bims-mimead Biomed News
on Adipose tissue and metabolic disease
Issue of 2025–06–22
seven papers selected by
Rachel M. Handy, University of Guelph
  1. Sex Hormone-Binding Globulin Controls Sex-Specific Lipolytic Activity in Human Abdominal Subcutaneous Adipocytes.
  2. Enhanced mitochondrial respiration in peripheral blood mononuclear cells (PBMCs) from young children with overweight/obesity and insulin resistance.
  3. FGF21 promotes longevity in diet-induced obesity through metabolic benefits independent of growth suppression.
  4. Sex differences in resting skeletal muscle and the acute and long-term response to endurance exercise in individuals with overweight and obesity.
  5. Dysfunctional mitochondria trap proteins in the intermembrane space.
  6. A nitroalkene derivative of salicylate, SANA, induces creatine-dependent thermogenesis and promotes weight loss.
  7. Non-equilibrium Thermodynamic Analysis of Human Bioenergetics in Obesity: Implications of the Second Law.
  1. Mol Metab. 2025 Jun 16. pii: S2212-8778(25)00096-1. [Epub ahead of print] 102189
    Sex Hormone-Binding Globulin Controls Sex-Specific Lipolytic Activity in Human Abdominal Subcutaneous Adipocytes.
    Julie Abildgaard, Aiste Aleliunaite, Carla Horvath, Nagendra Palani, Tora Ida Henriksen, Jiawei Zhong, Katja Munch Lorentsen, Victor Svenstrup, Hanne Frederiksen, Anders Juul, Camilla Charlotte Scheele, Søren Nielsen.
      Regulation of lipid metabolism is fundamental for metabolic health, and adipose tissue is a central component in this process. Adipose tissue differs considerably between women and men in terms of a higher subcutaneous capacity for storage, which is linked to metabolic health, in women. Sex hormone-binding globulin (SHBG) contributes to the regulation of circulating sex hormone bioavailability and has been shown to predict risk of metabolic dysfunction. Here, we investigate the sex-specific relationship of SHBG with metabolic status and adipocyte-dependent lipolysis. We measured serum concentrations of sex hormones, SHBG, fasting glucose, and insulin in a cohort of 63 women and 27 men from which adipose biopsies were collected and mature adipocytes isolated. In women, high serum SHBG concentrations were strongly associated with low in vivo Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), and lower unstimulated ex vivo lipolysis but higher isoprenaline stimulated ex vivo lipolysis. In contrast, no effect of SHBG on the above-mentioned parameters were observed in men. In vitro cultured human adipocytes also increased lipolytic activity in response to SHBG, but only in the absence of testosterone, suggesting that testosterone inhibits the catecholamine-induced lipolysis of SHBG in adipose tissue. In conclusion, we identify SHBG as a novel sex-specific regulator of adipocyte lipolysis and lipid metabolism. At the same time, our data emphasize sex-dependent effects of SHBG on adipocyte lipid metabolism, and we propose testosterone binding to SHBG as a driving factor mediating these sex differences.
    DOI:  https://doi.org/10.1016/j.molmet.2025.102189
  2. Eur J Clin Invest. 2025 Jun 17. e70090
    Enhanced mitochondrial respiration in peripheral blood mononuclear cells (PBMCs) from young children with overweight/obesity and insulin resistance.
    Eugenia Carvalho, Reid D Landes, Matthew Cotter, Leanna M Delhey, Elisabet Børsheim, Shannon Rose.
       BACKGROUND: Studies implicating dysfunctional mitochondrial respiration in metabolic tissues in the development of insulin resistance in obesity have only included adults. Peripheral blood mononuclear cells (PBMCs) and platelets have been found to reflect systemic mitochondrial fitness and bioenergetic health. We sought to identify bioenergetic differences in PBMCs and platelets from children with obesity and insulin resistance and determine associations with whole-body metabolism and/or biomarkers of metabolic health and inflammation.
