bims-mimead 2025-02-16 papers

bims-mimead

Biomed News

on Mitochondrial metabolism in ageing and metabolic disease

Issue of 2025–02–16
thirteen papers selected by
Rachel M. Handy, University of Guelph

Exercise alters molecular profiles of inflammation and substrate metabolism in human white adipose tissue.
GPR180 Reduces Adiposity by Inhibiting Lipogenesis and Fatty Acid Uptake in Adipocytes.
Combined deletion of cytosolic 5'-nucleotidases IA and II lowers glycemia by improving skeletal muscle insulin action and lowering hepatic glucose production.
Skeletal muscle growth to combat diabetes and obesity: the potential role of muscle-secreted factors.
The role of ovarian hormone dynamics in metabolic phenotype and gene expression in female mice.
Stearoyl-CoA Desaturase 1 Regulates Metabolism and Inflammation in Mouse Perivascular Adipose Tissue in Response to a High-Fat Diet.
Impact of physical activity on physical function, mitochondrial energetics, ROS production, and Ca2+ handling across the adult lifespan in men.
Single incretin receptor knockout mice do not compensate by increasing glucose-stimulated secretion of the remaining incretin hormone.
Metabolaging: a new geroscience perspective linking aging pathologies and metabolic dysfunction.
Metabolically unhealthy adipose tissue is characterized by reductions in mitochondrial size and function.
Novel pharmacotherapies for weight loss: Understanding the role of incretins to enable weight loss and improved health outcomes.
Redox imbalance and hypoxia-inducible factors: a multifaceted crosstalk.
Temporal phosphoproteomics reveals circuitry of phased propagation in insulin signaling.

Am J Physiol Endocrinol Metab. 2025 Feb 11.

Exercise alters molecular profiles of inflammation and substrate metabolism in human white adipose tissue.

Maria F Pino, Pieter Dijkstra, Katie L Whytock, Cheehoon Ahn, Gongxin Yu, James A Sanford, Josh Hansen, Chelsea Hutchinson, Marina A Gritsenko, Paul D Piehowski, Joshua N Adkins, Elvis A Carnero, Stuart C Sealfon, Elena Zaslavsky, Venugopalan Nair, Steven R Smith, Lauren M Sparks.

  White adipose tissue (WAT) plays a significant role in whole-body energy homeostasis, and its excess typifies obesity. In addition to WAT quantity, perturbations in the basic cellular processes of WAT (i.e. quality) are also associated with obesity and metabolic disease. Exercise training alleviates metabolic perturbations associated with obesity; however, the underlying molecular mechanisms that drive these metabolic adaptations in WAT are not well described. Abdominal subcutaneous WAT biopsies were collected after an acute bout of exercise (1 day after) at baseline and following three weeks of supervised aerobic training in sedentary overweight women (n = 6) without alterations in body weight and fat mass. RNA-seq, global proteomics, and phosphoproteomics in WAT revealed training-induced changes in 1527 transcripts, 154 proteins, and 144 phosphosites, respectively. Training decreased abundance of transcripts and proteins involved in inflammation and components of the extracellular matrix (ECM) and increased abundance of transcripts and proteins related with fatty acid esterification and lipolysis. In summary, short-term aerobic training significantly reduces local inflammation and increases lipid metabolism in WAT of sedentary overweight women - independent of alterations in body and fat mass. As such, some of the health benefits of aerobic training may occur through molecular alterations in WAT (i.e. enhanced quality) rather than a sheer reduction in WAT quantity.

Keywords:  ECM; adipose tissue; inflammation; metabolism; training

DOI:  https://doi.org/10.1152/ajpendo.00339.2024
Am J Physiol Endocrinol Metab. 2025 Feb 10.

GPR180 Reduces Adiposity by Inhibiting Lipogenesis and Fatty Acid Uptake in Adipocytes.

Ziming Zhu, Yaxu Yang, Lijun Sun, Yunhua Zhang, Xue Han, Chao Luo, Yue Yin, Weizhen Zhang.

