Chronic B3-AR stimulation activates distinct thermogenic mechanisms in brown and white adipose tissue and improves systemic metabolism in aged mice

Authors: NATARAJAN, DURAIPANDY - University Of Oklahoma Health Sciences Center; PLAKKOT, BHUVANA - Oklahoma State University; TIWARI, KRITIKA - University Of Oklahoma Health Sciences Center; EKAMBARAM, SHOBA - University Of Oklahoma Health Sciences Center; WANG, WEIDONG - University Of Oklahoma Health Sciences Center; RUDOLPH, MICHAEL - University Of Oklahoma Health Sciences Center; MOHAMMAD, MAHMOUD - Children'S Nutrition Research Center (CNRC); CHACKO, SHAJI - Children'S Nutrition Research Center (CNRC); SUBRAMANIAN, MADHAN - Oklahoma State University; TARANTINI, STEFANO - University Of Oklahoma Health Sciences Center; YABLUCHANSKIY, ANDRIY - University Of Oklahoma Health Sciences Center; UNGVARI, ZOLTAN - University Of Oklahoma Health Sciences Center; CSISZAR, ANNA - University Of Oklahoma Health Sciences Center; BALASUBRAMANIAN, PRIYA - University Of Oklahoma Health Sciences Center

Submitted to: Aging Cell
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/3/2024
Publication Date: 8/23/2024
Citation: Natarajan, D., Plakkot, B., Tiwari, K., Ekambaram, S., Wang, W., Rudolph, M., Mohammad, M.A., Chacko, S.K., Subramanian, M., Tarantini, S., Yabluchanskiy, A., Ungvari, Z., Csiszar, A., Balasubramanian, P. 2024. Chronic B3-AR stimulation activates distinct thermogenic mechanisms in brown and white adipose tissue and improves systemic metabolism in aged mice. Aging Cell. 23. Article e14321. https://doi.org/10.1111/acel.14321.
DOI: https://doi.org/10.1111/acel.14321

Interpretive Summary: Scientists have been looking at ways to boost fat-burning in the body as a potential treatment for obesity-related health problems. It is unclear if this approach works for older adults who have the highest rates of obesity in the U.S. (about 40%). The objective of this study was to investigate how a specific fat-burning treatment using a drug (CL316243), affects the metabolism of older mice. The researchers at CNRC and their collaborators found that treatment led to lower body fat, higher energy use, better fat burning, improved blood sugar control, and healthier metabolism-related hormones. The drug boosted heat production in brown fat, which naturally generates warmth. In white fat (which mainly stores energy), it didn’t create heat directly but instead sped up fat breakdown and rebuilding, a process that still helps burn calories. This suggests white fat can be reprogrammed to support metabolism as brown fat declines with age. Overall, the study suggests that boosting fat activity, especially in white fat, could be a useful strategy to fight obesity and metabolic decline in older adults.

Technical Abstract: Adipose thermogenesis has been actively investigated as a therapeutic target for improving metabolic dysfunction in obesity. However, its applicability to middle-aged and older populations, which bear the highest obesity prevalence in the United States (approximately 40%), remains uncertain due to age-related decline in thermogenic responses. In this study, we investigated the effects of chronic thermogenic stimulation using the B3-adrenergic (AR) agonist CL316,243 (CL) on systemic metabolism and adipose function in aged (18-month-old) C57BL/6JN mice. Sustained B3-AR treatment resulted in reduced fat mass, increased energy expenditure, increased fatty acid oxidation and mitochondrial activity in adipose depots, improved glucose homeostasis, and a favorable adipokine profile. At the cellular level, CL treatment increased uncoupling protein 1 (UCP1)-dependent thermogenesis in brown adipose tissue (BAT). However, in white adipose tissue (WAT) depots, CL treatment increased glycerol and lipid de novo lipogenesis (DNL) and turnover suggesting the activation of the futile substrate cycle of lipolysis and reesterification in a UCP1-independent manner. Increased lipid turnover was also associated with the simultaneous upregulation of proteins involved in glycerol metabolism, fatty acid oxidation, and reesterification in WAT. Further, a dose-dependent impact of CL treatment on inflammation was observed, particularly in subcutaneous WAT, suggesting a potential mismatch between fatty acid supply and oxidation. These findings indicate that chronic B3-AR stimulation activates distinct cellular mechanisms that increase energy expenditure in BAT and WAT to improve systemic metabolism in aged mice. Considering that people lose BAT with aging, activation of futile lipid cycling in WAT presents a novel strategy for improving age-related metabolic dysfunction.