bims-obesme 2025-07-20 papers

bims-obesme

Biomed News

on Obesity metabolism

Issue of 2025–07–20
ten papers selected by
Xiong Weng, University of Edinburgh

Synergistic Control of Mitochondrial Dynamics and Function by ERAD and Autophagy in Brown Adipocytes.
Sex difference in BAT thermogenesis depends on PGC-1α-mediated phospholipid synthesis in mice.
Adipose tissue-derived PRXL2A suppresses hepatic lipogenesis in a study with male mice.
Time is encoded by methylation changes at clustered CpG sites.
Human glycogenins maintain glucose homeostasis by regulating glycogen metabolism.
p21-activated Kinases (PAKs) Regulate FGF1/PDE4D Antilipolytic Pathway and Insulin Resistance in Adipocytes.
Polyglycine-mediated aggregation of FAM98B disrupts tRNA processing in GGC repeat disorders.
Growth Factor-Independent mTORC1 Signaling Promotes Primary Cilia Length via Suppression of Autophagy.
Characterizing primary and secondary senescence in vivo.
Recent evolution of the developing human intestine affects metabolic and barrier functions.

bioRxiv. 2025 Jun 15. pii: 2025.06.14.659625. [Epub ahead of print]

Synergistic Control of Mitochondrial Dynamics and Function by ERAD and Autophagy in Brown Adipocytes.

Xinxin Chen, Siwen Wang, Mauricio Torres, Sijie Hao, Shengyi Sun, Ling Qi.

Mitochondrial quality control is essential for maintaining cellular energy homeostasis, particularly in brown adipocytes where dynamic mitochondrial remodeling supports thermogenesis. Although the SEL1L-HRD1 endoplasmic reticulum (ER)-associated degradation (ERAD) pathway and autophagy are two major proteostatic systems, how these pathways intersect to regulate mitochondrial integrity in metabolically active tissues remains poorly understood. Here, using adipocyte-specific genetic mouse models combined with high-resolution 2D and 3D ultrastructural imaging technologies, we reveal an unexpected synergy between SEL1L-HRD1 ERAD and autophagy in maintaining mitochondrial structure and function in brown adipocytes. Loss of ERAD alone triggers compensatory autophagy, whereas combined deletion of both pathways (double knockout, DKO) results in severe mitochondrial abnormalities, including the accumulation of hyperfused megamitochondria penetrated by ER tubules, even under basal room temperature conditions. These phenotypes are absent in mice lacking either pathway individually or in SEL1L-IRE1α DKO, highlighting the pathway-specific coordination between ERAD and autophagy. Mechanistically, dual loss of ERAD and autophagy induces ER expansion, excessive ER-mitochondria contact, upregulation of mitochondria-associated membrane (MAM) tethering proteins, impaired calcium transfer, and defective mitochondrial turnover. As a result, DKO adipocytes accumulate dysfunctional mitochondria, exhibit respiratory deficits, and fail to sustain thermogenesis. Collectively, our study uncovers a cooperative and previously unrecognized mechanism of mitochondrial surveillance, emphasizing the critical role of ERAD-autophagy crosstalk in preserving mitochondrial integrity and thermogenic capacity in brown fat.
One-sentence summary: Our study uncovers a previously unrecognized synergy between SEL1L-HRD1 ERAD and autophagy that is essential for preserving mitochondrial integrity and thermogenic capacity in brown adipocytes, revealing new opportunities for targeting mitochondrial dysfunction in metabolic disease.

DOI: https://doi.org/10.1101/2025.06.14.659625
Nat Commun. 2025 Jul 14. 16(1): 6072

Sex difference in BAT thermogenesis depends on PGC-1α-mediated phospholipid synthesis in mice.

Akira Takeuchi, Kazutaka Tsujimoto, Jun Aoki, Kenji Ikeda, Nozomu Kono, Kuniyuki Kano, Yoshihiro Niitsu, Masato Horino, Kazunari Hara, Rei Okazaki, Ryo Kaneda, Masanori Murakami, Kumiko Shiba, Chikara Komiya, Junken Aoki, Tetsuya Yamada.

