bims-mimead Biomed News
on Mitochondrial metabolism in ageing and metabolic disease
Issue of 2025–01–26
seven papers selected by
Rachel M. Handy, University of Guelph
  1. Altered expression of aromatase and estrogen receptors in adipose tissue from men with obesity or type 2 diabetes.
  2. Mechanistic Insights Into the Exercise-Induced Changes in Muscle Lipids and Insulin Sensitivity-Expanding on the "Athlete's Paradox": Revisiting a 2011 Diabetes Classic by Amati et al.
  3. Depot-specific adiposity changes in ovariectomized mice on high-fat diet.
  4. Endothelial autophagy-related gene 7 contributes to high fat diet-induced obesity.
  5. Estrogen receptors in mitochondrial metabolism: age-related changes and implications for pregnancy complications.
  6. Homeobox C4 transcription factor promotes adipose tissue thermogenesis.
  7. Metabolic dysfunction in mice with adipocyte specific ablation of the adenosine A2A receptor.
  1. J Clin Endocrinol Metab. 2025 Jan 21. pii: dgaf038. [Epub ahead of print]
    Altered expression of aromatase and estrogen receptors in adipose tissue from men with obesity or type 2 diabetes.
    Fozia Ahmed, Susanne Hetty, Rutger Laterveer, Ece Busra Surucu, Argyri Mathioudaki, Edvin Hornbrinck, Vagia Patsoukaki, Johan Olausson, Magnus Sundbom, Maria K Svensson, Maria J Pereira, Jan W Eriksson.
       OBJECTIVE: Obesity and insulin resistance in men are linked to decreased testosterone and increased estradiol (E2) levels. Aromatase (ARO) converts testosterone into E2, and this occurs mainly in adipose tissue in men. E2 acts through estrogen receptors ESR1 and ESR2, and they potentially affect development of type 2 diabetes (T2D). This study explored alterations in ARO, ESR1 and ESR2 in men with obesity or T2D.
    METHODS: Subcutaneous adipose tissue (SAT) from men with or without obesity or T2D was analyzed for ARO, ESR1, and ESR2 gene and protein expression. Data were compared across groups and correlated with markers of obesity, glycaemia, insulin resistance, and sex hormones. Moreover, SAT was incubated with E2 or testosterone for ex vivo glucose uptake measurements.
    RESULTS: Aromatase ARO levels were higher in SAT from men with obesity compared to non-obese men, and gene expression correlated positively with adiposity, hyperglycaemia and insulin resistance. No association was found between ARO and circulating E2. Men with obesity had lower levels of ESR1 and ESR1:ESR2 ratio, but not ESR2. ESR1 gene expression in SAT correlated negatively with adiposity and insulin resistance markers as well as with ARO expression, and tended to be lower in men with T2D. E2 reduced insulin-stimulated glucose uptake, while testosterone increased basal glucose uptake in adipocytes.
    CONCLUSION: Elevated ARO in SAT was found in obese men, and this was linked to insulin resistance and glycaemia, supporting that local estrogen production contributes to metabolic dysregulation. ESR1 was reduced in men with T2D and was linked to adiposity and insulin resistance. Taken together, high ARO and low ESR1 expression in SAT in obese men may contribute to insulin resistance and T2D development.
    Keywords:  T2D; adipose tissue; aromatase; estradiol; estrogen receptors; obesity
    DOI:  https://doi.org/10.1210/clinem/dgaf038
  2. Diabetes. 2025 Feb 01. 74(2): 134-137
    Mechanistic Insights Into the Exercise-Induced Changes in Muscle Lipids and Insulin Sensitivity-Expanding on the "Athlete's Paradox": Revisiting a 2011 Diabetes Classic by Amati et al.
    Jeffrey F Horowitz, Bret H Goodpaster.
      Endurance exercise is widely recognized for its role in mitigating insulin resistance, yet the precise mechanisms remain unclear. In this Classics in Diabetes article, we revisit the article by Amati et al., "Skeletal Muscle Triglycerides, Diacylglycerols, and Ceramides in Insulin Resistance: Another Paradox in Endurance-Trained Athletes?" Published in the October 2011 issue of Diabetes, this article was among the first to highlight the nuanced roles of exercise-induced changes in bioactive lipids such as ceramide and diacylglycerol (DAG) in insulin signaling. The authors' groundbreaking work challenged some existing paradigms, revealing a more complex relationship between DAGs and insulin resistance than previously thought. Their findings helped lay the foundation for further exploration to unravel the intricate biochemical pathways through which exercise influences insulin sensitivity and metabolic health.
    DOI:  https://doi.org/10.2337/dbi24-0030
  3. J Vet Med Sci. 2025 Jan 22.
    Depot-specific adiposity changes in ovariectomized mice on high-fat diet.
    Danang Dwi Cahyadi, Katsuhiko Warita, Yoshinao Z Hosaka.
