bims-mimead Biomed News
on Adipose tissue and metabolic disease
Issue of 2026–09–27
six papers selected by
Rachel M. Handy, University of Guelph and Universiteit Mastricht
  1. Prohibitin-1 cysteine-69 plays a sex-dependent role in fatty acid metabolism.
  2. An RNA thermogenic therapy to preserve lean mass and enhance metabolic health during GLP-1 weight loss.
  3. Adipose ILC2s depend on acetyl-CoA carboxylase 1 to maintain metabolic health.
  4. IL-1RA administration exerts diet-dependent metabolic effects on adipose tissue function and lipid handling in male mice.
  5. Transcriptional and epigenomic analysis of insulin sensitivity in human adipocytes.
  6. Mitophagy's impact on obesity-related tissues.
  1. J Lipid Res. 2026 Sep 23. pii: S0022-2275(26)00188-4. [Epub ahead of print] 101158
    Prohibitin-1 cysteine-69 plays a sex-dependent role in fatty acid metabolism.
    Katherine J Bernier, Zhanguo Gao, Yeshika Bhatia, Niloofar Beheshti Dehkordi, Fatemeh Nasiri, Alexes C Daquinag, Renata Pasqualini, Wadih Arap, Mikhail G Kolonin, Suresh Mishra.
      Metabolic diseases are caused by dysregulation of glucose and lipid homeostasis, which relies on the function of adipose tissues. This regulation and the associated pathologies differ between sexes, which remain incompletely understood. Prohibitin-1 (PHB1) has multifaceted tissue-specific functions converging on metabolism. Here, we investigated the role of PHB1's evolutionarily conserved cysteine-69 by replacing it with an alanine in a knock-in (Phb1-KI) mouse model. We show that Phb1-KI mice lack cell surface localization of PHB1 and display sex-biased adipose tissue alterations in relative sizes of visceral and subcutaneous depots and their adipocyte sizes, expression of lipid metabolism effectors, and adipokine secretion. Phb1-KI adipocytes are defective in long-chain fatty acid uptake and mobilization, and their mitochondrial abnormalities and reduced oxidative capacity result in defective lipid metabolism. In compensation, Phb1-KI have increased glycolysis and Phb1-KI mice display improved glucose disposal and increased insulin sensitivity. Attributes of this phenotype manifested differently in males and females of Phb1-KI mice. Our results demonstrate the importance of cysteine-69 in sex-related function of PHB1 in integrative physiology and systemic metabolism.
    Keywords:  Brown adipose tissue; fatty acid transport; glucose metabolism; mitochondria; sex differences; white adipose tissue
    DOI:  https://doi.org/10.1016/j.jlr.2026.101158
  2. Proc Natl Acad Sci U S A. 2026 Oct 06. 123(40): e2618845123
    An RNA thermogenic therapy to preserve lean mass and enhance metabolic health during GLP-1 weight loss.
    Anneke K Thorne, Nathan J Waldeck, Jesse P Rose, Marisa J Stachowski, Hannah Guak, Alexander R Keeble, Britta Kuusik, Ella Simon, Biliana Marcheva, Joseph V Mastroni, Pei Zhu, Ling Wa Chong, Yumiko Kobayashi, Nicholas J Conley, Andrew B Cohen, Yasuhiro Omura, Chiaki Omura, Weimin Song, Michael Wellems, Kathryn M Ramsey, Grant D Barish, Lisa R Beutler, Rana K Gupta, Clara B Peek, Elizabeth M McNally, Chelsea Hepler, Mark Perelis, Joseph Bass.
      Current obesity therapies reduce weight but often fail to preserve lean mass or sustain metabolic benefit. Glucagon-like peptide-1 receptor agonists (GLP-1RA) improve obesity-associated metabolic disease, but weight loss is often accompanied by reduced energy expenditure, loss of lean mass, and rapid fat-predominant regain after treatment discontinuation. We hypothesized that pharmacologic activation of adipose thermogenesis could specifically target fat loss, complement appetite suppression by increasing energy expenditure, and improve the metabolic quality of weight loss. Guided by our finding that diet-induced thermogenesis is mediated by a zinc finger protein 423 (ZFP423)-controlled pathway, we developed adipose-directed antisense oligonucleotides (ASOs) targeting ZFP423, a transcriptional repressor of brown and beige adipocyte identity. In lean and diet-induced obese mice, weekly Zfp423 ASO treatment induced white adipose beiging, increased body temperature and oxygen consumption, and improved glucose homeostasis, insulin sensitivity, lipid metabolism, mitochondrial respiration, and hepatic steatosis. When combined with the GLP1-RA semaglutide, Zfp423 ASO produced greater weight and fat loss than either monotherapy while preserving lean mass and improving metabolic outcomes. These findings identify Zfp423 as an RNA therapeutic target and support adipose thermogenesis as a complementary strategy for metabolically healthier obesity treatment.
