bims-obesme 2025-11-30 papers

bims-obesme

Biomed News

on Obesity metabolism

Issue of 2025–11–30
eight papers selected by
Xiong Weng, University of Edinburgh

A metabolic atlas of mouse aging.
Fructose and follistatin potentiate acute MASLD during complete hepatic insulin resistance.
Sensory-neuron-derived CGRPα controls white adipocyte differentiation and tissue plasticity.
Avian GCGR-mediated continuous fat utilization offers perspectives for obesity treatment.
Adipose TGR5 Deletion Promotes Hepatic Steatosis Through Decreasing Adiponectin Secretion in Mice.
N-terminal α-amino SUMOylation promotes phosphorylation-independent cofilin-1 translocation to the mitochondrial matrix and induces apoptosis.
NAT10-mediated ac4C modification of KDM1B drives osteoarthritis progression through epigenetic suppression of SOX9.
Depot-specific roles for sphingosine kinase 1 in conversion of white adipose to thermogenic adipose.

Cell Metab. 2025 Nov 25. pii: S1550-4131(25)00476-0. [Epub ahead of print]

A metabolic atlas of mouse aging.

Steven E Pilley, Dominik Awad, Djakim Latumalea, Connie New, Edgar Esparza, Shuo Wang, Xuanyi Shi, Li Zhang, Maximilian Unfried, Jasinda H Lee, Ernst Schmid, Ipsita Mohanty, Jenna L E Blum, Shivaanishaa Raventhiran, Esther Wong, Preeti R Iyengar, Racheal Mulondo, Sriraksha Bharadwaj Kashyap, Darius Moaddeli, Peter Sajjakulnukit, Damien Sutton, Harrison K A Wong, Yaqi Gao, George Wang, Aeowynn J Coakley, Gilberto Garcia, Ryo Higuchi-Sanabria, Anja Karlstaedt, Timothy L Frankel, Marina Pasca di Magliano, Whitaker Cohn, Sophia Liu, Bingfei Yu, Pieter C Dorrestein, Ernest Fraenkel, Shawn M Davidson, William B Tu, Brian K Kennedy, Costas A Lyssiotis, Peter J Mullen.

  Humans are living longer and experiencing more age-related diseases, many of which involve metabolic dysregulation, but how metabolism changes in multiple organs during aging is not known. Answering this could reveal new mechanisms of aging and therapeutics. Here, we profile metabolic changes in 12 organs in male and female mice at 5 different ages. We also develop organ-specific metabolic aging clocks that identify metabolic drivers of aging, including alpha-ketoglutarate, previously shown to extend lifespan in mice. We also use the clocks to uncover that carglumic acid is a potential driver of aging and show that it is synthesized by human cells. Finally, we validate that hydroxyproline decreases with age in the human pancreas, emphasizing that our approach reveals insights across species. This study reveals fundamental insights into the aging process and identifies new therapeutic targets to maintain organ health.

Keywords:  LC-MS/MS; MALDI-MSI; aging; aging clocks; healthspan; human tissue; hydroxyproline; metabolism; scRNA-seq; sex

DOI:  https://doi.org/10.1016/j.cmet.2025.10.016
Nat Commun. 2025 Nov 24.

Fructose and follistatin potentiate acute MASLD during complete hepatic insulin resistance.

Rongya Tao, Oliver Stöhr, Ozlem Tok, Ana Andres-Hernando, Wei Qiu, Baiyu He, Caixia Wang, Lars Grøntved, Charles Burant, Sheng Hui, Miguel A Lanaspa, Norbert Stefan, Kyle D Copps, Morris F White.

MASLD (metabolic-associated steatotic liver disease) and MASH (steatohepatitis) are closely associated with hepatic IR (insulin resistance) and T2D. Regardless, insulin-stimulated hepatic lipogenesis is considered essential for MASLD development, as mouse models of complete hepatic IR become diabetic without MASLD when fed high-fat diets. Challenging this notion, we found that male LDKO mice lacking hepatic insulin receptor substrates acutely developed MASLD if fed a fructose-enriched "MASH diet" (GAN) or high-fructose diet. Fructose potentiated hepatic re-esterification of abundant circulating fatty acids in LDKO mice, evidenced by excess 13C incorporation into the glycerol backbone-but not fatty acid chains-of hepatic triacylglyceride after gavage with [U13C]fructose. Suppressing adipose lipolysis in LDKO mice by inactivating hepatic Fst (Follistatin) prevented acute MASLD, whereas over-expressing Fst in wild-type mouse liver accelerated GAN-promoted MASLD/MASH. Compatibly, higher serum FST levels among Tübingen Diabetes Family Study participants clustered with increased adipose IR and greater hepatic triacylglyceride accumulation.

