bims-obesme 2025-10-26 papers

bims-obesme

Biomed News

on Obesity metabolism

Issue of 2025–10–26
ten papers selected by
Xiong Weng, University of Edinburgh

Nuclear hormone-sensitive lipase regulates adipose tissue mass and adipocyte metabolism.
The protein phosphatase 6 subunit SAPS3 modulates lifespan by regulating metabolism.
Adipose cullin 3 mediates the antiobesity effect of pan neddylation inhibitors.
Reversal of diet-induced obesity by central insulin sensitizer FSTL1.
KnowYourCG: Facilitating base-level sparse methylome interpretation.
Angiopoietin-like 8 governs osteoblast-adipocyte lineage commitment during skeletal aging.
A distal enhancer of Pparα regulates thermogenesis and mitochondrial function in brown fat.
The enedioic acid analog 326E alleviates metabolic dysfunction-associated steatohepatitis via dual targeting at ACLY and PPARα.
Leptin as a key driver for organ fibrogenesis.
Time-resolved Mendelian randomization detects substantial variation in the detrimental effect of obesity throughout life.

Cell Metab. 2025 Oct 23. pii: S1550-4131(25)00433-4. [Epub ahead of print]

Nuclear hormone-sensitive lipase regulates adipose tissue mass and adipocyte metabolism.

Jérémy Dufau, Emeline Recazens, Laura Bottin, Camille Bergoglio, Aline Mairal, Karima Chaoui, Marie-Adeline Marques, Veronica Jimenez, Miquel García, Tongtong Wang, Henrik Laurell, Jason S Iacovoni, Remy Flores-Flores, Pierre-Damien Denechaud, Khalil Acheikh Ibn Oumar, Ez-Zoubir Amri, Catherine Postic, Jean-Paul Concordet, Pierre Gourdy, Niklas Mejhert, Mikael Rydén, Odile Burlet-Schiltz, Fatima Bosch, Christian Wolfrum, Etienne Mouisel, Genevieve Tavernier, Dominique Langin.

  In adipocytes, hormone-sensitive lipase (HSL) plays a key role in hydrolyzing triacylglycerols that are stored in lipid droplets. Contrary to the expected phenotype, HSL-deficient mice and humans exhibit lipodystrophy. Here, we show that HSL is also present in the adipocyte nucleus. Mouse models with different HSL subcellular localizations reveal that nuclear HSL is essential for the maintenance of adipose tissue. Gene silencing in human adipocytes shows that HSL, independently of its enzymatic activity, exerts opposing effects on mitochondrial oxidative phosphorylation and the extracellular matrix. Mechanistically, we found that HSL accumulates in the nucleus by interacting with the transforming growth factor β (TGF-β) signaling mediator, mothers against decapentaplegic homolog 3 (SMAD3). Conversely, HSL phosphorylation induces nuclear export. In vivo, HSL accumulates in the nucleus of adipocytes during high-fat feeding with the converse effect during fasting. Together, our data show that as both a cytosolic enzyme and a nuclear factor, HSL plays a pivotal role in adipocyte biology and adipose tissue maintenance.

Keywords:  TGF-β signaling; adipocyte; adipose tissue; cell nucleus; extracellular matrix; hormone-sensitive lipase; lipodystrophy; mitochondrial oxidative phosphorylation; obesity; protein-protein interaction

DOI:  https://doi.org/10.1016/j.cmet.2025.09.014
Sci Adv. 2025 Oct 24. 11(43): eadt3879

The protein phosphatase 6 subunit SAPS3 modulates lifespan by regulating metabolism.

Ying Yang, Da Eun Kang, Qi Fan, Eric A Hanse, Hosung Bae, Rocio A Barahona, Xiyu Shen, Bryan I Ruiz, Shelly H Lee, Katherine R Pasterczyk, Nainpriya Babbar, Katherine G Waldvogel, Roberto Tinoco, Kim N Green, Qin Yang, Cholsoon Jang, Mei Kong.

Aging is characterized by disruptions in metabolic homeostasis, yet the mechanisms that regulate these metabolic changes remain poorly understood. We show that the serine/threonine-protein phosphatase 6 (PP6) regulatory subunit 3, SAPS3, is a critical regulator of metabolism during aging. SAPS3 deletion significantly extends lifespan in mice and counteracts age-related impairments in metabolic health. SAPS3 deficiency improves the effects of aging on the affective behaviors, cognition, and motor functions in aged mice. We find that SAPS3 expression is increased during aging to inhibit adenosine monophosphate-activated kinase (AMPK) activity. Deletion of SAPS3 leads to AMPK activation and reverses cellular senescence and aging-induced metabolic alterations. Using in vivo U-13C6-D-glucose tracing and metabolomic analysis, we find that SAPS3 deficiency restores metabolic homeostasis with increased glycolysis, tricarboxylic acid (TCA) cycle, and decreased fatty acid synthesis in aged mice. These findings highlight a critical role of the SAPS3/PP6 phosphatase complex in aging and suggest that strategies targeting SAPS3 may promote longevity and healthy aging.