  Objective: In this study, we examined the effect of Gpr180, a G protein-coupled receptor (GPCR) family member, on lipid metabolism of adipose tissue. Methods: We utilized adeno-associated virus overexpression of Gpr180 in subcutaneous adipose tissue, adipocyte-specific Gpr180 knockout mice and stromal vascular fraction (SVF) cells to explore the role and mechanism of GPR180 in lipid metabolism in adipocytes. Results: Levels of Gpr180 mRNA in subcutaneous and epididymal adipose tissues were significantly reduced in mice fed high fat diet (HFD). Over-expression of Gpr180 in subcutaneous white adipose tissue (sWAT) improved lipid metabolism and protected mice from HFD-induced obesity. Conversely, adipocyte-specific knockout of Gpr180 exacerbated lipid metabolism disorders induced by HFD. In cultured adipocytes differentiated from SVF cells, GPR180 inhibited lipogenesis and fatty acid (FA) uptake. Conclusions: Collectively, our study reveals that GPR180 functions to suppress lipid accumulation in adipocytes.

Keywords:  Adiposity; Fatty Acid Uptake; G protein-coupled receptor 180; Lipogenesis

DOI:  https://doi.org/10.1152/ajpendo.00178.2024
J Biol Chem. 2025 Feb 11. pii: S0021-9258(25)00143-7. [Epub ahead of print] 108295

Combined deletion of cytosolic 5'-nucleotidases IA and II lowers glycemia by improving skeletal muscle insulin action and lowering hepatic glucose production.

Roxane Jacobs, Gaëtan Herinckx, Noémie Galland, Clémence Balty, Didier Vertommen, Mark H Rider, Manuel Johanns.

  Obesity and type 2 diabetes (T2D)-linked hyperglycemia, along with their associated complications, have reached pandemic proportions, constituting a major public health issue. Genetic deletion or pharmacological inhibition of purine nucleotide-metabolizing enzymes has emerged as a potential strategy for treating diseases. We previously showed that cytosolic 5'-nucleotidase II (NT5C2)-deficient mice were protected against high-fat diet (HFD)-induced insulin resistance. This study investigated effects of dual deletion of cytosolic 5'-nucleotidases IA (NT5C1A) and II (NT5C2) in mice. We found that NT5C1A/NT5C2 double-knockout (NT5C-dKO) mice exhibited mild hypoglycemia, associated with enhanced skeletal muscle insulin action and reduced hepatic glucose production. This phenotype was accompanied by liver and skeletal muscle proteomic alterations notably related to amino acid metabolism, besides potential involvement of adenosine monophosphate (AMP)-activated protein kinase (AMPK). Our findings support the development of novel anti-diabetic treatments using small-molecule cytosolic 5'-nucleotidase inhibitors.

Keywords:  AMP-activated protein kinase (AMPK); Purine nucleotide metabolism; glycemic regulation; liver glucose production; muscle glucose uptake

DOI:  https://doi.org/10.1016/j.jbc.2025.108295
Obesity (Silver Spring). 2025 Feb 13.

Skeletal muscle growth to combat diabetes and obesity: the potential role of muscle-secreted factors.

Mitchell J Sammut, Benjamin R Thorne, C W James Melling.

As the prevalence of obesity and metabolic disease continues to climb, the need for effective therapeutic interventions remains high. The growth of skeletal muscle (SkM) greatly influences systemic metabolism across the whole body, making this tissue an important therapeutic target to combat the rise of metabolic dysfunction. Transgenic rodent models of targeted SkM growth exhibit profound improvements in various remote tissues, including adipose tissue and the liver. It is currently unclear how selective stimulation of SkM growth alters the metabolism of distant tissues; however, evidence suggests that muscle-secreted factors may be involved. Here, we aim to provide basic biomedical researchers with a summary of the current knowledge regarding various muscle-secreted factors regulated by anabolic pathways and proteins in SkM, as well as their systemic metabolic effects, to implicate them in the whole-body metabolic effects of SkM growth. In this review, we also identify several knowledge gaps in this field, future directions of investigation, and implications for therapeutic interventions such as resistance exercise and pharmacology.

DOI: https://doi.org/10.1002/oby.24223
Horm Behav. 2025 Feb 12. pii: S0018-506X(25)00019-4. [Epub ahead of print]169 105693

The role of ovarian hormone dynamics in metabolic phenotype and gene expression in female mice.

