bims-mimead 2025-10-19 papers

Issue of 2025–10–19
five papers selected by
Rachel M. Handy, University of Guelph

J Physiol. 2025 Oct 12.

Molecular responses in abdominal subcutaneous adipose tissue after a session of endurance exercise: effects of exercise intensity.

Cheehoon Ahn, Tao Zhang, Thomas Rode, Gayoung Yang, Olivia K Chugh, Sierra Ellis, Sophia Ghayur, Shriya Mehta, Ryan Salzman, Hui Jiang, Stephen C J Parker, Charles F Burant, Jeffrey F Horowitz.

The primary aim of this study was to compare the acute effects of three exercise intensities on abdominal subcutaneous adipose tissue (aSAT) transcriptome in regular exercisers. A total of 45 adults who exercise regularly were assigned to perform a single session of either low-intensity continuous (LOW; 60 min at 30% VO2max; n = 15), moderate-intensity continuous (MOD; 45 min at 65% VO2max; n = 15) or high-intensity interval exercise (HIGH; 10 × 1 min at 90% VO2max interspersed with 1 min active recovery; n = 15). aSAT biopsy samples were collected before and 1.5 h after the exercise session for bulk RNA sequencing and targeted protein immunoassays. HIGH upregulated genes were involved in angiogenesis, protein secretion and insulin signalling pathways, whereas MOD and LOW upregulated genes regulated extracellular matrix (ECM) remodelling, ribosome biogenesis and oxidative phosphorylation pathways. Exercise-induced changes in aSAT clock genes, ERK protein phosphorylation and circulating cytokines were similar after all three exercise treatments. Network analysis identified exercise-responsive gene clusters linked to cardiometabolic health traits. Cell-type analysis highlighted a heterogeneous response of aSAT cell types to exercise, with distinct patterns observed across exercise intensities. Collectively, our data characterize early responses in aSAT after a single session of exercise. Because adaptations to exercise training stem from an accrual of responses after each session of exercise, these early responses to exercise are likely important contributors to the long-term structural and functional changes that occur in adipose tissue in response to exercise training. KEY POINTS: Chronic adaptations in adipose tissue from regular exercise support cardiometabolic health, but the acute molecular triggers of these adaptations remain unclear. We show that acute exercise alters gene expression, along with ERK phosphorylation in adipose tissue of regular exercisers. Exercise intensity shapes the transcriptomic response: high-intensity exercise induces inflammatory, cytokine and genes, whereas lower intensities upregulate genes involved in protein translation and oxidative phosphorylation. Network and cell-type analyses highlight intensity-specific adipose responses, revealing gene modules linked to health traits and differential engagement of adipocyte subpopulations.

Keywords: acute exercise; adipose tissue; exercise intensity

DOI: https://doi.org/10.1113/JP289339

Cell Rep. 2025 Oct 15. pii: S2211-1247(25)01216-1. [Epub ahead of print]44(10): 116445

Adipose m6A reader YTHDF2 promotes obesity, insulin resistance, and liver steatosis by suppressing β-adrenergic signaling and lipolysis.

Ruoyu Zhou, Liping Ju, Qianqian Kang, Qiantao Zheng, Decheng Ren, Liangyou Rui.

RNA N6-methyladenosine (m6A) modification induces catecholamine resistance and lipolysis inhibition in white adipose tissue (WAT), contributing to obesity pathogenesis; however, the responsible m6A readers remain elusive. Here, we identify YTHDF2 as a key m6A reader governing both β-adrenergic signaling and lipolytic machinery. YTHDF2 binds to m6A-marked mRNAs encoding β3-adrenergic receptor (Adrb3), adipose triacylglycerol lipase (Atgl), and comparative gene identification-58 (Cgi-58), promoting their degradation and thereby suppressing β-adrenergic signaling and lipolysis. Deletion of adipose Ythdf2 enhances lipolysis in vivo, in WAT explants ex vivo, and in cultured adipocytes. Conversely, YTHDF2 overexpression suppresses adipocyte lipolysis. High-fat diet feeding upregulates adipose YTHDF2 and increases its binding to Adrb3, Atgl, and Cgi-58 mRNAs. Adipocyte-specific deletion of Ythdf2 protects against diet-induced obesity, insulin resistance, and liver steatosis. Moreover, deletion of adipose Mettl14-but not Ythdf2-disrupts brown adipose tissue development. These results unveil an adipose-intrinsic METTL3/METTL14/m6A/YTHDF2 pathway that drives catecholamine resistance and lipolysis suppression in obesity.

Keywords: CP: Metabolism; MAFLD; METTL14; YTHDF2; adipocytes; brown adipose tissue; insulin resistance; lipolysis; m(6)A; obesity

DOI: https://doi.org/10.1016/j.celrep.2025.116445

Obesity (Silver Spring). 2025 Oct 12.

Characterization of Visceral Adipose Tissue Proteome Reveals Metabolic Changes and Inflammatory Signatures in Severe Obesity.

Prince Dadson, Miikka-Juhani Honka, Tomi Suomi, Anne Rokka, Saila Kauhanen, Paulina Salminen, Mika Helmiö, Peter James, Laura L Elo, Vesa M Olkkonen, Pirjo Nuutila.