DOI: https://doi.org/10.1126/sciadv.adt3879
Proc Natl Acad Sci U S A. 2025 Oct 28. 122(43): e2515947122

Adipose cullin 3 mediates the antiobesity effect of pan neddylation inhibitors.

Lijie Gu, Yanhong Du, Mohammad Nazmul Hasan, Yung-Dai Clayton, Tiangang Li.

  Cullin Ring E3 Ligases (CRLs) belong to the largest family of multisubunit ubiquitin E3 ligases. A cullin serves as the scaffold protein that recruits E3 ligases and substrate receptors in a CRL complex, whose activity requires cullin neddylation, a posttranslational modification that can be pharmacologically targeted by neddylation inhibitors. Elevated neddylation activity has been observed in the liver and adipose tissue of obese mice, implicating a pathogenic link between altered CRL activity and the development of metabolic disorders. Emerging evidence has also shown that neddylation inhibitors possess antiobesity and hypoglycemic property. However, the roles of cullin proteins in regulating adipocyte biology are still incompletely defined. Here, we report that pan neddylation inhibitor TAS4464 treatment reversed obesity and adipose inflammation, resulting in improved hepatic steatosis and insulin sensitivity in obese mice. Among all mammalian cullin proteins that were targeted by TAS4464, we identified that cullin 3 (Cul3) was required for adipogenesis and adipocyte hypertrophy. A complete absence of Cul3 in adipocytes caused severely inhibited adipose expansion associated with ectopic fat accumulation in the liver and brown adipose tissue and insulin resistance, while adipocyte-specific Cul3 haploinsufficiency attenuated obesity and improved overall metabolic homeostasis, which recapitulated the metabolic benefits of TAS4464. Mechanistically, we found that Cul3 inhibition caused adipose nuclear factor erythroid 2-related factor 2 (NRF2) stabilization, which contributed to impaired adipogenesis by inhibiting lipogenesis. Together, these findings demonstrate that Cul3 is required during adipogenesis and acts as a downstream mediator of the antiobesity effect of pan neddylation inhibitors.

Keywords:  adipogenesis; diabetes; insulin resistance; obesity

DOI:  https://doi.org/10.1073/pnas.2515947122
Neuron. 2025 Oct 21. pii: S0896-6273(25)00749-4. [Epub ahead of print]

Reversal of diet-induced obesity by central insulin sensitizer FSTL1.

Kejia Li, Han Dai, Ke Li, Sheng Qiu, Dongfang Liu, Cong Wang, Shengbin Li, Gangyi Yang, Ling Li, Min-Dian Li, Mengliu Yang.

  Follistatin-like 1 (FSTL1) is a signaling molecule that modulates energy metabolism in peripheral tissues and is also expressed in the brain. However, whether hypothalamic FSTL1 regulates carbohydrate/lipid metabolism and energy balance remains unknown. Here, we show that FSTL1 is enriched in the hypothalamus, especially the arcuate nucleus (ARC). FSTL1 expression is decreased in diet-induced obese (DIO) and db/db mice. Agouti-related peptide (AgRP) neuron-specific Fstl1 deletion increased food intake, decreased energy expenditure, and impaired insulin sensitivity in DIO mice. Conversely, Fstl1 overexpression in AgRP neurons resulted in the opposite phenotypes. Insulin signaling was required for the anti-obesity effect of hypothalamic FSTL1. Intranasal FSTL1 delivery promoted weight loss and improved insulin sensitivity in DIO mice. Mechanistically, FSTL1 interacts with Akt, an intracellular mediator of insulin signaling, to inhibit forkhead box protein O1 (FoxO1) nuclear translocation. Our findings identify hypothalamic FSTL1 as a key mediator counteracting DIO and provide a potential pharmacological strategy for obesity-related metabolic disorders.

Keywords:  AgRP; FSTL1; metabolic disorder; obesity

DOI:  https://doi.org/10.1016/j.neuron.2025.09.036
Sci Adv. 2025 Oct 24. 11(43): eadw3027

KnowYourCG: Facilitating base-level sparse methylome interpretation.

David C Goldberg, Hongxiang Fu, Daniel Atkins, Ethan Moyer, Chin Nien Lee, Yanxiang Deng, Wanding Zhou.