Laila Ouldibbat, Devin Rocks, Branden Sampson, Marija Kundakovic.

  Ovarian hormones, particularly estradiol, play an important role in the regulation of metabolic function including in food intake, thermogenesis, activity, fat distribution, and overall weight management. While it is known that weight and food intake follow cyclical patterns across the rodent estrous cycle, the majority of metabolic studies still focus on ovariectomized rodent models and estrogen replacement. Here we provide a comprehensive metabolic profiling of female mice under different ovarian hormone states, from having naturally-cycling ovarian hormone levels to complete ovarian hormone depletion and "estrous cycle-like" estrogen replacement (0.2 or 1 μg estradiol benzoate every 4 days). Every domain of metabolic function that we examined including activity levels, food intake, and body composition was affected by ovariectomy and contributed to >30 % weight gain and nearly two-fold increase in fat mass in ovarian hormone-depleted mice over the 12-week period. By combining physiological and hormone replacement paradigms, we show that cyclical estrogen levels are necessary and sufficient to maintain optimal body weight and fat mass. We show that the hypothalamic expression of genes encoding estrogen receptor alpha (Esr1) and neuropeptides involved in feeding behavior (Agrp, Pomc) changes across the cycle and with ovariectomy, and is partially "rescued" by cyclical estrogen treatment. The drastic fat mass changes following ovariectomy are accompanied by changes in adipose tissue gene expression, including a decreased responsiveness to estrogens due to Esr1 down-regulation. Our study highlights the importance of understanding the dynamic regulation of metabolic function by ovarian hormones and calls for more naturalistic and higher-resolution approaches to studying the molecular basis of ovarian hormone action.

Keywords:  Estradiol; Estrous cycle; Fat tissue; Gene expression; Hypothalamus; Metabolic function; Ovarian hormones

DOI:  https://doi.org/10.1016/j.yhbeh.2025.105693
J Cell Physiol. 2025 Feb;240(2): e31510

Stearoyl-CoA Desaturase 1 Regulates Metabolism and Inflammation in Mouse Perivascular Adipose Tissue in Response to a High-Fat Diet.

Adrian Sowka, Volodymyr V Balatskyi, Viktor O Navrulin, James M Ntambi, Pawel Dobrzyn.

  The dysregulation of perivascular adipose tissue (PVAT) is a key contributor to obesity-induced vascular dysfunction. Mouse periaortic adipose tissue is divided into two parts: thoracic perivascular adipose tissue (TPVAT) and abdominal perivascular adipose tissue (APVAT). These two parts have different physiological properties, which translate into different effects on the vascular wall in the onset of metabolic syndrome. Stearoyl-CoA desaturase 1 (SCD1) is an enzyme that is involved in the synthesis of monounsaturated fatty acids and has been shown to play an important role in metabolic syndrome, including vascular homeostasis. Despite a considerable focus on the role of SCD1 in the development of vascular disorders, there is currently a lack of knowledge of the relationship between SCD1 and PVAT. The present study investigated effects of SCD1 deficiency on lipolysis, β-oxidation, mitochondrial dynamics, and inflammation in mouse TPVAT and APVAT under high-fat diet (HFD) feeding conditions. We found lower triglyceride levels in PVAT in SCD1-/- mice both in vitro and in vivo compared with wildtype perivascular adipocytes, attributable to activated lipolysis and β-oxidation. Moreover, PVAT in HFD-fed SCD1-/- mice was characterized by higher levels of oxidative phosphorylation complexes and mitochondrial respiratory potential and alterations of mitochondrial morphology compared with wildtype mice. Furthermore, TPVAT and APVAT in SCD1-/- mice showed signs of greater pro-inflammatory macrophage polarization and higher inflammatory markers that were induced by a HFD. This may be related to the accumulation free fatty acids and diacylglycerols, which are enriched in saturated fatty acids. These findings elucidate the role of SCD1 in maintaining vascular integrity.

Keywords:  PVAT; fatty acids; inflammation; lipid metabolism; mitochondria

DOI:  https://doi.org/10.1002/jcp.31510
Cell Rep Med. 2025 Feb 06. pii: S2666-3791(25)00041-2. [Epub ahead of print] 101968

Impact of physical activity on physical function, mitochondrial energetics, ROS production, and Ca2+ handling across the adult lifespan in men.

