The metabolic benefits of thermogenic stimulation are preserved in aging

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 US (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 β3-adrenergic (AR) agonist CL316,243 (CL) on systemic metabolism and adipose function in aged (18-month-old) C57BL/6JN mice. Sustained β3-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 β3-AR stimulation activates distinct cellular mechanisms that increase energy expenditure in BAT and WAT to improve systemic metabolism in aged mice. Our study provides foundational evidence for targeting adipose thermogenesis to improve age-related metabolic dysfunction.

Chronic β3 adrenergic agonist treatment improves brain microvascular endothelial function and cognition in aged mice

“…To test this, we chose thermogenic stimulation using β3AR agonists, a method previously well-established to improve adipose and systemic metabolism in both rodents and humans 53 54 55 56 . Although the effects of β3AR agonists on systemic metabolism have only been well-characterized in young animals, our studies showed that it also effectively improved multiple metabolic parameters including adiposity, glucose metabolism, insulin sensitivity, circulating adiponectin, and ectopic lipid deposition 43 . More importantly, these systemic improvements were associated with improved microvascular endothelial function and cognition in aged mice, indicating that the beneficial effects of thermogenesis extend beyond metabolic tissues.…”

“…Addressing this, we have recently shown that the metabolic benefits of β3AR agonist treatment are preserved in aged mice. Chronic β3AR stimulation increased whole-body energy expenditure, reduced fat mass, improved glucose tolerance and insulin sensitivity, increased circulating adiponectin levels, and reduced ectopic lipid deposition in aged mice 43 . In the present study, we wanted to examine whether β3AR stimulationmediated improvements in systemic metabolism and circulating milieu can mitigate microvascular endothelial dysfunction and cognitive decline in aged mice.…”

“…We have recently reported that the pharmacological activation of adipose thermogenesis, a catabolic phenomenon marked by increased fuel oxidation and energy expenditure, improved the overall systemic metabolism in aged mice 43 . Specifically, we used a β3-adrenergic receptor agonist (β3AR, CL, 216243) to stimulate thermogenesis in aged mice.…”