Decoding DNA methylomes for biological insights is critical in epigenetics research. We present KnowYourCG (KYCG), a data interpretation framework designed for functional DNA methylation analysis. Unlike existing tools that target genes or genomic intervals, KYCG features direct base-level screenings of diverse biological and technical influences, including sequence motifs, transcription factor binding, histone modifications, replication timing, cell-type-specific methylation, and trait associations. Through implementing efficient infrastructure that rapidly screens and investigates thousands of knowledgebases, KYCG addresses the challenges of data sparsity in various methylation datasets, including low-pass or single-cell DNA methylomes, 5-hydroxymethylation (5hmC) profiles, spatial DNA methylation maps, and array-based datasets for epigenome-wide association studies. Applying KYCG to these datasets provides valuable insights into cell differentiation, cancer origins, epigenome-trait associations, and technical issues such as array artifacts, single-cell batch effects, and Nanopore 5hmC detection accuracy. Our tool simplifies large-scale methylation analysis and integrates seamlessly with standard assay technologies.

DOI: https://doi.org/10.1126/sciadv.adw3027
JCI Insight. 2025 Oct 21. pii: e189371. [Epub ahead of print]

Angiopoietin-like 8 governs osteoblast-adipocyte lineage commitment during skeletal aging.

Yaming Guo, Zeqing Zhang, Junyu He, Peiqiong Luo, Zhihan Wang, Yurong Zhu, Xiaoyu Meng, Limeng Pan, Ranran Kan, Yuxi Xiang, Beibei Mao, Yi He, Siyi Wang, Yan Yang, Fengjing Guo, Hongbo You, Feng Li, Danpei Li, Yong Chen, Xuefeng Yu.

  A distinguishing feature of older mesenchymal stem cells (MSCs) from bone marrow (BM) is the transition in their differentiation capabilities from osteoblasts to adipocytes. However, the mechanisms underlying these cellular events during the aging process remain unclear. We identified Angiopoietin-like protein 8 (ANGPTL8), a newly found adipokine implicated in lipid metabolism, that influences the fate of MSCs in BM during skeletal aging. Our studies revealed that ANGPTL8 steered MSCs towards adipogenic differentiation, overshadowing osteoblastogenesis. Mice with overexpressed ANGPTL8 exhibited reduced bone mass and increased bone marrow adiposity, while those with transgenic depletion of ANGPTL8 showed lowered bone loss and less accumulation of bone marrow fat. ANGPTL8 influenced the bone marrow niche of MSCs by inhibiting the Wnt/β-catenin signaling pathway. Partial inhibition of PPARγ rescued some aspects of the phenotype in MSCs with ANGPTL8 overexpression. Furthermore, treatment with Angptl8-Antisense Oligonucleotide (Angptl8-ASO) improved the phenotype of aging mice. The research proposes that ANGPTL8 is a critical regulator of senesence-related changes in the BM niche and the cell fate switch of MSCs.

Keywords:  Adult stem cells; Aging; Bone disease; Bone marrow differentiation; Endocrinology

DOI:  https://doi.org/10.1172/jci.insight.189371
PLoS Genet. 2025 Oct 23. 21(10): e1011915

A distal enhancer of Pparα regulates thermogenesis and mitochondrial function in brown fat.

Tingting Jiang, Duo Su, Jing Ke, Xin Dai, Maohua Wang, Yan Wang, Siyuan Zhan, Tao Zhong, Jiazhong Guo, Li Li, Honping Zhang, Linjie Wang.

Peroxisome proliferator-activated receptor α (PPARα) is a crucial transcription factor in regulating brown adipose tissue (BAT) physiological function. However, the mechanisms of enhancer-promoter chromatin interactions that control transcription regulation of Pparα in BAT remain unclear. In this study, we used circularized chromosome conformation capture coupled with next-generation sequencing (4C-seq) to reveal distinct differences in Pparα-associated chromatin interactions between intrascapular BAT (iBAT) and epididymal white adipose tissue (eWAT). In addition, we identified an iBAT-specific active enhancer (Pparα-En4) that was activated by cold stimulation. Functional assays demonstrated that targeted repression of Pparα-En4 region significantly decreased Pparα expression and impaired brown adipocyte differentiation and thermogenesis. Moreover, the transcription factor CREB regulated Pparα-En4 activity and increased Pparα expression in cooperation with the acetyltransferase CBP. Repression of Pparα-En4 using a lentiviral system in iBAT resulted in reduced thermogenic capacity and mitochondrial damage during cold acclimation conditions in vivo. These findings reveal that Pparα-En4 is a critical regulatory element in thermogenesis and mitochondrial function, and provide important insights into enhancer-mediated transcriptional regulation of Pparα expression in BAT.

DOI: https://doi.org/10.1371/journal.pgen.1011915
Cell Metab. 2025 Oct 22. pii: S1550-4131(25)00396-1. [Epub ahead of print]

The enedioic acid analog 326E alleviates metabolic dysfunction-associated steatohepatitis via dual targeting at ACLY and PPARα.