      Ovariectomized (OVX) mice serve as a key model for studying postmenopausal metabolic changes, particularly obesity, as they mimic the hormonal state of postmenopausal women. However, our understanding remains limited regarding how hormonal and dietary factors affect different adipose tissues. Furthermore, precise documentation of experimental procedures and their effects on specific adipose tissue depots is essential for reproducible translational research. This study investigated depot-specific adiposity development in OVX mice fed a high-fat diet (HFD), focusing on how reduced estrogen levels and dietary intervention affect distinct fat depots. We composed subcutaneous and visceral white adipose tissue (WAT) depots from sham-operated (Sham) and OVX female C57BL/6JJcl mice on a regular diet (RD) and high-fat diet (HFD) for 20 weeks. OVX mice on HFD gained significantly more weight than Sham controls. Adiposity increased in abdominal subcutaneous WAT (sWAT) and perirenal WAT (prWAT) of OVX mice, but not in mesenteric WAT (mWAT). Analysis of adipose tissue morphology revealed that OVX mice exhibited enlarged adipocyte cross-sectional areas under low estrogen (E2) conditions, suggesting enhanced adipogenesis in an estrogen-deficient state. These findings suggest that low estrogen condition accelerated adiposity, in a tissue site-dependent manner.
    Keywords:  adipose depots; animal model; mouse; obesity; white adipose tissue
    DOI:  https://doi.org/10.1292/jvms.24-0442
  4. Mol Metab. 2025 Jan 18. pii: S2212-8778(25)00006-7. [Epub ahead of print] 102099
    Endothelial autophagy-related gene 7 contributes to high fat diet-induced obesity.
    Guang Ren, Sushant Bhatnagar, Martin E Young, Timmy Lee, Jeong-A Kim.
       OBJECTIVE: Obesity-associated metabolic dysfunction is a major public health concern worldwide. Endothelial dysfunction is a hallmark of metabolic dysfunction, and endothelial cells affect metabolic functions. Because autophagy-related gene 7 (ATG7) is involved in various cellular physiology, we investigated the roles of endothelial cell-ATG7 (EC-ATG7) on high-fat diet-induced obesity and its related metabolic dysfunction.
    METHODS: We generated an endothelial-specific Atg7 knock-out mouse by breeding Atg7flox/flox mouse with the Chd5-Cre mouse, and investigated the metabolic phenotypes associated with high-fat diet (HFD)-induced obesity. Body weight, food intake, glucose tolerance, insulin sensitivity, and liver fat accumulation were measured in endothelial Atg7 deficient (Atg7ΔEnd) and control mice (Atg7f/f). Adipose tissue inflammation was assessed by measuring the expression of pro-inflammatory genes. Furthermore, we performed indirect calorimetry and examined the insulin signaling pathway molecules.
    RESULTS: We found that deletion of EC-Atg7 ameliorated HFD-induced weight gain, fatty liver, and adipocyte hypertrophy and inflammatory response in adipose tissue, and improved insulin sensitivity without changing glucose tolerance. These metabolic effects seem to be due to the reduced food intake because there were no differences in energy expenditure, energy excretion to feces, and physical activity. Interestingly, the deletion of EC-Atg7 protected from HFD-induced vascular rarefaction, and the knock-down of Atg7 in endothelial cells protected from fatty acid-induced cell death.
    CONCLUSIONS: Our results suggest that EC-Atg7 deletion ameliorates HFD-induced obesity and its related metabolic dysfunction, such as insulin resistance and fatty liver by attenuating appetite and vascular rarefaction. The EC-Atg7 deletion may protect the endothelial cells from lipotoxicity and impaired angiogenesis, which preserves the endothelial function in metabolic tissues. These findings may have implications for developing new therapeutic strategies for preventing and treating obesity and its associated health risks.
    Keywords:  ATG7; Autophagy; Endothelial cell; Insulin resistance; Obesity
    DOI:  https://doi.org/10.1016/j.molmet.2025.102099
  5. Aging Adv. 2024 Dec;1(2): 154-171
    Estrogen receptors in mitochondrial metabolism: age-related changes and implications for pregnancy complications.
    Antentor Hinton, Kit Neikirk, Han Le, Chanel Harris, Ashton Oliver, Pamela Martin, Amadou Gaye.