Brown adipose tissue (BAT), a thermogenic tissue that plays an important role in systemic energy expenditure, has histological and functional sex differences. BAT thermogenic activity is higher in female mice than in male mice. However, the molecular mechanism underlying this functional sex difference has not been fully elucidated. Herein, we demonstrate the role and mechanism of PGC-1α in this sex difference. Inducible adipocyte-specific PGC-1α knockout (KO) mice display mitochondrial morphological defects and decreased BAT thermogenesis only in females. Expression of carbohydrate response-element binding protein beta (Chrebpβ) and its downstream de novo lipogenesis (DNL)-related genes are both reduced only in female KO mice. BAT-specific knockdown of ChREBPβ displays decreased DNL-related gene expression and mitochondrial morphological defects followed by reduced BAT thermogenesis in female wild-type mice. Lipidomics reveals that, PGC-1α increases ether-linked phosphatidylethanolamine (PE) and cardiolipin(18:2)4 levels through Chrebpβ-dependent and -independent mechanisms in female BAT. Furthermore, PGC-1α enhances the sensitivity of female BAT estrogen signaling, thereby increasing Chrebpβ and its downstream DNL-related gene expression. These findings demonstrate that PGC-1α-mediated phospholipid synthesis plays a pivotal role in BAT thermogenesis in a sex-dependent manner.

DOI: https://doi.org/10.1038/s41467-025-61219-w
Nat Commun. 2025 Jul 16. 16(1): 6567

Adipose tissue-derived PRXL2A suppresses hepatic lipogenesis in a study with male mice.

Zhiyuan Li, Zheng Tian, Xiaoliu Shi, Aijun Long, Yazhuo Wang, Yan Yang, Yaqi Wang, Jingjing Zhang, Yiguo Wang.

Hepatic de novo lipogenesis (DNL) is crucial for maintaining lipid homeostasis, and its dysregulation is implicated in various metabolic diseases. While it is well established that hepatic DNL is tightly regulated by hormones such as insulin and glucagon secreted from the pancreatic islets during feeding and fasting, further investigations are required to identify more hormones affecting hepatic DNL during the feeding-fasting transition. Here, we identify PRXL2A (peroxiredoxin like 2 A), an adipokine secreted during fasting, as an inhibitor of hepatic DNL. Mechanistically, PRXL2A binds to its receptor PTAFR (platelet activating factor receptor), promoting calcium mobilization and activating AMPK (AMP-activated protein kinase), thereby suppressing SREBP1 (sterol regulatory element-binding protein 1)-controlled hepatic DNL. Disruption of this axis by knockout of either Prxl2a or Ptafr increases hepatic DNL and lipid accumulation. Exogenous PRXL2A reduces hepatic DNL, suggesting a potential therapeutic strategy for diseases associated with hepatic lipid accumulation. Therefore, the PRXL2A-PTAFR signaling axis links adipose tissues and the liver to regulate hepatic lipid metabolism.

DOI: https://doi.org/10.1038/s41467-025-61963-z
Cell Rep. 2025 Jul 08. pii: S2211-1247(25)00729-6. [Epub ahead of print] 115958

Time is encoded by methylation changes at clustered CpG sites.

Bracha-Lea Ochana, Daniel Nudelman, Daniel Cohen, Ayelet Peretz, Sheina Piyanzin, Ofer Gal Rosenberg, Amit Horn, Netanel Loyfer, Miri Varshavsky, Ron Raisch, Ilona Shapiro, Yechiel Friedlander, Hagit Hochner, Benjamin Glaser, Yuval Dor, Tommy Kaplan, Ruth Shemer.

  Age-dependent changes in DNA methylation allow chronological and biological age inference, but the underlying mechanisms remain unclear. Using ultra-deep sequencing of >300 blood samples from healthy individuals, we show that age-dependent methylation changes occur regionally across clusters of CpG sites either stochastically or in a coordinated block-like manner. Deep learning of single-molecule patterns from two genomic loci predicts chronological age with a median accuracy of 1.36-1.7 years on held-out samples, dramatically improving current clocks. Predictions are robust to sex, smoking, BMI, and biological age measures. Longitudinal 10-year analysis shows that early deviations from predicted age persist throughout life, and subsequent changes faithfully record time. Strikingly, accurate chronological age predictions are possible using as few as 50 DNA molecules, suggesting that age is encoded by individual cells. Overall, DNA methylation changes in clustered CpG sites illuminate the principles of time measurement by cells and tissues and facilitate medical and forensic applications.

Keywords:  CP: Metabolism; CP: Molecular biology; DNA methylation; age prediction; aging; biological age; chronological age; computational biology; deep learning; epigenetics; forensics; neural networks

DOI:  https://doi.org/10.1016/j.celrep.2025.115958
Nat Commun. 2025 Jul 16. 16(1): 6556

Human glycogenins maintain glucose homeostasis by regulating glycogen metabolism.

Tzu-Han Weng, Yu-Chung Pien, Ching-Jou Chen, Po-Pang Chen, Yu-Ting Tseng, Ying-Chen Chen, Wen-Po Hsiao, Ying-Ting Lee, Yi-An Chen, Yao-Chi Chen, Carmay Lim, Tzu-Han Hsu, Sung-Jan Lin, Hsin-Yung Yen, Kuo-Chiang Hsia, Su-Yi Tsai.

