesmann, Julian Koch, Mathilde Deichmann, Josef Gullmets, Lien Verboom, Geert van Loo, Nieves Peltzer, Lisa B Frankel, Paul R Elliott, Mads Gyrd-Hansen, Jörn Dengjel, Brent J Ryan, D Grahame Hardie, Annika Meinander, Kei Sakamoto, Rune Busk Damgaard.

Methionine-1 (M1)-linked ubiquitin chains, assembled by the linear ubiquitin chain assembly complex (LUBAC) and disassembled by the deubiquitinase OTULIN, are critical regulators of inflammation and immune homoeostasis. Genetic loss or mutation of the LUBAC subunits HOIP and HOIL-1 or of OTULIN causes autoinflammatory syndromes accompanied by metabolic defects, including amylopectinosis, lipodystrophy, and fatty liver disease. Yet, it remains unclear how LUBAC and OTULIN control metabolic signalling. Here, we demonstrate that LUBAC and OTULIN dynamically regulate the energy-sensing kinase AMPK, a central sensor and switch for cellular and organismal energy balance. LUBAC's activity through the catalytic subunit HOIP is required for full AMPK activation in response to energetic stress, whereas OTULIN antagonises this response. LUBAC and OTULIN form a complex with AMPK, and LUBAC can directly ubiquitinate AMPKα and β subunits in cells and in vitro, establishing AMPK as a bona fide M1-linked ubiquitin substrate. Loss of LUBAC blunts AMPK activation, reduces bioenergetic adaptability, impairs autophagy, and sensitises cells to starvation-induced death, while Drosophila lacking Lubel - the fly orthologue of LUBAC - exhibit defective AMPK activation and reduced survival during starvation. Our findings identify M1-linked ubiquitination as a previously unrecognised regulatory layer controlling AMPK activation, metabolic adaptability, and the cellular response to energetic stress.

DOI: https://doi.org/10.1038/s41418-026-01675-z
Cell Rep Med. 2026 Feb 10. pii: S2666-3791(26)00033-9. [Epub ahead of print] 102616

Hypothalamic malate dehydrogenase 2 modulates systemic glucose metabolism through oxytocin-mediated thermogenesis.

Ting Yao, Guoming Wu, Yu Zeng, Yinyin Xie, Xiao Cui, Qiongyue Zhang, Chaoying Yan, Zhicheng Cui, Hongyu Gong, Tianze Xiong, Xian Liang, Yan Zhang, Ruiqi Zheng, Hui Wang, Mingchun Gao, Peng Zhang, Ru Wang, Xiao Zhao, Zhihui Feng, Lei Xiao, Tiemin Liu, Zhi Zhang.

  Bariatric surgery improves hyperglycemia in obesity and type 2 diabetes (T2D), yet its central mechanisms remain unclear. Through cerebrospinal fluid proteomic profiling of rats, we identify reduced central malate dehydrogenase 2 (MDH2) levels that correlate with surgery-induced restoration of normoglycemia. Central MDH2 blockade with the selective antagonist LW6 attenuates hyperglycemia under high-glucose conditions, independent of its enzymatic activity. Mechanistically, MDH2 inhibition activates oxytocinergic neurons in the hypothalamic paraventricular nucleus (PVN), promoting glucose disposal via sympathetic activation of brown adipose tissue (BAT) thermogenesis. Chemogenetic activation of PVN oxytocin neurons recapitulates this effect, while their silencing, oxytocin receptor blockade, or sympathetic inhibition abolishes LW6's metabolic benefits. PVN-specific Mdh2 deletion abrogates LW6's glucose-lowering effects and impairs systemic glucose homeostasis. LW6 demonstrates robust long-lasting glucose-lowering effects in a T2D mouse model. These findings establish MDH2 as a central glucose modulator and therapeutic target linking hypothalamic signaling to peripheral energy metabolism via an oxytocin-sympathetic nervous system (SNS)-BAT axis.

Keywords:  BAT; MDH2; SNS; T2D; brown adipose tissue; hypothalamus; malate dehydrogenase 2; metabolic surgery; oxytocin; sympathetic nervous system; type 2 diabetes

DOI:  https://doi.org/10.1016/j.xcrm.2026.102616
Cell Metab. 2026 Feb 09. pii: S1550-4131(26)00008-2. [Epub ahead of print]

Semaglutide ameliorates osteoarthritis progression through a weight loss-independent metabolic restoration mechanism.