DOI: https://doi.org/10.1038/s41467-025-66296-5
Cell Rep. 2025 Nov 21. pii: S2211-1247(25)01385-3. [Epub ahead of print]44(12): 116613

Sensory-neuron-derived CGRPα controls white adipocyte differentiation and tissue plasticity.

Kyle D Dumont, Saba Seradj, Yu Wang, Shanshan Liu, Igor Cervenka, Chao Wu, Paulo R Jannig, Margareta Porsmyr-Palmertz, Gerard Baiges-Gaya, Xun Huang, Carina Nihlen, José M Dias, Simona S Skiotyte, Stine Marie Præstholm, Dawn Wilbert, Aurel B Leuchtmann, Melissa A Quinn, Ziming Zhu, Chelsea Hepler, Jon O Lundberg, Ana I Teixeira, Anthony Rosenzweig, Jun Wu, Li Ye, Jorge L Ruas.

  Communication between the brain and adipose tissue is mediated in part by the peripheral nervous system. The sympathetic branch transmits lipolytic and thermogenic signals toward adipose tissue, while sensory nerves relay information to the central nervous system. Importantly, sensory nerve activation also triggers local neuropeptide release. Here, we show that sensory-neuron-derived α-calcitonin gene-related peptide (CGRPα) inhibits white, but not brown, preadipocyte differentiation in a cell-autonomous manner. In vivo, CGRPα expression in mouse subcutaneous adipose tissue during cold exposure shifts the expected increase in smaller adipocytes to an increase in larger cells. Importantly, people on anti-CGRPα/CGRP receptor (CGRPR) medications for migraine treatment show reductions in weight and glycemia, while these measures increase in the matched control group. Similarly, mice treated with a CGRPR antagonist and exposed to cold show a reduction in body weight. These findings identify a neuron-adipocyte communication pathway that regulates white adipose tissue plasticity and metabolism.

Keywords:  CGRP; CP: metabolism; CP: neuroscience; adipogenesis; adipose tissue; calcitonin gene-related peptide; inter-organ communication; metabolism; neuron-adipocyte; sensory neuron; somatosensory innervation

DOI:  https://doi.org/10.1016/j.celrep.2025.116613
Nat Commun. 2025 Nov 28.

Avian GCGR-mediated continuous fat utilization offers perspectives for obesity treatment.

Chang Zhang, Xue Wang, Chenxi Feng, Huaping Zheng, Song Leng, Yiheng Jiang, Qian Sun, Xiaoou Li, Ting Zhang, Jiacheng Zhang, Haidi Chen, Shanshan Lai, Wojciech Makalowski, Jürgen Brosius, Yujun Shi, Yang He, Peng Hu, Qiu Sun, Cheng Deng.

Human obesity is the fifth leading cause of global mortality. Fat mass loss and maintenance are central challenges for obesity management. In contrast, birds exhibit modest weight gain and limited fat accumulation due to rapid fat utilization as flight fuel. The physiology of this adaptation remained a mystery for a century. Here we show that cross-species single-nucleus RNA-sequencing analysis revealed high GCGR expression levels in avian adipocytes, while minimal in the adipose tissue of other vertebrates. Avian GCGR employs a unique rapid fat utilization mechanism for retaining a light body. Avian GCGR or other constitutively active GCGR variants (human GCGRH339R) expressed in white adipose tissue of male mice with obesity effectively promoted fat mobilization and sustained body weight loss, with decreased food intake partially contributing to the observed weight reduction. We suggest that avian GCGR plays this crucial role for fat utilization and may offer therapeutic potential for human obesity.

DOI: https://doi.org/10.1038/s41467-025-66305-7
Diabetes. 2025 Nov 26. pii: db250344. [Epub ahead of print]

Adipose TGR5 Deletion Promotes Hepatic Steatosis Through Decreasing Adiponectin Secretion in Mice.

Jiahui Li, Qinhui Liu, Yimin Xiong, Ying Xu, Jinhang Zhang, Yan Xia, Xiandan Jing, Zijing Zhang, Juan Pang, Cuiyuan Huang, Haiying Song, Ailin Zhang, Yanping Li, Qin Tang, Jinhan He.

Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as a global epidemic, yet its underlying molecular mechanisms remain elusive, and therapeutic options are limited. The interorgan communication between liver and adipose tissue plays a crucial role in maintaining hepatic lipid homeostasis. This study investigates the role of G-protein-coupled bile acid receptor 1 (TGR5) in adipose tissue-liver communication and its impact on hepatic lipid metabolism during the progression of MASLD. We observed that TGR5 expression in white adipose tissue was significantly upregulated under both fasting and high-fat diet (HFD) conditions, whereas its levels in brown adipose tissue remained unchanged. Notably, mice with adipocyte-specific TGR5 deletion exhibited exacerbated fasting/HFD-induced hepatic steatosis and impaired hepatic fatty acid oxidation. Mechanistically, adipose tissue TGR5 deficiency reduced adiponectin secretion, which in turn suppressed hepatic fatty acid oxidation and aggravated hepatic lipid accumulation; conversely, restoration of circulating adiponectin rescued these metabolic abnormalities. Collectively, our findings highlight a critical role for adipose tissue TGR5 in promoting adiponectin secretion, thereby enhancing hepatic fatty acid oxidation and protecting against hepatic steatosis.
ARTICLE HIGHLIGHTS: Systemic G-protein-coupled bile acid receptor 1 (TGR5) is involved in modulating hepatic triglyceride accumulation, but whether adipose-derived TGR5 regulates hepatic lipid metabolism remains undefined. We investigated whether fasting or a high-fat diet (HFD) altered TGR5 levels in adipose tissue and the effect of TGR5 ablation in adipose tissue on hepatic lipid metabolism. We found that TGR5 protein expression was upregulated in white adipose tissue upon fasting or HFD. Adipose-specific TGR5 deficiency decreased adiponectin secretion, which ultimately suppressed hepatic fatty acid oxidation and exacerbated intrahepatic lipid deposition. Given the limited therapeutic options for metabolic dysfunction-associated steatotic liver disease (MASLD), our findings highlight the therapeutic potential of targeting adipocyte TGR5 for MASLD intervention.

DOI: https://doi.org/10.2337/db25-0344
Nat Commun. 2025 Nov 27.

N-terminal α-amino SUMOylation promotes phosphorylation-independent cofilin-1 translocation to the mitochondrial matrix and induces apoptosis.

Qi Deng, Xiaokun Gu, Jiaqian Feng, Jinhua Xiang, Xinyue Li, Weiji Weng, Gerald W Zamponi, Ou Huang, Si-Jian Pan, Yong Li.

Cofilin is a central regulator of actin filament turnover, traditionally thought to act through phosphorylation-dependent control of filament assembly. However, its mitochondrial functions remain poorly understood. Here we show that N-terminal α-amino SUMOylation, rather than phosphorylation or actin interaction, governs cofilin-1 translocation to mitochondria and activation of the apoptotic pathway. This modification strengthens the association of cofilin-1 with the mitochondrial import receptors Tom20 and Tom70 through the molecular chaperone HSP70, enabling its delivery to the mitochondrial matrix. Once imported, SUMO-modified cofilin-1 binds cytochrome c1, promotes the dissociation of cytochrome c from complex III, and initiates mitochondrial-mediated apoptosis. These findings redefine cofilin-1 as a regulator of mitochondrial integrity independent of its actin-related roles, uncovering a mechanism by which SUMOylation directs protein targeting and apoptotic signaling. This work broadens current understanding of mitochondrial regulation and may inform therapeutic strategies for diseases linked to defective cell death.

DOI: https://doi.org/10.1038/s41467-025-66859-6
Cell Mol Life Sci. 2025 Nov 26. 82(1): 422

NAT10-mediated ac4C modification of KDM1B drives osteoarthritis progression through epigenetic suppression of SOX9.

Shuxiang Chen, Wenhuan Ou, Xiaotao Li, Mufu Jie, Yi Zheng, Jian Situ, Zhipeng Liao, Li Huang, Weizhong Qi, Songjia Ni.

