bims-mimead 2026-09-13 papers

Am J Physiol Regul Integr Comp Physiol. 2026 Sep 10.

Increased Energy Expenditure through Intermittent Cold Exposure Does Not Enhance Tirzepatide Induced Weight-loss in Obese Mice.

Annalaura Bellucci, Hadil Alfares, Clara Gale, Michael Akcan, Ben Waters, Katelyn Eisner, Bradley J Baranowski, Stewart Jeromson, Ailish Babicki-Moore, David C Wright.

Obesity results from an imbalance between energy intake and energy expenditure. While pharmacological approaches such as tirzepatide, a dual GIP/GLP-1 receptor agonist, reduce food intake and body weight, enhancing energy expenditure via intermittent cold exposure-induced activation of thermogenesis may provide complementary benefits. Intermittent cold exposure increases energy expenditure and improves glucose homeostasis independent of weight loss. The objective of this study was to investigate the individual and combined effects of tirzepatide and intermittent cold exposure (ICE) on weight loss and glucose homeostasis. We hypothesized that combining ICE with tirzepatide would lead to greater weight loss and improvements in glucose homeostasis than tirzepatide alone. Male and female C57BL/6J mice were fed a high fat diet for 8 weeks and then treated with tirzepatide (10 nmol/kg) or vehicle and exposed, or not, to ICE (4°C, 1 h/day, 5 days/week) for 3 weeks. Body weight/composition, energy expenditure, food intake and glucose homeostasis were assessed. Tirzepatide reduced body weight, food intake, and adiposity in both sexes while ICE, acutely increased energy expenditure and improved glucose homeostasis independent of changes in body weight. There were no additive effects of combining tirzepatide and ICE. Our findings highlight that combining tirzepatide-mediated reduction in energy intake with ICE-induced activation of thermogenesis yields complementary, but not necessarily additive improvements in metabolic health.

Keywords: GLP-1; mice; obesity; thermogenesis; tirzepatide

DOI: https://doi.org/10.1152/ajpregu.00220.2026

Cell Metab. 2026 Sep 08. pii: S1550-4131(26)00338-4. [Epub ahead of print]

Implications of GLP-1 receptor agonists for the fertility of women with polyendocrine metabolic ovarian syndrome.

Pawel Kordowitzki, Anju E Joham, Clifford J Rosen.

Women with polyendocrine metabolic ovarian syndrome (PMOS) represent a particularly challenging patient population, characterized by the convergence of reproductive dysfunction, obesity, insulin resistance, and chronic inflammation. The emergence of glucagon-like peptide-1 receptor agonists (GLP-1RAs) offers a transformative therapeutic opportunity, addressing the complex endocrine and reproductive disturbances that underpin this disorder.

DOI: https://doi.org/10.1016/j.cmet.2026.08.013

Mol Cell Endocrinol. 2026 Sep 11. pii: S0303-7207(26)00194-2. [Epub ahead of print] 112917

Metabolic Effects of a GLP-1 Analog Combined with Aerobic Training in Ovariectomized Rats.

Bruna Selau, Leonardo Marensi Bastos, Rafaella Sanfelice Normann, Gustavo Kasper Cubas, Rodrigo de Oliveira Corrêa da Cunha Herrmann, Lucas Dos Anjos de Oliveira de Barros, Marjoriane de Amaral, Márcia Trapp, Luiz Carlos Kucharski, Éverton Lopes Vogt, Jorge Felipe Argenta Model, Anapaula Sommer Vinagre.

Menopause is associated with visceral obesity, low-grade chronic inflammation, and increased risk of dyslipidemia, insulin resistance, and type 2 diabetes. Although exercise (EXE) and GLP-1 receptor agonists, such as semaglutide (SEM), have demonstrated beneficial effects on metabolic regulation, their combined impact in menopause models has been less investigated. In this study, ovariectomized female Wistar rats were divided into four experimental groups: sedentary plus saline (SED + SAL), sedentary plus semaglutide (SED + SEM), exercise (EXE + SAL), and EXE + SEM. The aerobic exercise protocol consisted of treadmill running at moderate intensity for four weeks, during which the rats received either SEM or SAL weekly. At the end of the protocol, metabolic parameters were assessed in blood, liver, soleus and gastrocnemius muscles. Both SEM groups had lower body weight, weight gain, relative subcutaneous white adipose tissue (scWAT) mass, glucose, total proteins, and triglycerides in serum and liver, while LDL cholesterol, glycogen in liver and gastrocnemius, and AMPK and HSF1 expression in gastrocnemius increased. EXE decreased total and LDL cholesterol, liver triglycerides and HSF1 expression in both tissues, while glycogen in liver and gastrocnemius, liver HSF1 expression and relative mass were increased. The combination of SEM + EXE increased glycogen content in the gastrocnemius and AMPK expression in both gastrocnemius and liver. This combined treatment reduced HDL levels, hepatic triglycerides and scWAT relative weight. These results suggest that SEM and EXE exert complementary effects on glycemic and lipid metabolism, with partially distinct metabolic outcomes that may involve different underlying mechanisms.

Keywords: Aerobic exercise; Female rats; Menopause; Metabolism; Ovariectomy; Semaglutide

DOI: https://doi.org/10.1016/j.mce.2026.112917

J Physiol. 2026 Sep 11.