Hongyu Qin, Jiamin Yu, Huan Yu, Chuqiao Zhou, Dongfeng Yuan, Ziling Wang, Zhenglin Zhu, Guizheng Wei, Peiyan Ou, Zhibin Li, Hua Jiang, Jie Shen, Guozhi Xiao, Xiaochun Bai, Huaiyu Wang, Huan-Tian Zhang, John R Speakman, Di Chen, Liping Tong.

  Metabolic disorders have been recognized as a major contributor to the occurrence and progression of osteoarthritis (OA). Identifying novel therapeutic agents to ameliorate the progression of OA with metabolic disorder is crucial. In this study, we demonstrate that semaglutide (SG), a glucagon-like peptide-1 receptor (GLP-1R) agonist, exhibits strong chondroprotective effects in an OA mouse model with obesity, as evidenced by reduced pathological changes, including cartilage degeneration, osteophyte formation, synovial lesion, and pain sensitivity. A randomized pilot clinical study (ChiCTR2200066291) further supports these findings. By designing a precise diet-controlled setting to rule out the effect of appetite suppression and weight loss induced by SG, we demonstrate a weight loss-independent mechanism. Through regulating the "GLP-1R-AMPK-PFKFB3" axis, the SG reprograms chondrocyte metabolism profile from glycolysis to oxidative phosphorylation under inflammatory conditions, resulting in cartilage restoration.

Keywords:  AMPK; GLP-1R; metabolic reprogramming; obesity; osteoarthritis; semaglutide

DOI:  https://doi.org/10.1016/j.cmet.2026.01.008
Mol Metab. 2026 Feb 05. pii: S2212-8778(26)00014-1. [Epub ahead of print] 102330

ANKRD53 is downregulated in human obesity and coordinates lipolysis with mitochondrial oxidative metabolism in adipocytes.

Yingying Su, Xiaoya Li, Yikai Wang, Xuhong Lu, Yafen Ye, Jingjing Sun, Tianwen Liu, Jinghao Cai, Xiaojing Ma, Ying Yang, Jian Zhou.

   AIMS: Human adipose tissue is central to obesity-associated metabolic dysfunction. ANKRD53 is a human-specific, adipocyte-enriched ankyrin repeat scaffold protein with largely unknown function. We investigated its role in human adipocyte metabolism and the underlying mechanism.
METHODS: RNA-seq analysis of subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) from 236 individuals quantified ANKRD53 expression and its association with metabolic traits. In human primary adipocytes, we assessed lipolysis (free fatty acid and glycerol release) and mitochondrial respiration (oxygen consumption rate) after ANKRD53 overexpression or knockdown. An AAV was used to overexpress ANKRD53 in mouse inguinal white adipose tissue (iWAT). Protein interactors were identified by immunoprecipitation-mass spectrometry, and knockdown experiments confirmed a functional role of ACSL1.
RESULTS: ANKRD53 expression in both adipose depots was markedly reduced in obesity and inversely correlated with BMI, adiposity measures, insulin resistance indices, and circulating triglycerides, while positively associated with adiponectin and HDL. In human adipocytes, ANKRD53 overexpression enhanced forskolin-stimulated lipolysis and mitochondrial respiration, whereas silencing impaired these processes. Adipose-targeted ANKRD53 overexpression in mice increased lipolysis in vivo. Mechanistically, ANKRD53 interacted with ACSL1 and promoted its mitochondrial localization, channeling lipolysis-derived FFAs into β-oxidation; silencing ACSL1 abrogated ANKRD53's effects.
CONCLUSIONS: ANKRD53 is reduced in obesity and coordinates lipolysis with mitochondrial oxidative metabolism in human adipocytes, promoting efficient use of lipolysis-derived FFAs via ACSL1. These findings establish ANKRD53 as a key regulator of adipocyte energy metabolism and a potential therapeutic target for improving metabolic health in obesity.

Keywords:  ACSL1; ANKRD53; Human primary adipocytes; Lipolysis; Mitochondrial oxidative metabolism; Obesity

DOI:  https://doi.org/10.1016/j.molmet.2026.102330
Nat Commun. 2026 Feb 07.

Interleukin-10 expressing B lineage cells in visceral adipose tissue protect against aging-related insulin resistance and extend lifespan.

Jielong Guo, Xue Han, Yue Qin, Kexin Hong, Yuchen Lin, Shuping Han, Ning Hou, Lihui Cao, Xiaoxiang Gao, Weidong Huang, Xiaomeng Liu, Jicheng Zhan, Yilin You.