Zhifu Xie, Long Cheng, Yue Hu, Gaolei Song, Fan Wang, Mei Zhang, Yangming Zhang, Xinwen Zhang, Chendong Zhou, Xiaoxue Zhu, Xinyu Sun, Honghong Xu, Qian Song, Yulin Yang, Jie Zheng, Shaohui Ji, Jiming Ye, Chen Zhou, Xiaoying Lai, Wei Li, Yifan Zhang, Xiaoyan Chen, Junqi Niu, Yanhua Ding, Fajun Nan, Jingya Li.

  The rise in the prevalence of metabolic dysfunction-associated steatohepatitis (MASH) is attributed significantly to dysregulated lipid metabolism. This study discovered that the enedioic acid ATP-citrate lyase (ACLY) inhibitor 326E, an investigational new drug in a phase 2a study for hypercholesterolemia, markedly reduces hepatic lipid accumulation and alleviates MASH in mouse models of MASH. Mechanistic studies demonstrated that 326E exerts these effects not only by inhibiting ACLY to reduce de novo lipogenesis (DNL) but also as a peroxisome proliferator-activated receptor α (PPARα) allosteric regulator to increase hepatic fatty acid oxidation (FAO). The efficacy of activated PPARα for MASH is enhanced by suppressed recycling of FAO products to lipid accumulation as a result of ACLY inhibition. Subsequent studies in cynomolgus monkeys (Macaca fascicularis) confirmed the effectiveness of 326E for MASH in primate species. In a randomized phase 1b/2a clinical trial in patients with MASH (NCT06491576), 326E was well tolerated and reduced circulating gamma-glutamyl transferase (γ-GGT). Taken together, our results indicate the therapeutic potential of 326E for MASH via distinctive dual mechanisms of inhibiting ACLY while activating PPARα.

Keywords:  326E; ACLY; PPARα; fatty acid β-oxidation; lipogenesis; metabolic dysfunction-associated steatohepatitis; phase 1b/2a clinical trial

DOI:  https://doi.org/10.1016/j.cmet.2025.09.011
Sci Adv. 2025 Oct 24. 11(43): eady7904

Leptin as a key driver for organ fibrogenesis.

Xue-Nan Sun, Shiuhwei Chen, Shangang Zhao, Jan-Bernd Funcke, Megan Virostek, Line Pedersen, Chao Li, Chanmin Joung, Qian Lin, Yan Li, Ayanna Cobb, May-Yun Wang, Kyounghee Min, Lisandro Maya-Ramos, Giovanna Degasperi, Junquan Liu, Ningyan Zhang, Zhiqiang An, Diana R Tomchick, R Max Wynn, Da Young Oh, Philipp E Scherer.

Leptin, a hormone primarily secreted by adipocytes, regulates energy balance and systemic metabolism through its interaction with the leptin receptor (LEPR). Beyond these functions, leptin signaling has been implicated in the pathogenesis of tissue fibrosis. Here, we report the x-ray crystal structures of a leptin-neutralizing antibody (hLep3) in the unbound and leptin-bound states. The interaction of this antibody with leptin mimics the interaction of the LEPR with leptin, providing direct insights into the mechanism by which the antibody disrupts leptin signaling. We furthermore evaluate the therapeutic potential of neutralizing leptin with this antibody across distinct mouse models of fibrosis affecting the kidney, liver, lung, heart, and blood vessels. Leptin neutralization markedly inhibited fibrosis progression in all models. Mechanistically, suppression of leptin activity reduces pro-inflammatory and profibrotic processes, underscoring its therapeutic potential. These findings suggest that leptin signaling plays a vital role in tissue fibrosis and that treatment with a leptin-neutralizing antibody may be a promising therapeutic approach.

DOI: https://doi.org/10.1126/sciadv.ady7904
Sci Adv. 2025 Oct 24. 11(43): eadv0926

Time-resolved Mendelian randomization detects substantial variation in the detrimental effect of obesity throughout life.

Torgny Karlsson, Fatemeh Hadizadeh, Mathias Rask-Andersen, Daniel Schmitz, Åsa Johansson.

The global burden of disease attributable to obesity continues to rise. The disease incidence is substantially higher in elderly populations, but how obesity affects disease risk across a lifetime is largely unknown. To quantify the long-term temporal impact of obesity, access to large-scale longitudinal cohorts spanning many decades would typically be required. However, these longitudinal studies are rare and may be heavily biased by the presence of unaccountable confounding. Here, we develop a method-time-resolved Mendelian randomization-to estimate the cumulative effect of body mass index on disease risk at different ages. Using the UK Biobank, we find strong age-varying patterns for type 2 diabetes mellitus, coronary artery disease, and atrial fibrillation, as well as for osteoarthritis. We demonstrate that some of the most notable temporal characteristics are sex specific, while other features are shared between sexes. Analyses suggest that these features can be manifestations of primary prevention strategies.

DOI: https://doi.org/10.1126/sciadv.adv0926