Marina Cefis, Vincent Marcangeli, Rami Hammad, Jordan Granet, Jean-Philippe Leduc-Gaudet, Pierrette Gaudreau, Caroline Trumpff, Qiuhan Huang, Martin Picard, Mylène Aubertin-Leheudre, Marc Bélanger, Richard Robitaille, José A Morais, Gilles Gouspillou.

  Aging-related muscle atrophy and weakness contribute to loss of mobility, falls, and disability. Mitochondrial dysfunction is widely considered a key contributing mechanism to muscle aging. However, mounting evidence positions physical activity as a confounding factor, making unclear whether muscle mitochondria accumulate bona fide defects with aging. To disentangle aging from physical activity-related mitochondrial adaptations, we functionally profiled skeletal muscle mitochondria in 51 inactive and 88 active men aged 20-93. Physical activity status confers partial protection against age-related decline in physical performance. Mitochondrial respiration remains unaltered in active participants, indicating that aging per se does not alter mitochondrial respiratory capacity. Mitochondrial reactive oxygen species (ROS) production is unaffected by aging and higher in active participants. In contrast, mitochondrial calcium retention capacity decreases with aging regardless of physical activity and correlates with muscle mass, performance, and the stress-responsive metabokine/mitokine growth differentiation factor 15 (GDF15). Targeting mitochondrial calcium handling may hold promise for treating aging-related muscle impairments.

Keywords:  calcium retention capacity; functional capacities; intermuscular fat accumulation; mitochondria; mitochondrial permeability transition pore; muscle atrophy and weakness; physical performance; reactive oxygen species; sarcopenia; skeletal muscle aging

DOI:  https://doi.org/10.1016/j.xcrm.2025.101968
Am J Physiol Endocrinol Metab. 2025 Feb 11.

Single incretin receptor knockout mice do not compensate by increasing glucose-stimulated secretion of the remaining incretin hormone.

Katrine D Galsgaard, Jon Vergara, Sara L Jepsen, Alice Bazzichi, Hannelouise Kissow, Mark M Smits, Jens J Holst.

  Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are incretin hormones. Lack of GLP-1 receptor signaling has been reported to be compensated for by increased GIP secretion and action. Conversely GLP-1 sensitivity has been reported to be increased in GIP receptor knockout (Gipr-/-) mice. This suggests a compensatory adaptation to loss of incretin signaling via increased action/secretion of the remaining incretin hormone. We assessed glucose-stimulated GIP and GLP-1 secretion during oral glucose tolerance tests (OGTTs) and in isolated perfused intestines of GLP-1 receptor knockout (Glp-1r-/-) mice and their wild-type littermates (Glp-1r+/+) and in Gipr-/- mice and their wild-type littermates (Gipr+/+). Sensitivity to GIP and GLP-1 was assessed in isolated perfused pancreases of Glp-1r-/- and Glp-1r+/+ mice and Gipr-/- and Gipr+/+ mice, respectively. We found similar GIP responses in Glp-1r-/- and Glp-1r+/+ mice and similar GLP-1 responses in Gipr-/- and Gipr+/+ mice during the OGTTs and in the isolated perfused intestines. Insulin responses to GIP and GLP-1 were similar in Glp-1r-/- and Glp-1r+/+ mice and in Gipr-/- and Gipr+/+ mice, respectively. Our results do not support the existence of a compensatory adaptation to loss of single incretin signaling via increased glucose-stimulated secretion of, or sensitivity to, the remaining incretin hormone.

Keywords:  Glucose tolerance test; Gut hormones; Incretin Hormones; Intestine; Pancreas

DOI:  https://doi.org/10.1152/ajpendo.00437.2024
Metabolism. 2025 Feb 11. pii: S0026-0495(25)00027-7. [Epub ahead of print]166 156158

Metabolaging: a new geroscience perspective linking aging pathologies and metabolic dysfunction.

Fadi Khalaf, Dalia Barayan, Sean Saldanha, Marc G Jeschke.

