bims-mimead 2025-09-07 papers

Issue of 2025–09–07
five papers selected by
Rachel M. Handy, University of Guelph

Redox Biol. 2025 Aug 28. pii: S2213-2317(25)00357-X. [Epub ahead of print]86 103844

Skeletal muscle Rac1 mediates exercise training adaptations towards muscle glycogen resynthesis and protein synthesis.

Long-term exercise training elicits tremendous health benefits; however, the molecular understanding is incomplete and identifying therapeutic targets has been challenging. Rho GTPases are among the most regulated groups of proteins after exercise in human skeletal muscle, yet, unexplored candidates for mediating the effects of exercise training. We found that the Rho GTPase Rac1 was activated acutely after multiple exercise modalities in human skeletal muscle. Loss of Rac1 specifically in muscle attenuated contraction-induced muscle protein synthesis, diminished improvements in running capacity, and prevented muscle hypertrophy after exercise training in mice. Additionally, Ncf1∗ mice revealed that Rac1 regulated glycogen resynthesis via a NOX2-dependent mechanism. Molecularly, Rac1 was required for contraction-induced p38MAPK signaling towards HSP27, MNK1, and CREB phosphorylation. In vivo muscle-targeted overexpression of a hyperactive Rac1-mutant elevated reactive oxidant species production during exercise but did not affect muscle mass. Using mass spectrometry-based proteomics, we found that loss or gain of Rac1 muscle protein affected pathways related to cytoskeleton organization, muscle adaptation, and large ribosomal subunits. Thus, skeletal muscle Rac1 mediates both molecular and functional adaptation to exercise training.

Keywords: Contraction; Exercise training; Glycogen; Metabolism; Muscle hypertrophy; Protein synthesis; Rac1; Skeletal muscle

DOI: https://doi.org/10.1016/j.redox.2025.103844

Mol Metab. 2025 Sep 03. pii: S2212-8778(25)00153-X. [Epub ahead of print] 102246

Adipose tissue macrophage-derived miR-690 modulates adipocyte precursor cell maintenance and adipogenesis.

Karina Cunha E Rocha, Breanna Tan, Julia Kempf, Cristina Medina, Varsha Beldona, Chengjia Qian, Ying Duan, Qian Xiang, Ahjin Yoo, Xiaomi Du, Amit R Majithia, Wei Ying.

Obesity is intricately linked to various metabolic diseases; however, some individuals maintain metabolic health despite being classified as obese. A critical factor underlying this paradox is the expansion of white adipose tissue (WAT), which can occur through two mechanisms: hypertrophy (the enlargement of existing fat cells) and hyperplasia (the formation of new fat cells from adipocyte precursor cells, or APCs). Hyperplasia is regarded as a healthier mode of WAT expansion, as it tends to reduce inflammation and protect against insulin resistance. Thus, interventions that promote hyperplasia over hypertrophy could improve metabolic health in obese individuals. In this study, we investigate the role of microRNA-690 (miR-690), an anti-inflammatory and insulin-sensitizing molecule, in maintaining the APC population and facilitating the healthy expansion of epididymal WAT (eWAT). Our findings indicate that in lean mice, macrophages support the APC population by transferring miR-690 to APCs. However, during obesity, the recruitment of pro-inflammatory lipid-associated macrophages (LAMs) to eWAT diminishes miR-690 delivery to APCs, impairing adipogenesis and leading to unhealthy WAT expansion. We demonstrate that strategies aimed at increasing the availability of miR-690 to APCs or mimicking its effects can restore APC functionality. Additionally, mutations in Nadk, the target of miR-690, were shown to mitigate the adverse effects of obesity on APC maintenance in eWAT. These findings suggest that targeting the miR-690-Nadk axis in APCs may provide novel therapeutic strategies to promote healthy adipose tissue expansion and protect against obesity-related metabolic diseases.

DOI: https://doi.org/10.1016/j.molmet.2025.102246

J Clin Invest. 2025 09 02. pii: e183567. [Epub ahead of print]

Intermittent ischemia-reperfusion as a potent insulin-sensitizing intervention via blood flow enhancement and muscle Decanoyl-L-carnitine suppression.

Kohei Kido, Janne R Hingst, Johan Onslev, Kim A Sjøberg, Jesper B Birk, Nicolas O Eskesen, Tongzhu Zhou, Kentaro Kawanaka, Jesper F Havelund, Nils J Færgeman, Ylva Hellsten, Jørgen F P Wojtaszewski, Rasmus Kjøbsted.

A single bout of exercise improves muscle insulin sensitivity for up to 48 hours via the AMP-activated protein kinase (AMPK). Limb ischemia activates AMPK in muscle, and subsequent reperfusion enhances insulin-stimulated vasodilation, potentially eliciting a more pronounced exercise effect with reduced workload. Here, we investigated the combined effect of upper leg intermittent ischemia-reperfusion (IIR) and continuous knee-extension exercise on muscle insulin sensitivity regulation. We found that IIR-exercise potentiated AMPK activation and muscle insulin sensitivity. The potentiating effect of IIR-exercise on muscle insulin sensitivity was associated with increased insulin-stimulated blood flow in parallel with enhanced phosphorylation of endothelial nitric oxide synthase. Metabolomics analyses demonstrated a suppression of muscle medium-chain acylcarnitines during IIR-exercise, which correlated with insulin sensitivity and was consistent with findings in isolated rat muscle treated with Decanoyl-L-carnitine. Collectively, combining IIR with low-to-moderate intensity exercise may represent a promising intervention to effectively enhance muscle insulin sensitivity. This approach could offer potential for mitigating muscle insulin resistance in clinical settings and among individuals with lower physical activity levels.