Proper regulation of glycogen metabolism is fundamental to cellular energy homeostasis, and its disruption is associated with various metabolic disorders, including glycogen storage diseases (GSDs) and potentially diabetes. Despite glycogen's role as an essential energy reservoir, the mechanisms governing its synthesis and structural diversity across tissues remain unclear. Here, we uncover the distinct physiological roles of the human glycogenins GYG1 and GYG2 in glycogen synthesis. Through cellular models, structural biology, and biochemical analyses, we demonstrate that, unlike GYG1, GYG2 exhibits minimal autoglycosylation activity and acts as a suppressor of glycogen formation. Together, these two glycogenins coordinate glycogen synthase activity and influence glycogen assembly in a cell-type-dependent manner. Importantly, these glycogenins modulate glucose metabolic pathways, thereby ensuring cellular glucose homeostasis. These findings address longstanding questions in glycogen metabolism and establish both GYG1 and GYG2 as critical regulators of glycogen synthesis and breakdown in human, providing insights with potential therapeutic implications for treating GSDs and metabolic diseases.

DOI: https://doi.org/10.1038/s41467-025-61862-3
Mol Metab. 2025 Jul 12. pii: S2212-8778(25)00117-6. [Epub ahead of print] 102210

p21-activated Kinases (PAKs) Regulate FGF1/PDE4D Antilipolytic Pathway and Insulin Resistance in Adipocytes.

Judith Seigner, Johannes Krier, David Spähn, Leontine Sandforth, Judith L Nono, Robert Lukowski, Andreas L Birkenfeld, Gencer Sancar.

Increasing evidence suggests that adipose tissue plays a key role in the development, progression, and treatment of the globally epidemic disease type 2 diabetes (T2D). For example, adipose tissue dysfunction, lipotoxicity, and insulin resistance (IR) are major contributors and targets for the treatment of T2D. We previously identified the Fibroblast growth factor 1 (FGF1) / Phosphodiesterase 4D (PDE4D) pathway, which lowers plasma glucose concentration by suppressing lipolysis in adipose tissue and ultimately regulating hepatic glucose production in obese insulin-resistant mice. While phosphorylation of PDE4D is critical for its activity, the upstream signaling mechanisms remain unclear. In this study, we identified p21-activated kinases (PAKs) as regulator of PDE4D phosphorylation and suppression of lipolysis by FGF1. Inhibition of PAK-induced cAMP accumulation prevented antilipolytic function of FGF1, and reversed suppression of lipolysis caused by PDE4D overexpression, linking PAKs to the regulation of cAMP by PDE4D in murine adipocytes in vitro. Chronic inhibition of PAKs decreased lipid accumulation in both mouse and human adipocyte cultures, lowered expression of adipogenic markers, and induced IR, suggesting a previously unidentified role of PAKs in adipocyte function and differentiation. We conclude that PAKs play a crucial role in regulating the FGF1/PDE4D antilipolytic pathway, adipogenesis and IR, thereby highlighting their potential as therapeutic targets for T2D.

DOI: https://doi.org/10.1016/j.molmet.2025.102210
Science. 2025 Jul 17. 389(6757): eado2403

Polyglycine-mediated aggregation of FAM98B disrupts tRNA processing in GGC repeat disorders.

Jason Yang, Yunhan Xu, David R Ziehr, Martin S Taylor, Max L Valenstein, Evgeni M Frenkel, Jack R Bush, Kate Rutter, Igor Stevanovski, Charlie Y Shi, Maheswaran Kesavan, Ricardo Mouro Pinto, Ira Deveson, David P Bartel, David M Sabatini, Raghu R Chivukula.

Aggregation-prone polyglycine-containing proteins produced from expanded GGC repeats are implicated in an emerging family of neurodegenerative disorders. In this study, we showed that polyglycine itself forms aggregates that incorporate endogenous glycine-rich proteins, including FAM98B, a component of the transfer RNA (tRNA) ligase complex (tRNA-LC) that harbors the most glycine-rich sequence in the human proteome. Through this glycine-rich intrinsically disordered region (IDR), polyglycine sequesters and depletes the tRNA-LC, disrupting tRNA processing. Accordingly, patient tissues revealed aggregate-associated FAM98B depletion and accumulation of aberrant tRNA splicing intermediates. Furthermore, Fam98b depletion in adult mice caused progressive motor coordination deficits and hindbrain pathology. Our data suggest that the FAM98B glycine-rich IDR mechanistically links previously disparate neurodegenerative disorders of protein aggregation and tRNA processing.

