Thermogenic stimulation improves systemic metabolism and healthspan outcomes in aged mice
Authors: Balasubramanian Priya , Subramanian Madhan , Plakkot Bhuvana 
Published: May 2023

Adipose tissue metabolism plays a pivotal role in systemic aging by regulating whole-body energy and glucose metabolism. Emerging evidence links increased thermogenesis in the adipose tissue to longevity and potentially delayed onset of age-related diseases. Thermogenesis (or increase in cellular energy expenditure) is mediated by uncoupling protein 1 (UCP1) localized on the inner mitochondrial membrane which generates heat by uncoupling mitochondrial respiration from ATP synthesis. Chronic β3-adrenergic receptor (β3-AR) activation is a well-established method to induce thermogenesis in both white and brown adipose tissue (WAT and BAT, respectively). Both UCP1 dependent (formation of brown adipocytes in WAT called beiging) and UCP1 independent mechanisms (futile metabolic cycles) have been shown to increase energy expenditure in the adipose depots. Activation of the thermogenic program results in remodeling of both WAT and BAT marked by increased fuel utilization and insulin sensitivity. It also results in an overall improvement in systemic inflammatory milieu and a favorable adipokine profile, which could potentially delay systemic aging. In this study, we hypothesized that chronic thermogenic stimulation using β3-AR agonist treatment will improve systemic metabolism and this will translate to improved healthspan outcomes in aged mice. Aged C57BL/6J mice (18 mos old, both sexes) were continuously infused with CL 316,243 (β3-AR) for 6 weeks at the dose rate of 1mg/kg body weight via osmotic minipumps. Chronic b3-AR treatment reduced body weight, fat mass and improved glucose tolerance. Further, we observed improvements in adipokine profile marked by increase in adiponectin/leptin ratio, and increased mitochondrial activity and decreased inflammation. CL treatment also induced UCP1 expression in BAT and inguinal WAT and increased the expression of enzymes involved in triglyceride-fatty acid cycling (UCP1-independent mechanism) in all fat pads. Improved systemic metabolism was associated with improvements in other healthspan outcomes including cognition and endothelial function. We also performed untargeted metabolomics in serum and WAT isolated from controls and CL treated aged mice. Our results show that thermogenic stimulation resulted in changes in lipid, urea, creatine and branched-chain amino acid metabolism which are some of the common metabolic pathways that were affected in the adipose tissue of long-lived mice (dwarf mice and calorie-restricted mice). Overall, our results show that thermogenesis positively affects adipose and systemic metabolism and thus can be therapeutically targeted to delay aging and the onset of age-related diseases. NIA K01AG073613, Presbyterian Health Foundation and American Federation for Aging Research This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.