Uncoupling protein-1 (UCP1) is dispensable for the metabolic benefits of thermogenic stimulation in aged mice

Adipose tissue plays a pivotal role in regulating whole-body energy homeostasis through its direct impact on glucose and lipid metabolism and also indirectly through secreted factors that have endocrine actions on other systemic tissues. Age-related pathological changes in the adipose tissue characterized by immune cell infiltration, preadipocyte senescence, reduced sympathetic input, increased fibrosis, and altered adipokine secretion, significantly contribute to metabolic dysfunction. Notably, metabolic dysfunction in middle age precedes the onset of several age-related diseases, underscoring the potential of interventions targeting adipose tissue metabolism to extend the health span of elderly individuals. Adipose thermogenesis or increased cellular energy expenditure has been actively investigated as a therapeutic target for improving metabolic dysfunction in obesity. However, its applicability to the aged and middle-aged population, which bears the highest prevalence of obesity, is not clear. We have recently reported that thermogenic stimulation using β3AR agonists activates distinct thermogenic mechanisms (UCP1-dependent thermogenesis in brown adipose tissue (BAT) and futile lipid cycling mediated UCP1-independent thermogenesis in the white adipose tissue (WAT)) to increase energy expenditure and improve overall systemic metabolism in aged C57BL/6J mice. Considering that BAT is a limiting tissue target in the aging population, we wanted to test the hypothesis that UCP1 is dispensable for the metabolic benefits of thermogenic stimulation in aged mice. To address this, we selectively eliminated UCP1-positive adipocytes using surgical (BAT removal) and genetic means (UCP1-DTR transgenic mice, an inducible system that allows for transient and efficient ablation of UCP1+ cells in adult mice with diphtheria toxin) and examined their impact on β3AR agonist treatment-mediated improvements in systemic metabolism in aged mice (18 months old wild-type and UCP1-DTR mice). Our results demonstrated that the elimination of UCP1+ adipocytes, using both surgical and genetic approaches, did not affect β3AR agonist-induced reductions in fat mass, improvements in glucose metabolism, or increases in adipose mitochondrial activity. These findings suggest that the metabolic benefits of thermogenic stimulation are UCP1-independent and hold significant translational potential for the aging population. Ongoing gain-of-function studies are investigating the therapeutic potential of activating futile lipid cycling in WAT, a UCP1-independent thermogenic mechanism, for improving metabolic dysfunction in aging. Funding was provided by NIH K01AG073613, AFAR Junior Faculty Award, American Heart Association Career Development Award, and Stephenson Cancer Center, OUHSC. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.