Preserved mitochondrial respiration in presence of oxidative stress and reduced mitochondrial mass after 10-day bed rest in older adults.

Evgeniia Motanova, Lucrezia Zuccarelli, Evgenii Lysenko, Stefano Amoretti, Marco Pirazzini, Ornella Rossetto, Lorenza Brocca, Roberto Bottinelli, Maria Antonietta Pellegrino, Giovanni Baldassarre, Clarissa Gissi, Giovanna Lippe, Mladen Gasparini, Boštjan Šimunic, Rado Pišot, Bruno Grassi, Marco V Narici.

Ageing affects mitochondrial integrity in skeletal muscle, and physical inactivity may further exacerbate these changes. Although mitochondrial alterations are documented in ageing and disuse independently, how disuse impacts the mitochondrial phenotype in older populations remains unclear. This work aimed to characterise how physical inactivity impacts mitochondrial function, morphology and gene expression in the skeletal muscle of older adults. Ten healthy older men (65+ years) underwent 10 days of bed rest. Skeletal muscle biopsies were collected before and after bed rest to assess mitochondrial respiration (high-resolution respirometry), H2O2 emission, mitochondrial protein expression, morphology and volume density (electron microscopy) and transcriptomic profile. Ten days of inactivity increased mitochondrial reactive oxygen species (ROS) emission under non-phosphorylating conditions but did not impair oxidative phosphorylation (OXPHOS) capacity, indicating preserved respiratory efficiency. Consistently, mitochondrial respiratory complex and supercomplex protein abundance were unchanged. Mitochondrial mass decreased, as shown by reduced mitochondrial volume density. Reduced dynamin-like protein 1 (DRP1) phosphorylation at serine 637 was observed, whereas other mitochondrial fission and fusion protein levels remained unchanged. Mitochondrial morphology remained unaltered. Transcriptomic analysis revealed >3000 differentially expressed genes, characterised by downregulation of oxidative phosphorylation genes alongside altered mitophagy, antioxidant and oxidoreductase pathways. In summary, 10-day bed rest increased mitochondrial ROS emission and reduced mitochondrial mass in older skeletal muscle despite preserved respiratory function, indicating that elevated ROS production occurs upstream of respiratory dysfunction and is potentially linked to impaired antioxidant defence and ROS clearance. These findings suggest that preserving redox balance during inactivity may be a key strategy to maintain muscle health and functional independence in ageing populations. KEY POINTS: The impact of short-term physical inactivity on mitochondrial function within the context of ageing remains poorly defined. This study examined the impact of 10-day bed rest on skeletal muscle mitochondrial function, morphology and gene expression in older adults. Short-term inactivity increased mitochondrial ROS production, accompanied by a dysregulation of antioxidant and oxidoreductase genes, indicating a reduced capacity for ROS clearance. Mitochondrial respiration was preserved under both submaximal and maximal stimulation. When normalised to mitochondrial content (citrate synthase activity), respiratory capacity increased, suggesting improved intrinsic efficiency. Mitochondrial mass was reduced, supported by decreased mitochondrial volume density assessed morphologically. Transcriptomic alterations in the mitophagy pathway suggest a potential role of altered mitochondrial degradation in this reduction. These findings indicate a transient compensatory response of ageing mitochondria to short-term disuse, suggesting that functional impairments are likely driven by cardiovascular and microvascular factors rather than mitochondrial respiration itself.

Keywords: OXPHOS; ROS; inactivity; mitochondria; mitochondrial dynamics; oxidative metabolism

DOI: https://doi.org/10.1113/JP291588

Mitochondrion. 2026 Sep 10. pii: S1567-7249(26)00108-X. [Epub ahead of print] 102218

Linking cellular metabolism to mitochondrial outer membrane potential.

Kaitlin Abrantes, Bethel G Beyene, Nina A Bautista, Wendy Fitzgerald, Tatiana K Rostovtseva, Sergey M Bezrukov, Megha Rajendran.

The voltage-dependent anion channel (VDAC) of the mitochondrial outer membrane (MOM) responds to transmembrane voltage through intrinsic gating and voltage-dependent interactions with cytosolic proteins, such as α-synuclein and β-tubulin. Despite this characteristic voltage sensitivity found in vitro, the existence of a substantial MOM potential (ΔΨMOM) in vivo remains controversial. Using pH sensors targeted to the cytosol and the intermembrane space (IMS), we measured the difference in proton concentration across the MOM and calculated a ΔΨMOM of ~33 mV, positive from the IMS side in HeLa cells; in contrast, HEK-293 cells lacked substantial ΔΨMOM. Hexokinase 2 (HK2) is known to be overexpressed in cancer cells. Consistent with the previously proposed role of VDAC- HK complexation in ΔΨMOM generation, we observed lower HK2 expression in HEK-293 cells than in HeLa cells. In addition, by studying pH changes in the IMS and cytosol in response to changes in glucose and glucose-6-phosphate concentrations in HeLa cells, we establish a relationship between ΔΨMOM and metabolic activity in cancer cells. Thus, our results demonstrate the metabolism-dependent generation of ΔΨMOM and provide strong evidence that VDAC regulation by voltage, observed in in vitro studies, is highly relevant to cell physiology.

Keywords: Hexokinase; VDAC; Voltage-dependent anion channel; pH sensors

DOI: https://doi.org/10.1016/j.mito.2026.102218