    Keywords:  GLP-1 receptor agonist; ZFP423; adipose thermogenesis; antisense oligonucleotide; obesity
    DOI:  https://doi.org/10.1073/pnas.2618845123
  3. Cell Metab. 2026 Sep 23. pii: S1550-4131(26)00371-2. [Epub ahead of print]
    Adipose ILC2s depend on acetyl-CoA carboxylase 1 to maintain metabolic health.
    Fotios Karagiannis, Maria Rafailia Theodorou, Fabian Nikolka, Maria Doverman, Dhruvi Shah, Chantal Wientjens, Timothy R McCulloch, Ronja Kardinal, David Colon, Jelena Zurkovic, Jiangyan Yu, Julia Anna Noras, Patricia Weiss, Roman Rombo, Tim Sparwasser, Zeinab Abdullah, Felix Meissner, Christoph Thiele, Jan Hasenauer, Dagmar Wachten, Karsten Hiller, Christoph Wilhelm.
      Adipose group 2 innate lymphoid cells (ILC2s) are essential to maintain metabolic homeostasis. Obesity severely impairs the number and function of ILC2s, resulting in the progression of metabolic inflammation. How ILC2s are perturbed in obesity remains unknown. Here, we find that high-fat diet (HFD)-induced obesity in mice increases fatty acid oxidation, leading to suppression of acetyl-coenzyme A (CoA) carboxylase 1 (ACC1) in adipose ILC2s. ACC1 is essential for maintaining the citrate shuttle, NAD+/NADH balance, and cellular metabolism. Mimicking the effects of HFD, ACC1 deletion impairs differentiation, maintenance, and function of ILC2s. This results in adipose tissue hypertrophy and inflammation at steady state, predisposing mice to the development of diabetes. Supplementing with the NAD+ precursor nicotinamide riboside rescues ACC1 deficiency, restoring ILC2 function and adipose tissue homeostasis. These findings establish ACC1 as a critical regulator of adipose ILC2 maintenance and function and provide a rationale for the adverse effects of ACC inhibition in obesity.
    Keywords:  ACC1; ILC2; NAD+/NADH; SLC25A1; adipose tissue; fatty acids; innate lymphoid cells; metabolism; obesity
    DOI:  https://doi.org/10.1016/j.cmet.2026.08.019
  4. Transl Res. 2026 Sep 21. pii: S1931-5244(26)00198-2. [Epub ahead of print]297 255-264
    IL-1RA administration exerts diet-dependent metabolic effects on adipose tissue function and lipid handling in male mice.
    Laura Salmón-Gómez, Norman Carcaño, Victoria Catalán, Beatriz Ramírez, Julia Lanza-Argueta, Gabriela Neira, Sara Becerril, Amaia Rodríguez, Gema Frühbeck, Javier Gómez-Ambrosi.
      Interleukin-1 (IL-1) signaling is a key mediator of metabolic inflammation, yet its tissue-specific contribution to obesity-associated dysfunction remains incompletely understood. Here, we investigated the effects of pharmacological IL-1 receptor antagonism on systemic metabolism, adipose tissue dysfunction, and hepatic lipid handling under distinct nutritional conditions. Male mice fed a normal diet (ND) or high-fat diet (HFD) were treated subcutaneously with the IL-1 receptor antagonist (IL-1RA) anakinra for three weeks. IL-1RA did not significantly affect body weight or global adiposity; however, under ND conditions, it reduced fat mass and circulating leptin levels and increased the adiponectin/leptin ratio, indicating improved adipose endocrine function. In adipose tissue, IL-1RA partially restored Acaca expression and selectively modulated extracellular matrix remodeling genes, including Mmp9, without broadly suppressing inflammatory markers. In the liver, triglyceride content was altered in a diet-dependent manner without changes in the expression of key metabolic genes (Fasn, Acaca, Ppara), suggesting that IL-1 blockade does not directly reprogram intrinsic hepatic lipid metabolism. Consistent with this, analyses in complementary models, including leptin-deficient mice, showed that Il1rn expression is regulated by local inflammatory and endocrine cues rather than adiposity per se. Together, these findings identify IL-1 signaling as a context-dependent modulator of adipose tissue function and systemic lipid handling. The dissociation between adipose tissue responses and hepatic triglyceride accumulation highlights the tissue-specific effects of IL-1 receptor antagonism and underscores the need for direct metabolic flux studies to define the mechanisms underlying these effects.