    METHODS: We stratified prepubertal children (ages 5-10 years) into three groups: normal weight insulin sensitive (N-IS; n = 20), overweight/obese insulin sensitive (O-IS; n = 28) and overweight/obese insulin resistant (O-IR; n = 17). We measured oxygen consumption rate and proton efflux rate in PBMCs and platelets. We estimated whole-body resting metabolic rate by bioimpedance and dietary fatty acid oxidation by oral deuterated palmitate and quantifying recovery of D2O in urine. We used ANOVA for comparisons among groups and Spearman correlations for associations between circulating cell bioenergetics and whole-body metabolism and biomarkers.
    RESULTS: O-IS and O-IR PBMCs exhibited increased maximal mitochondrial respiration and spare respiratory capacity compared to N-IS. Bioenergetics shifted towards glycolysis in O-IS PBMCs as compared to both N-IS and O-IR PBMCs. In platelets, glycolysis and ATP production rates were decreased in O-IR compared to O-IS children. PBMC respiration positively correlated with BMIz, HOMA-IR and fasting glucose and insulin, but negatively correlated with inflammatory cytokines. Dietary fatty acid oxidation was higher in O-IS compared to N-IS children and positively correlated with PBMC spare respiratory capacity. Resting metabolic rate correlated positively with several parameters of PBMC mitochondrial respiration.
    CONCLUSIONS: PBMCs from young children with overweight/obesity exhibit adaptations to the metabolic stressors associated with insulin resistance, and PBMC metabolism correlates well with whole-body metabolism.
    Keywords:  bioenergetics; circulating cells; inflammation; insulin resistance; metabolic health; paediatric obesity
    DOI:  https://doi.org/10.1111/eci.70090
  3. Cell Metab. 2025 Jun 12. pii: S1550-4131(25)00267-0. [Epub ahead of print]
    FGF21 promotes longevity in diet-induced obesity through metabolic benefits independent of growth suppression.
    Christy M Gliniak, Ruth Gordillo, Yun-Hee Youm, Qian Lin, Clair Crewe, Zhuzhen Zhang, Bianca C Field, Teppei Fujikawa, Megan Virostek, Shangang Zhao, Yi Zhu, Clifford J Rosen, Tamas L Horvath, Vishwa Deep Dixit, Philipp E Scherer.
      Approximately 35% of US adults over 65 are obese, highlighting the need for therapies targeting age-related metabolic issues. Fibroblast growth factor 21 (FGF21), a hormone mainly produced by the liver, improves metabolism and extends lifespan. To explore its effects without developmental confounders, we generated mice with adipocyte-specific FGF21 overexpression beginning in adulthood. When fed a high-fat diet, these mice lived up to 3.3 years, resisted weight gain, improved insulin sensitivity, and showed reduced liver steatosis. Aged transgenic mice also displayed lower levels of inflammatory immune cells and lipotoxic ceramides in visceral adipose tissue, benefits that occurred even in the absence of adiponectin, a hormone known to regulate ceramide breakdown. These results suggest that fat tissue is a central site for FGF21's beneficial effects and point to its potential for treating metabolic syndrome and age-related diseases by promoting a healthier metabolic profile under dietary stress and extending healthspan and lifespan.
    Keywords:  FGF21; adipocytes; adiponectin; adipose tissue; aging; ceramides; inflammation; insulin sensitivity; longevity; obesity
    DOI:  https://doi.org/10.1016/j.cmet.2025.05.011
  4. Mol Metab. 2025 Jun 12. pii: S2212-8778(25)00092-4. [Epub ahead of print] 102185
    Sex differences in resting skeletal muscle and the acute and long-term response to endurance exercise in individuals with overweight and obesity.
    Simon I Dreher, Thomas Goj, Christine von Toerne, Miriam Hoene, Martin Irmler, Meriem Ouni, Markus Jähnert, Johannes Beckers, Martin Hrabe de Angelis, Andreas Peter, Anja Moller, Andreas L Birkenfeld, Annette Schürmann, Stefanie M Hauck, Cora Weigert.