Keywords: Glucose metabolism; Insulin; Metabolism; Muscle biology; Skeletal muscle

DOI: https://doi.org/10.1172/JCI183567

Mol Metab. 2025 Aug 29. pii: S2212-8778(25)00148-6. [Epub ahead of print] 102241

Suppression of adipocyte ABHD6 favors anti-inflammatory and adipogenic programs to preserve adipose tissue fitness in obesity.

Pegah Poursharifi, Camille Attané, Isabelle Chenier, Clemence Schmitt, Roxane Lussier, Anfal Al-Mass, Yat Hei Leung, Abel Oppong, Élizabeth Dumais, Nicolas Flamand, Mohamed Abu-Farha, Jehad Abubaker, Fahd Al-Mulla, Ying Bai, Dongwei Zhang, Marie-Line Peyot, André Tchernof, S R Murthy Madiraju, Marc Prentki.

Some individuals exhibit metabolically healthy obesity, characterized by the expansion of white adipose tissue (WAT) without associated complications. The monoacylglycerol (MAG) hydrolase α/β-hydrolase domain-containing 6 (ABHD6) has been implicated in energy metabolism, with its global deletion conferring protection against obesity. However, the immunometabolic roles of adipocyte ABHD6 in WAT remodeling in response to nutri-stress and obesity are not known. Here, we demonstrate that in insulin resistant women, ABHD6 mRNA expression is elevated in visceral fat and positively correlates with obesity and metabolic dysregulation. ABHD6 expression is also elevated in the WATs of diet-induced obese and db/db mice. Although adipocyte-specific ABHD6 knockout (AA-KO) mice become obese under high-fat diet, they show higher plasma adiponectin, reduced circulating insulin and inflammatory markers, improved insulin sensitivity, and lower plasma and liver triglycerides. They also show enhanced insulin action in various tissues, but normal glucose tolerance. In addition, AA-KO mice display healthier and less inflamed expansion of visceral fat, with smaller adipocytes and higher stimulated lipolysis and fatty acid oxidation levels. Similar but less prominent phenotype was found in the subcutaneous and brown fat depots. Thus, adipocyte ABHD6 suppression prevents most of the metabolic and inflammatory complications of obesity, but not obesity per se. Mechanistically, this beneficial process involves a rise in MAG levels in mature adipocytes, and their secretion, resulting in a crosstalk among adipocytes, preadipocytes and macrophages in the adipose microenvironment. Elevated intracellular MAG causes PPARs activation in adipocytes, and MAG secreted from adipocytes curtails the inflammatory polarization of macrophages and promotes preadipocyte differentiation. Hence, adipocyte ABHD6 and MAG hydrolysis contribute to unhealthy WAT remodeling and expansion in obesity, and its suppression represents a candidate strategy to uncouple obesity from many of its immunometabolic complications.

Keywords: Adipose tissue; Inflammation; Insulin signaling; Macrophages; Monoacylglycerol; Obesity; PPARs; α/β-hydrolase domain-containing 6

DOI: https://doi.org/10.1016/j.molmet.2025.102241

Cell Metab. 2025 Aug 22. pii: S1550-4131(25)00360-2. [Epub ahead of print]

Effect of ultra-processed food consumption on male reproductive and metabolic health.

Jessica M Preston, Jo Iversen, Antonia Hufnagel, Line Hjort, Jodie Taylor, Clara Sanchez, Victoria George, Ann N Hansen, Lars Ängquist, Susan Hermann, Jeffrey M Craig, Signe Torekov, Christian Lindh, Karin S Hougaard, Marcelo A Nóbrega, Stephen J Simpson, Romain Barrès.

Consumption of ultra-processed food is associated with increased caloric intake and impaired health. Here, we conducted a nutrition trial (NCT05368194) with controlled, 2 × 2 crossover design and tested whether ultra-processed food impairs reproductive and metabolic fitness, with further aggravation by excess caloric intake. Comparing the response from an unprocessed to ultra-processed diet identified increased body weight and low-density lipoprotein (LDL):high-density lipoprotein (HDL) ratio, independent of caloric load. Several hormones involved in energy metabolism and spermatogenesis were affected, including decreased levels of growth/differentiation factor 15 and follicle-stimulating hormone. Sperm quality trended toward impairment, with a decrease in total motility. Differential accumulation of pollutants between the discordant diets were detected, such as decreased plasma lithium and a trend for increased levels of the phthalate mono(4-methyl-7-carboxyheptyl)phthalate (cxMINP) in serum, following the ultra-processed diet. Alteration in caloric load alone had distinct effects on the measured outcomes. This study provides evidence that consumption of ultra-processed food is detrimental for cardiometabolic and reproductive outcomes, regardless of excessive caloric intake.

Keywords: body weight management; cholesterol; depression score; diet intervention; hormones; phthalates; pollutants; reproduction; sperm quality; ultra-processed diet

DOI: https://doi.org/10.1016/j.cmet.2025.08.004