DOI: https://doi.org/10.1126/science.ado2403
bioRxiv. 2025 May 07. pii: 2025.05.07.652626. [Epub ahead of print]

Growth Factor-Independent mTORC1 Signaling Promotes Primary Cilia Length via Suppression of Autophagy.

Jong Shin, Yann Cormerais, Khaled Tighanimine, Pratima Niroula, Madi Y Cisse, Samuel C Lapp, Krystle C Kalafut, Sandra Schrötter, Brendan D Manning.

The mechanistic target of rapamycin (mTOR) complex 1 (mTORC1), as a sensor of growth signals that subsequently controls cell growth, has been predominantly studied in actively proliferating cells. Primary cilia are sensory organelles present on most quiescent cells, where they play essential roles in receiving environmental and developmental signals. Given that ciliated cells are non-proliferative, we investigated whether mTORC1 signaling influences the growth of primary cilia. Here, we show that mTORC1 promotes primary cilia elongation, without effects on ciliogenesis or cell growth, by suppressing autophagy. Inhibition of mTORC1 signaling through pharmacological, nutritional, or genetic interventions gave rise to shortened primary cilia, while activation of the pathway resulted in elongation. Furthermore, pharmacological or genetic inhibition of autophagy, a key downstream process blocked by mTORC1, also elongated primary cilia and rendered them resistant to mTORC1 inhibition. Notably, these mTORC1-mediated effects on primary cilia extend to mouse neurons ex vivo and in vivo. These findings highlight a previously unrecognized role for mTORC1 signaling in the control of primary cilia length that may contribute to diseases where ciliary function is altered, referred to as ciliopathies.

DOI: https://doi.org/10.1101/2025.05.07.652626
Nat Aging. 2025 Jul 11.

Characterizing primary and secondary senescence in vivo.

Yuko Sogabe, Hirofumi Shibata, Mio Kabata, Akito Tanaka, Kanae Mitsunaga, Kazunori Sunadome, May Nakajima-Koyama, Michitada Hirano, Eisuke Nishida, Knut Woltjen, Hiroshi Seno, Yasuhiro Yamada, Takuya Yamamoto.

There is robust evidence that senescence can be propagated in vitro through mechanisms including the senescence-associated secretory phenotype, resulting in the non-cell-autonomous induction of secondary senescence. However, the induction, regulation and physiological role of secondary senescence in vivo remain largely unclear. Here we generated senescence-inducible mouse models expressing either the constitutively active form of MEK1 or MKK6 and mCherry, to map primary and secondary senescent cells. Our models recapitulate characteristic features of senescence and demonstrate that primary and secondary phenotypes are highly tissue- and inducer-dependent. Spatially resolved RNA expression analyses at the single-cell level reveal that each senescence induction results in a unique transcriptional profile-even within cells of the same cell type-explaining the heterogeneity of senescent cells in vivo. Furthermore, we show that interleukin-1β, primarily derived from macrophages, induces secondary phenotypes. Our findings provide insight into secondary senescence in vivo and useful tools for understanding and manipulating senescence during aging.

DOI: https://doi.org/10.1038/s43587-025-00917-y
Science. 2025 Jul 17. eadr8628

Recent evolution of the developing human intestine affects metabolic and barrier functions.

Qianhui Yu, Umut Kilik, Stefano Secchia, Lukas Adam, Yu-Hwai Tsai, Christiana Fauci, Jasper Janssens, Charlie J Childs, Katherine D Walton, Rubén López-Sandoval, Angeline Wu, Marina Almató Bellavista, Sha Huang, Calen A Steiner, Yannick Throm, Michael James Boyle, Zhisong He, Joep Beumer, Barbara Treutlein, Craig B Lowe, Jason R Spence, J Gray Camp.

Diet, microbiota, and other exposures place the intestinal epithelium as a nexus for evolutionary change; however, little is known about genomic changes associated with adaptation to a uniquely human environment. Here, we interrogate the evolution of cell types in the developing human intestine by comparing tissue and organoids from humans, chimpanzees, and mice. We find that recent changes in primates are associated with immune barrier function and lipid/xenobiotic metabolism, and that human-specific genetic features impact these functions. Enhancer assays, genetic deletion, and in silico mutagenesis resolve evolutionarily significant enhancers of Lactase (LCT) and Insulin-like Growth Factor Binding Protein 2 (IGFBP2). Altogether, we identify the developing human intestinal epithelium as a rapidly evolving system, and show that great ape organoids provide insight into human biology.

DOI: https://doi.org/10.1126/science.adr8628