      Endurance exercise reduces the risk of metabolic diseases by improving skeletal muscle metabolism, particularly in individuals with overweight and obesity. As biological sex impacts glucose and fatty acid handling in skeletal muscle, we hypothesized sex differences at the transcriptomic and proteomic level in the acute response to exercise and after an 8-week exercise intervention. We analyzed skeletal muscle biopsies from 25 sedentary subjects (16f/9m) with overweight and obesity using transcriptomics and proteomics at baseline, after acute exercise, and following an 8-week endurance training program. Regulation of sex-specific differences was studied in primary myotubes from the donors. At baseline, differentially methylated CpG-sites potentially explain up to 59% of transcriptomic and 67% of proteomic sex differences. Differences were dominated by higher abundance of fast-twitch fiber type proteins, and transcripts and proteins regulating glycogen degradation and glycolysis in males. Females showed higher abundance of proteins regulating fatty acid uptake and storage. Acute exercise induced stress-responsive transcripts and serum myoglobin predominantly in males. Both sexes adapted to 8-week endurance training by upregulating mitochondrial proteins involved in TCA cycle, oxidative phosphorylation, and β-oxidation. Training equalized fast-twitch fiber type protein levels, mainly by reducing them in males. In vivo sex differences in autosomal genes were poorly retained in myotubes but partially restored by sex hormone treatment. In conclusion, our findings highlight sex-specific molecular signatures that reflect known differences in glucose and lipid metabolism between female and male skeletal muscle. After just 8 weeks of endurance training, these sex differences were attenuated, suggesting a convergence towards a shared beneficial adaptation at the molecular level.
    Keywords:  Exercise; LC-MSMS based quantitative proteomics; Sex-specific; Skeletal muscle
    DOI:  https://doi.org/10.1016/j.molmet.2025.102185
  5. EMBO J. 2025 Jun 16.
    Dysfunctional mitochondria trap proteins in the intermembrane space.
    Tamara Flohr, Markus Räschle, Johannes M Herrmann.
      The accumulation of mitochondrial precursor proteins in the cytosol due to mitochondrial dysfunction compromises cellular proteostasis and is a hallmark of diseases. Why non-imported precursors are toxic and how eukaryotic cells prevent their accumulation in the cytosol is still poorly understood. Using a proximity labeling-based assay to globally monitor the intramitochondrial location of proteins, we show that, upon mitochondrial dysfunction, many mitochondrial matrix proteins are sequestered in the intermembrane space (IMS); something we refer to as "mitochondrial triage of precursor proteins" (MitoTraP). MitoTraP is not simply the result of a general translocation block at the level of the inner membrane, but specifically directs a subgroup of matrix proteins into the IMS, many of which are constituents of the mitochondrial ribosome. Using the mitoribosomal protein Mrp17 (bS6m) as a model, we found that IMS sequestration prevents its mistargeting to the nucleus, potentially averting interference with assembly of cytosolic ribosomes. Thus, MitoTraP represents a novel, so far unknown mechanism of the eukaryotic quality control system that protects the cellular proteome against the toxic effects of non-imported mitochondrial precursor proteins.
    Keywords:  Intermembrane Space; Mitochondria; Nucleolus; Protein Targeting; Ribosome
    DOI:  https://doi.org/10.1038/s44318-025-00486-1
  6. Nat Metab. 2025 Jun 17.
    A nitroalkene derivative of salicylate, SANA, induces creatine-dependent thermogenesis and promotes weight loss.
    Karina Cal, Alejandro Leyva, Jorge Rodríguez-Duarte, Santiago Ruiz, Leonardo Santos, Maria Pia Garat, Lucía Colella, Mariana Ingold, Andrés Benitez-Rosendo, Valentina Pérez-Torrado, Cecilia Vilaseca, German Galliussi, Lucía Ziegler, Thais R Peclat, Mariana Bresque, Rachel M Handy, Rachel King, Larissa Menezes Dos Reis, João Manoel Alves, Camila Espasandín, Victoria de la Sovera, Peter Breining, Rosina Dapueto, Andrés Lopez, Katie L Thompson, Caroline A Lino, Julia V França, Thayna S Vieira, Ramandeep Rattan, Guillermo Agorrody, Evan DeVallance, Jacqueline Haag, Ethan Meadows, Sara E Lewis, Gabriele Catarine Santana Barbosa, Leonardo Osbourne Lai de Souza, Marina Santos Chichierchio, Valeria Valez, Adrián Aicardo, Paola Contreras, Mikkel H Vendelbo, Steen Jakobsen, Andrés Kamaid, Williams Porcal, Aldo Calliari, José Manuel Verdes, Jianhai Du, Yekai Wang, John M Hollander, Thomas A White, Rafael Radi, Guillermo Moyna, Celia Quijano, Robert O'Doherty, Pedro Moraes-Vieira, Shailendra Giri, Graham P Holloway, William T Festuccia, Luiz Osório Leiria, Roberta Leonardi, Marcelo A Mori, Juliana Camacho-Pereira, Eric E Kelley, Rosario Duran, Gloria V López, Eduardo N Chini, Carlos Batthyány, Carlos Escande.