  With age, our metabolic systems undergo significant alterations, which can lead to a cascade of adverse effects that are implicated in both metabolic disorders, such as diabetes, and in the body's ability to respond to acute stress and trauma. To elucidate the metabolic imbalances arising from aging, we introduce the concept of "metabolaging." This framework encompasses the broad spectrum of metabolic disruptions associated with the hallmarks of aging, including the functional decline of key metabolically active organs, like the adipose tissue. By examining how these organs interact with essential nutrient-sensing pathways, "metabolaging" provides a more comprehensive view of the systemic metabolic imbalances that occur with age. This concept extends to understanding how age-related metabolic disturbances can influence the response to acute stressors, like burn injuries, highlighting the interplay between metabolic dysfunction and the ability to handle severe physiological challenges. Finally, we propose potential interventions that hold promise in mitigating the effects of metabolaging and its downstream consequences.

Keywords:  Adipose tissue; Aging; Burn injury; Hypermetabolism; Inflammaging; Metabolaging; Metabolism

DOI:  https://doi.org/10.1016/j.metabol.2025.156158
Obesity (Silver Spring). 2025 Feb 13.

Metabolically unhealthy adipose tissue is characterized by reductions in mitochondrial size and function.

Darla DeStephanis, Masha R Long, Abigail G Williams, McKinley Santiago, Jack Tonkin, Christina M Stevens, Matthew A Davis, Alistaire D Ruggiero, Darren C Henstridge, Dino Premilovac, Kylie Kavanagh.

OBJECTIVE: Adipose function, not mass, underpins metabolic health. Lean and obese nonhuman primates (NHPs) naturally develop metabolic syndrome. Mitochondria-related measures in subcutaneous adipose tissue (SQ AT) and peripheral blood mononuclear cells may elucidate differences that transcend adiposity measures.
METHODS: Obesity statuses ranged from very lean to severely obese (<9%->50%, n = 44), which were equivalent in healthy or unhealthy NHPs (metabolic syndrome score difference, p < 0.001). We evaluated SQ AT histology, electron microscopy, tissue proteins, and bioenergetics.
RESULTS: Unhealthy adipocytes had mitochondria one-half the size of healthy adipocytes (p < 0.01), whereas adipocyte cell sizes were comparable. Consistent with small mitochondria, we saw deficiencies in mitochondrial fusion and quality-control proteins in SQ AT from unhealthy NHPs (all p < 0.05). Smaller mitochondria in unhealthy adipocytes were consistent with low SQ AT tissue respiration (p < 0.05). Mitochondrial size was specifically reduced with unhealthiness, as mitochondrial abundance, size, and related metrics were unrelated to adiposity. Isolated stromal vascular cells showed comparable respirometry profiles, substantiating specificity of adipocyte-related mitochondrial defects. Peripheral blood mononuclear cell bioenergetic indices were increased in unhealthy NHPs, indicative of immune cell activation, and correlated to SQ AT inflammatory cytokines.
CONCLUSIONS: We conclude that targeting mitochondrial fusion processes would be a rational strategy to improve metabolic health, independent of total fat mass.

DOI: https://doi.org/10.1002/oby.24221
Diabetes Obes Metab. 2025 Feb 11.

Novel pharmacotherapies for weight loss: Understanding the role of incretins to enable weight loss and improved health outcomes.

Thomas Forst, Christophe De Block, Stefano Del Prato, Juan Frias, Anne Lautenbach, Bernhard Ludvik, Marina Marinez, Chantal Mathieu, Timo D Müller, Oliver Schnell.

  Obesity and type 2 diabetes mellitus (T2D) are widespread diseases that significantly impact cardiovascular and renal morbidity and mortality. In the recent years, intensive research has been performed to assess the role of adipose tissue and body fat distribution in the development of metabolic and non-metabolic complications in individuals with obesity. In addition to lifestyle modifications, glucagon-like peptide-1 receptor agonists (GLP-1-RA) have become a meaningful treatment expansion for the management of both disorders. In addition to improving metabolic control and reducing body weight, treatment with GLP-1-RAs reduces cardiovascular and renal events in individuals with obesity with and without diabetes. These important benefits of GLP-1-RAs have triggered new interest in other enteroendocrine and enteropancreatic peptides for treating obesity and its metabolic and non-metabolic consequences. The first peptide dual-agonist targeting glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptors has been approved for the treatment of T2D and obesity. GIP/GLP-1 dual-agonism appear to provide better metabolic control and greater weight reduction compared with GLP-1-R mono-agonism. Other peptide and non-peptide co-agonists are in clinical development for obesity, T2D, metabolic dysfunction-associated steatotic liver disease (MASLD) and other metabolic disorders. This narrative review aims to summarize the available data on approved and emerging enteroendocrine and enteropancreatic based treatment approaches for obesity and metabolic disorders. In addition to available clinical efficacy measures, side effects, limitations and open challenges will also be addressed.