  Histone methylation acts as a crucial regulator of diverse pathophysiological processes in humans. However, the involvement of histone methylation modification enzymes in osteoarthritis (OA) remains poorly characterized. Here, we delineated lysine demethylase 1B (KDM1B) as a nodal epigenetic effector driving OA pathobiology through an integrated strategy that combined data mining, bioinformatics analysis, and experimental validation. Gain-of-function studies revealed that chondrocyte - specific KDM1B overexpression amplified IL-1β-induced chondrocyte injury primarily through the inhibition of SRY-box transcription factor 9 (SOX9). Conversely, KDM1B knockdown inhibited IL-1β-induced chondrocyte damage in vitro and significantly alleviated OA progression in vivo by upregulating SOX9. Mechanistically, NAT10-catalyzed ac4C epitranscriptomic editing to KDM1B mRNA stabilization, leading to its overexpression in osteoarthritic chondrocytes. Elevated KDM1B subsequently binds to the promoter region of the SOX9 and catalyzes the demethylation of H3K4me2 to suppress SOX9 expression in osteoarthritic chondrocytes. Furthermore, our data also demonstrated that chondrocyte-specific NAT10 knockdown attenuated IL-1β-induced chondrocyte injury by modulating the KDM1B/SOX9 axis. Collectively, our findings unveil a novel NAT10/KDM1B/SOX9 regulatory cascade in OA pathogenesis, highlighting the potential of targeting epigenetic regulators to restore chondrocyte function and mitigate OA progression.

Keywords:  Cartilage degradation; KDM1B; N4-acetylcytidine; NAT10; Osteoarthritis; SOX9

DOI:  https://doi.org/10.1007/s00018-025-05918-z
bioRxiv. 2025 Oct 16. pii: 2025.10.16.682897. [Epub ahead of print]

Depot-specific roles for sphingosine kinase 1 in conversion of white adipose to thermogenic adipose.

Yolander Valentine, Maryam Jamil, Anna Kovilakath, Ryan D R Brown, Jordon Dail, Saaid Farooq, Sarah Spiegel, L Ashley Cowart.

Background: As of 2023, approximately 100.1 million adults and 14.7 million children in the USA are obese. Many comorbidities develop with obesity, which impairs quality of life and burdens the health care system. Consequently, there is an urgent need for interventions and treatments to reverse obesity and its comorbidities and restore health. Sphingosine Kinase 1 (SphK1), a key enzyme in sphingolipid metabolism, produces sphingosine-1-phosphate (S1P), a bioactive lipid implicated in obesity and metabolic dysfunction. While global deletion of Sphk1 protects against diet-induced obesity, adipocyte-specific SPHK1 deficiency paradoxically promotes weight gain, glucose intolerance, and adipose inflammation. Given the known role of sphingolipids in adipose thermogenesis, we investigated whether Sphk1 regulates adipocyte beiging and mitochondrial function.
Methods: We assessed thermogenic responses in SphK1-deficient adipocytes and adipocyte-specific Sphk1 knockout (Ad-SphK1Δ) mice under basal and β3-adrenergic stimulation using CL 316,243. Thermoneutral housing (30°C) and room temperature (23°C) conditions were used to minimize and assess ambient temperature effects on thermogenesis. Molecular, histological, and bioenergetic analyses were conducted across multiple adipose depots.
Results: β3-adrenergic stimulation upregulated Sphk1 expression in mature white adipocytes, while SphK1-deficient adipocytes exhibited enhanced Ucp1 expression, indicating a suppressive role for SphK1 in beiging. In vivo, adipocyte-specific Sphk1 knockout (Ad-SphK1Δ) mice showed elevated Ucp1 expression in inguinal and gonadal white adipose tissue (iWAT, gWAT), both basally and after CL 316,243 treatment. These changes were accompanied by depot-specific alterations in adipocyte size and increased adiposity, independent of ambient temperature. Despite similar elevation of thermogenic markers, Sphk1 deletion had differential effect on mitochondrial function: iWAT showed increased mitochondrial content but reduced complex IV activity and ATP production, whereas gWAT showed reduced mitochondrial abundance without changes in respiration.
Conclusion: Our work suggests that Sphk1 may act as a negative regulator of thermogenic expression and affect mitochondrial function in a depot-specific manner. Loss of Sphk1 enhances beiging but compromises mitochondrial efficiency, revealing a complex role for the SphK1/S1P axis in adipose plasticity and metabolic regulation. These insights may inform future therapeutic strategies targeting sphingolipid pathways for obesity and metabolic disease.

DOI: https://doi.org/10.1101/2025.10.16.682897