    Keywords:  Adipose tissue remodeling; Anakinra; Hepatic steatosis; Interleukin-1 receptor antagonist; Metabolic inflammation
    DOI:  https://doi.org/10.1016/j.trsl.2026.09.013
  5. Cell Rep. 2026 Sep 25. pii: S2211-1247(26)01120-4. [Epub ahead of print]45(10): 118042
    Transcriptional and epigenomic analysis of insulin sensitivity in human adipocytes.
    Qianbin Zhang, Audrey Zhou, Adam G Maynard, Margo P Emont, Christopher Jacobs, Soumya Nagesh, Thiago M Batista, Renee M Gibson, Yi Huang, Rama Kaalia, Joaquín Pérez-Schindler, Bellis Min, Anna Lyubetskaya, Brian Dawes, Anlu Chen, Danielle Tenen, Eleanna De Filippis, Erin Merkel, Rachael Ivison, Amrita Kar, Hesam Dashti, Melina Claussnitzer, Linus Tsai, Evan D Rosen.
      Insulin resistance is a key feature of type 2 diabetes (T2D) and is also associated with a wide variety of other disease states. We isolated adipocytes from subjects with and without insulin resistance and subjected them to transcriptional and epigenomic profiling, allowing us to identify genes, cis-regulatory elements, and pathways that associate with insulin resistance in this critical cell type. We focused on several differentially enriched regions near the IRS1 gene that were close to, but distinct from, single-nucleotide polymorphisms associated with T2D and insulin resistance. CRISPR interference (CRISPRi)-mediated repression of these elements identified two major enhancer regions that regulate IRS1 expression in a cell-state-dependent manner. Finally, we identified specific transcription factors that act through these sites to enhance IRS1 gene expression. These studies help to define the molecular events that characterize, and potentially determine, human insulin sensitivity and resistance.
    Keywords:  CP: metabolism; CP: molecular biology; CRISPRi; H3K27ac; IRS1; RNA-seq; adipocyte; epigenomics; human; insulin resistance; insulin sensitivity
    DOI:  https://doi.org/10.1016/j.celrep.2026.118042
  6. Int Rev Cell Mol Biol. 2026 ;pii: S1937-6448(25)00166-2. [Epub ahead of print]406 87-130
    Mitophagy's impact on obesity-related tissues.
    Rana El Nahas, Sandra Cutanda-Tesouro, Meritxell Espino-Guarch, Pablo M Garcia-Roves.
      Obesity, a global health crisis, results from an energy imbalance, leading to metabolic dysfunction and associated conditions such as type 2 diabetes, cardiovascular disease, and metabolic dysfunction-associated steatotic liver disease. A strong link exists between obesity and mitochondrial dysfunction, characterized by reduced mitochondrial mass, impaired oxidative capacity, and decreased ATP production. Mitophagy, a specific type of autophagy targeting mitochondria for degradation, plays a complex, tissue-specific role in regulating metabolism and mitigating the harmful effects of obesity. Both insufficient and excessive mitophagy can negatively influence disease progression. In white adipose tissue, mitophagy functions as a quality control mechanism that reduces oxidative stress and helps maintain insulin sensitivity. However, chronic obesity impairs mitophagy due to overactivation of mTORC1 and inhibition of AMPK, leading to inflammation and insulin resistance. In brown adipose tissue, mitophagy is essential for thermogenesis and energy expenditure, but excessive activation in obesity may impair thermogenesis. In the liver, mitophagy is crucial for preserving mitochondrial function and preventing metabolic dysfunction-associated steatotic liver disease. In the heart, mitophagy supports cardiac function, particularly in obesity-related cardiomyopathy. In skeletal muscle, obesity worsens impairments in mitochondrial quality control, disrupting the clearance of damaged mitochondria. Therefore, there is a pressing need for therapies that restore mitophagic balance in a context- and depot-specific manner, as the dysregulation of mitophagy contributes not only to local dysfunction but also to broader metabolic phenotypes.
    Keywords:  autophagy; mitochondria and metabolic dysfunction; mitophagy; obesity
    DOI:  https://doi.org/10.1016/bs.ircmb.2025.12.003
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