OBJECTIVE: Severe obesity poses a major public health concern due to its links with cardiometabolic complications and mortality. Visceral adipose tissue (VAT) plays a key role in these processes through distinct molecular features. This study aimed to characterize the VAT proteome of individuals with severe obesity and investigate its association with serum metabolic biomarkers.
METHODS: A cross-sectional analysis was performed for 46 individuals with severe obesity undergoing metabolic bariatric surgery and 17 healthy controls undergoing elective abdominal surgery. VAT proteomes were analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS), and serum metabolites were quantified using nuclear magnetic resonance-based metabolomics.
RESULTS: LC-MS/MS identified 22 differentially expressed proteins (FDR < 0.05) in VAT with 12 downregulated and 10 upregulated in severe obesity. Downregulated proteins included mitochondrial enzymes involved in substrate metabolism and mitochondrial transmembrane transport. Circulating glucose, valine, and isoleucine correlated negatively with VAT mitochondrial transmembrane and electron transport proteins. Upregulated proteins were associated with inflammation, immune activation, oxidative stress, cytoskeletal remodeling, and protein turnover.
CONCLUSIONS: These findings demonstrate significant molecular alterations in the VAT proteome associated with severe obesity, providing insights into the underlying mechanisms of metabolic disease. The differentially expressed proteins may serve as biomarkers or therapeutic targets for obesity-related complications.
TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT00793143 and NCT01373892.

Keywords: metabolomics; proteomics; severe obesity; visceral adipose tissue

DOI: https://doi.org/10.1002/oby.70041

Cell Rep. 2025 Oct 15. pii: S2211-1247(25)01221-5. [Epub ahead of print]44(10): 116450

CCL26 and CXCL12 preserve insulin-sensitizing macrophages in subcutaneous adipose tissue in obesity.

Ishtiaq Jeelani, Flavia Franco da Cunha, Theresa V Rohm, Chanond A Nasamran, Letian Wang, Jae-Su Moon, Sruthika Prakash, Justin Oswari, Roi Isaac, Cairo Murphy, Christopher K Glass, Jerrold M Olefsky, Yun Sok Lee.

Unlike visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT) can protect against insulin resistance and metabolic dysfunction in obesity. Here, we show that, in obesity, subcutaneous adipose tissue macrophages (ATMs) release small extracellular vesicles (sEVs) that can improve insulin sensitivity, opposite to the effect of visceral ATM sEVs. This functional difference is associated with an increase in the proportion of insulin-sensitizing, resident ATMs in SAT. In vivo and in vitro measurements of ATM growth and trafficking combined with single-cell RNA sequencing revealed that higher resident ATM survival and lower blood monocyte immigration along with decreased transition to pro-inflammatory ATMs collectively lead to the relative abundance of resident ATMs in SAT in obesity. These changes are mediated by CCL26 derived from subcutaneous adipocytes and adipocyte progenitors and CXCL12 secreted from resident ATMs. Our results elucidate previously unknown mechanisms for how SAT retains protective functions against metabolic dysfunction in obesity.

Keywords: CCL26; CP: Metabolism; CXCL12; T2DM; adipose tissue macrophages; exosome; inflammation; insulin resistance; obesity; resident vs. recruited macrophages; sEVs; small extracellular vesicles; type 2 diabetes mellitus

DOI: https://doi.org/10.1016/j.celrep.2025.116450

Endocr J. 2025 Oct 16.

Selective β3-adrenoceptor agonist reduces energy intake and elevates GDF15 levels in lean and diet-induced obese mice.

Arata Mori, Yasuo Oguri, Sho Matsui, Satoshi Tsuzuki, Tsutomu Sasaki.

β3-Adrenoceptors (β3ARs) are expressed in the adipose tissue, the brain, and the bladder. In rodents, selective β3AR agonists have been shown to reduce normal chow intake through central and peripheral mechanisms. However, the impact of β3AR agonists on nutritional balance, as well as the relative contribution of each organ system to this effect, remains elusive. In this study, we aimed to determine whether the peripheral effect of β3AR agonists on food intake is nutrient-specific or energy in general using food choice experiments that allow for independent analysis of energy and nutrients. Mice were presented with two different diet options (normal diet [ND] vs. high-sucrose diet [HSD], high-fat diet [HFD], or high-protein diet [HPD]), and the effects of the β3AR agonist CL316,243 on the intake of these diets were examined. Treatment with CL316,243 reduced total energy intake, primarily through decreased consumption of HSD, HFD, and HPD. Accordingly, CL316,243 reduced food intake in a non-nutrient-specific manner, resulting in decreased caloric intake. In addition, CL316,243 increased plasma levels of fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15). In the ND vs. HSD food choice test, CL316,243 reduced HSD intake, even in liver-specific Fgf21 knockout mice. Furthermore, CL316,243 reduced food intake in mice with diet-induced obesity. These findings suggest that the CL316,243-mediated reduction in HSD intake occurs independently of liver-derived FGF21. Moreover, elevated plasma GDF15 levels were positively associated with reduced food intake induced by CL316,243.

Keywords: Fibroblast growth factor 21; Food intake; Growth differentiation factor 15; β3-adrenoceptor agonist

DOI: https://doi.org/10.1507/endocrj.EJ25-0364