Visceral adipose tissue (VAT) inflammation is considered as an important contributor of aging, however, whether there is endogenous factor(s) in VAT that counteract this process remains obscure. Here we reported that interleukin (IL)-10 expressing B lineage (B-10) cells are greatly expanded in aged VAT in human and mouse. In aged VAT, B-10 cells are the primary source of IL-10. B cell-specific knockout of IL-10 exaggerated aging-related inflammation and insulin resistance (IR) and reduced lifespan, which could be partially recovered via adoptive transfer of B-10 cells from wild-type mice. Aged VAT microenvironment enhanced IL-10 secretion and proliferation of B-10 cells. The proliferation of B-10 cells was mediated by increases in BAFF in aged VAT. Knock-down of BAFF in VAT compromised aging-related expansion of B-10 cells. On the contrary, VAT-specific overexpression of BAFF promoted B-10 cells expansion, improved aging-related inflammation and IR, and prolonged lifespan.

DOI: https://doi.org/10.1038/s41467-026-69371-7
Nat Commun. 2026 Feb 11.

Genetic regulation of methylation across East Asian and European populations.

Ruize Liu, Tzu-Ting Chen, Yan Xia, Shu-Chin Lin, Tian Ge, Chia-Yen Chen, Yen-Chen Anne Feng, Hailiang Huang, Yen-Feng Lin.

Methylation quantitative trait loci (mQTL) studies have predominantly focused on European populations (EUR), limiting understanding of the genetic regulation of DNA methylation in other populations. We conduct an East Asian (EAS) mQTL analysis, integrating data from three independent samples comprising 7619 Han Chinese individuals. We identified 331,048 mCpGs, including 28,978 novel mCpGs in EAS. While observing substantial sharing of mQTL between EUR and EAS, we also identify EAS-specific mQTLs, often driven by variants with low minor allele frequencies in EUR. We found that mQTLs enriched for disease and trait heritability, especially for matched-ancestry mQTLs, underscoring their utility for interpreting GWAS results and highlighting the role of DNA methylation in diseases. Our EAS mQTL resource provides valuable insights into the genetic architecture of DNA methylation and its contribution to complex traits.

DOI: https://doi.org/10.1038/s41467-026-69372-6
Cell Metab. 2026 Feb 06. pii: S1550-4131(26)00007-0. [Epub ahead of print]

Compartmentalized branched-chain amino acid metabolism orchestrates colorectal cancer dissemination via an UMP-vimentin axis.

Fenfen Ji, Pingmei Huang, Qiming Zhou, Lok Hin Ko, Qinyao Wei, Charis Cheuk-Lok Chan, Danyu Chen, Huarong Chen, Wei Kang, Alvin Ho-Kwan Cheung, Cillian H Cheng, Jianming Shen, Yasi Pan, Ying Jiao, Lin Zhu, Tat Wai Chik, Peisi Xie, Xiao Liang, Onno Kranenburg, Zongwei Cai, Jun Yu, Chi Chun Wong.

  The role of metabolic compartmentalization in cancer metastasis is unexplored. Here, we identified that compartmentalized branched-chain amino acid (BCAA) metabolism modulates colorectal cancer (CRC) metastasis. Cytosolic BCAA transaminase (BCAT1) promotes epithelial-to-mesenchymal transition (EMT) and cancer spread of CRC cells, whereas the mitochondrial isoform (BCAT2) exerted opposite effects. The location of BCAT is critical, as mitochondria-targeted BCAT1 and cytosolic BCAT2 demonstrated opposite functions in EMT and cell migration, compared with their wild-type counterparts. Mechanistically, cytosolic BCAT promotes nitrogen flux from BCAA to glutamate, aspartate, and uridine monophosphate (UMP), whereas mitochondrial BCAT activity diverts nitrogen flux via glutamate dehydrogenase (GDH) to give NH3. UMP binds to vimentin and protects it against ubiquitination-proteasome degradation. Dietary BCAA restriction or blockade of UMP biosynthesis impaired cancer spread of BCAT1-high CRC, and BCAT1-to-BCAT2 expression ratio is an independent prognostic factor in CRC and pan-cancer cohorts, highlighting translational relevance of BCAA metabolic compartmentalization in cancer metastasis.

Keywords:  BCAA; BCAT1; BCAT2; UMP; branched-chain amino acids; colorectal cancer; dietary restriction; metabolic compartmentalization; metastasis; uridine monophosphate

DOI:  https://doi.org/10.1016/j.cmet.2026.01.007