Grant: Project Grant

Thermogenic (brown and beige) adipocytes dissipate energy (thermogenesis) due to their high mitochondrial respiratory capacity. For example, in a cold environment, muscle shivering is triggered first but is subsequently replaced by non-shivering thermogenesis in brown adipose tissue (BAT). In rodents, the thermogenic capacity of BAT has been causally linked to metabolic health. Humans have BAT, and it is positively correlated with a healthier cardiometabolic profile. A major goal of the field is to understand how to make more thermogenic fat cells and how to maximally activate them. For the latter, it is critical to understand the effector proteins that control a major function of these cells, which is energy dissipation. The molecular nature of energy dissipation in thermogenic fat has been largely ascribed to the action of uncoupling protein 1 (UCP1). Germline Ucp1 knockout mice (herein referred to as Ucp1-/-) have been the primary tool to explore the relevance of UCP1 for adipocyte-driven energy dissipation, leading to the conventional view that non-shivering thermogenesis is exclusively dependent on UCP1. Whether UCP1-independent pathways promote thermogenesis in parallel to UCP1, or only in the context of chronic Ucp1 ablation, has not been resolved. Notably, defining the contribution of UCP1-independent thermogenesis within thermogenic fat has been challenging because brown adipocytes from Ucp1-/- mice acquire secondary changes to key metabolic circuits that are required to trigger and sustain thermogenesis by any mechanism. To investigate UCP1-dependent and -independent thermogenesis without confounding effects of chronic UCP1 inactivation, we have developed inducible adipocyte-selective knockout mice. We are now poised to delineate the quantitative contribution of UCP1 and alternative effectors (focusing on an alternative pathway involving creatine) over body temperature regulation, adipocyte thermogenesis, and energy balance and metabolic health.