      Estrogen hormones are primarily associated with their role as female sex hormones responsible for primary and secondary sexual development. Estrogen receptors are known to undergo age-dependent decreases due to age-related changes in hormone production. In the mitochondria, estrogen functions by reducing the production of reactive oxygen species in the electron transport chain, inhibiting apoptosis, and regulating mitochondrial DNA content. Moreover, estrogen receptors may be the key components in maintaining mitochondrial membrane potential and structure. Although estrogen plays a crucial role in the development of pregnancy, our understanding of how estrogen receptors change with aging during pregnancy remains limited. During pregnancy, estrogen levels are significantly elevated, with a corresponding upregulation of estrogen receptors, which play various roles in pregnancy. However, the exact role of estrogen receptors in pregnancy complications remains to be further investigated. The paper reviews the role of estrogen receptors in the regulation of mitochondrial metabolism and in pregnancy complications, with a special focus on the effect of age-related changes on estrogen levels and estrogen receptors function. We also address how estrogen maintains mitochondrial function, including reducing the production of reactive oxygen species in the electron transport chain, inhibiting apoptosis, regulating mitochondrial DNA content, and maintaining mitochondrial membrane potential and structure. However, the effects of estrogen on mitochondria-endoplasmic reticulum contacts have not been well studied. Based on these emergent roles in mitochondria, the differential roles of estrogen receptors in pregnancy complications are of great relevance. The paper emphasizes the association between maternal health and estrogen receptors and indicates the need for future research to elucidate the interdependence of estrogen receptor-regulated maternal health with mitochondrial function and their relationship with the gut microbiome. Overall, we summarize the important role of estrogen receptors during pregnancy and highlight the need for further research to better understand the role of estrogen receptors in aging and pregnancy complications. This not only helps to reveal the mechanism underlying the role of estrogen in maternal health but also has potential clinical implications for the development of new therapies targeting age-related diseases and pregnancy complications.
    Keywords:  age-related changes; aging; estrogen; estrogen receptors; mitochondria; pregnancy complications
    DOI:  https://doi.org/10.4103/agingadv.agingadv-d-24-00012
  6. Diabetes. 2025 Jan 24. pii: db240675. [Epub ahead of print]
    Homeobox C4 transcription factor promotes adipose tissue thermogenesis.
    Ting Yang, Yuxuan Wang, Hang Li, Fengshou Shi, Siqi Xu, Yingting Wu, Jiaqi Xin, Yi Liu, Mengxi Jiang.
      The homeobox (HOX) family has shown potential in adipose development and function, yet the specific HOX proteins fueling adipose thermogenesis remain elusive. In this study, we uncovered the novel function of HOXC4 in stimulating adipose thermogenesis. Our bioinformatic analysis indicated an enrichment of Hoxc4 co-expressed genes in metabolic pathways and linked HOXC4 polymorphisms to metabolic parameters, suggesting its involvement in metabolic regulation. In mouse brown adipose tissue, HOXC4 expression negatively correlated with body weight and positively correlated with Ucp1 expression. Through gain- and loss-of-function experiments in mice, we established that HOXC4 is both sufficient and necessary for adipose thermogenesis, leading to enhanced cold tolerance and protection against diet-induced obesity and insulin resistance. Human and mouse primary adipocyte models further confirmed that the thermogenic activation function of HOXC4 is cell-autonomous. Mechanistically, HOXC4 collaborates with cofactor NCOA1 via its hexapeptide motif to form a transcriptional complex at the Ucp1 promoter, thereby promoting Ucp1 transcription and adipose thermogenesis. These findings delineate a novel mechanism by which HOXC4 drives thermogenic transcription and adipose energy metabolism, offering potential therapeutic targets for obesity-related metabolic disorders.
    DOI:  https://doi.org/10.2337/db24-0675
  7. J Biol Chem. 2025 Jan 17. pii: S0021-9258(25)00053-5. [Epub ahead of print] 108206
    Metabolic dysfunction in mice with adipocyte specific ablation of the adenosine A2A receptor.
    Narendra Verma, Luce Perie, Michele Silvestro, Anupama Verma, Bruce N Cronstein, Bhama Ramkhelawon, Elisabetta Mueller.
      It has been well established that adenosine plays a key role in the control of inflammation through G protein coupled receptors and recently shown that it can regulate thermogenesis. Here we investigated the specific requirements of the adenosine A2A receptor (A2AR) in mature adipocytes for thermogenic functionality and metabolic homeostasis. We generated fat tissue specific adenosine A2A receptor knock-out mice to assess the influence of signaling through this receptor on brown and beige fat functionality, obesity, insulin sensitivity, inflammation and liver function. Fat specific A2AR knock-out and wild type littermate mice were compared for potential differences in cold tolerance and energy metabolism. In addition, we measured glucose metabolism, AT inflammation and liver phenotypes in mice of the two genotypes after exposure to a diet rich in fat. Our results provide novel evidence indicating that loss of the adenosine A2A receptor specifically in adipocytes is associated with cold intolerance and decreased oxygen consumption. Furthermore, mice with fat specific ablation of the A2AR exposed to a diet rich in fat showed increased propensity to obesity, decreased insulin sensitivity, elevated adipose tissue inflammation and hepato-steatosis and -steatitis. Overall, our data provide novel evidence that A2AR in mature adipocytes safeguards metabolic homeostasis, suggesting the possibility of targeting this receptor selectively in fat for the treatment of metabolic disease.
    Keywords:  UCP1; adenosine A2A receptor; brown and beige adipose tissue; insulin resistance; obesity
    DOI:  https://doi.org/10.1016/j.jbc.2025.108206
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