Keywords:  adipocytes; co‐agonists; incretins; obesity

DOI:  https://doi.org/10.1111/dom.16247
FEBS J. 2025 Feb 11.

Redox imbalance and hypoxia-inducible factors: a multifaceted crosstalk.

Ravi, Jogender Singh.

  Redox homeostasis, the delicate balance between oxidative and reductive processes, is crucial for cellular function and overall organismal health. At the molecular level, cells need to maintain a fine balance between the levels of reactive oxygen species (ROS) and reducing equivalents such as glutathione and nicotinamide adenine dinucleotide phosphate. The perturbation of redox homeostasis due to excessive ROS production leads to oxidative stress that can damage lipids, proteins, and nucleic acids. Conversely, an overly reduced cellular environment due to overabundant reducing equivalents results in reductive stress, which also interferes with important cellular signaling and physiological processes. Disrupted redox homeostasis is linked to various pathological conditions, including neurodegenerative diseases, inflammatory diseases, cancer, and cardiovascular diseases. Cells employ diverse mechanisms to manage redox imbalance. The hypoxia response pathway, mediated by hypoxia-inducible factors and responsible for sensing and defending against low oxygen levels, plays a vital role in maintaining redox homeostasis. In this review, we highlight the complex and multifaceted crosstalk between hypoxia-inducible factors and redox homeostasis and discuss avenues for future research. Understanding the molecular mechanisms that link hypoxia-inducible factors to oxidative and reductive stresses is essential for comprehending several pathological conditions associated with hypoxia and redox imbalance.

Keywords:  HIF‐1; antioxidants; oxidative stress; reactive oxygen species; reductive stress

DOI:  https://doi.org/10.1111/febs.70013
Nat Commun. 2025 Feb 12. 16(1): 1570

Temporal phosphoproteomics reveals circuitry of phased propagation in insulin signaling.

Michael Turewicz, Christine Skagen, Sonja Hartwig, Stephan Majda, Kristina Thedinga, Ralf Herwig, Christian Binsch, Delsi Altenhofen, D Margriet Ouwens, Pia Marlene Förster, Thorsten Wachtmeister, Karl Köhrer, Torben Stermann, Alexandra Chadt, Stefan Lehr, Tobias Marschall, G Hege Thoresen, Hadi Al-Hasani.

Insulin is a pleiotropic hormone that elicits its metabolic and mitogenic actions through numerous rapid and reversible protein phosphorylations. The temporal regulation of insulin's intracellular signaling cascade is highly complex and insufficiently understood. We conduct a time-resolved analysis of the global insulin-regulated phosphoproteome of differentiated human primary myotubes derived from satellite cells of healthy donors using high-resolution mass spectrometry. Identification and tracking of ~13,000 phosphopeptides over time reveal a highly complex and coordinated network of transient phosphorylation and dephosphorylation events that can be allocated to time-phased regulation of distinct and non-overlapping subcellular pathways. Advanced network analysis combining protein-protein-interaction (PPI) resources and investigation of donor variability in relative phosphosite occupancy over time identifies novel putative candidates in non-canonical insulin signaling and key regulatory nodes that are likely essential for signal propagation. Lastly, we find that insulin-regulated phosphorylation of the pre-catalytic spliceosome complex is associated with acute alternative splicing events in the transcriptome of human skeletal muscle. Our findings highlight the temporal relevance of protein phosphorylations and suggest that synchronized contributions of multiple signaling pathways form part of the circuitry for propagating information to insulin effector sites.

DOI: https://doi.org/10.1038/s41467-025-56335-6