      The emergence of glucagon-like peptide-1 agonists represents a notable advancement in the pharmacological treatment of obesity, yet complementary approaches are essential. Through phenotypic drug discovery, we developed promising nitroalkene-containing small molecules for obesity-related metabolic dysfunctions. Here, we present SANA, a nitroalkene derivative of salicylate, demonstrating notable efficacy in preclinical models of diet-induced obesity. SANA reduces liver steatosis and insulin resistance by enhancing mitochondrial respiration and increasing creatine-dependent energy expenditure in adipose tissue, functioning effectively in thermoneutral conditions and independently of uncoupling protein 1 and AMPK activity. Finally, we conducted a randomized, double-blind, placebo-controlled phase 1A/B clinical trial, which consisted of two parts, each with four arms: (A) single ascending doses (200-800 mg) in healthy lean volunteers; (B) multiple ascending doses (200-400 mg per day for 15 days) in healthy volunteers with overweight or obesity. The primary endpoint assessed safety and tolerability. Secondary and exploratory endpoints included pharmacokinetics, tolerability, body weight and metabolic markers. SANA shows good safety and tolerability, and demonstrates beneficial effects on body weight and glucose management within 2 weeks of treatment. Overall, SANA appears to be a first-in-class activator of creatine-dependent energy expenditure and thermogenesis, highlighting its potential as a therapeutic candidate for 'diabesity'. Australian New Zealand Clinical Trials Registry registration: ACTRN12622001519741 .
    DOI:  https://doi.org/10.1038/s42255-025-01311-z
  7. Am J Physiol Endocrinol Metab. 2025 Jun 16.
    Non-equilibrium Thermodynamic Analysis of Human Bioenergetics in Obesity: Implications of the Second Law.
    Nawfal Istfan.
      The fundamental principle of energy balance, a statement of the first law of thermodynamics, overlooks the second law, resulting in gaps in our knowledge of body weight regulation and obesity. This study develops research tools to implement non-equilibrium thermodynamics in human subjects based on a mitochondrial energy conversion model. A key advancement measures ATP phosphorylation through its relationship to the mitochondrial redox couple, beta-hydroxybutyrate, and acetoacetate. Applying this methodology in humans, utilizing data from a recent study, provides a comprehensive understanding of the impact of the second law. The results demonstrate that oxidative phosphorylation efficiency is approximately 57%, with minor but significant variations among individuals. Four out of 24 healthy subjects exhibited sufficiently higher efficiency of oxidative phosphorylation and lower free energy dissipation compared to the remaining subjects. Feeding is associated with lower efficiency, a higher rate of free energy dissipation, and a slight reduction in coupling. The amount of energy utilized for useful work represents only one-third of resting energy expenditure. These findings are integrated with the current principle of energy balance to adhere to the constraints of the first and second laws. Based on theoretical modeling, it is demonstrated that inter-individual differences and variations in mitochondrial efficiency and energy dissipation during specific metabolic conditions can lead to discrepancies between total energy balance and the balance of the fraction of energy used for useful work. Consequently, the constraints imposed by the second law should be incorporated into the current understanding of energy balance and obesity.
    Keywords:  entropy production; metabolic efficiency; second law of thermodynamics; total energy expenditure
    DOI:  https://doi.org/10.1152/ajpendo.00487.2024
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