Uncoupling Protein 1 (UCP1) is a mitochondrial protein specific to thermogenic adipocytes (brown and beige fat) that uncouples cellular respiration and mitochondrial ATP synthesis to dissipate energy in the form of heat. Because UCP1 has been considered the sole thermogenic protein responsible for non-shivering thermogenesis in the adipose tissue, the prevailing dogma is that the action of UCP1 primarily mediates the functions of brown and beige fat, which promote the anti-obesity and anti-diabetic effects when activated. However, our data from the previous funding cycle and other labs suggest an incongruity in the metabolic phenotypes between brown/beige fat-deficiency and UCP1-deficiency: we found that beige fat-deficient mice, caused by the fat-specific deletion of PRDM16 or its co-factor EHMT1, develop obesity and glucose intolerance even under ambient temperature, whereas UCP1 knockout mice are not diabetic and develop obesity only under thermoneutrality. This discrepancy motivated us to search for UCP1-independent mechanisms in the regulation of energy homeostasis. We recently identified a non-canonical (UCP1-independent) thermogenic mechanism that may explain the above quandary. UCP1-independent thermogenesis involves ATP-dependent Ca2+ cycling through Sarco/endoplasmic reticulum Ca2+-ATPase2b (SERCA2b) and Ryanodine Receptor 2 (RyR2) in beige fat. Ca2+ cycling thermogenesis is activated, in part, through α1-AR signaling in response to a cold stimulus, and requires active glucose oxidation. Thereby beige fat functions as a “glucose sink” and improves systemic glucose tolerance. Notably, Ca2+ cycling thermogenesis is an evolutionally conserved mechanism in humans, mice, and also in pigs, a rare mammalian species that lacks a functional UCP1 protein. Accordingly, the current proposal aims to determine the biological significance and the mechanisms pertinent to this non-canonical thermogenesis in beige fat.

Obesity and obesity-associated metabolic disorders, such as type 2 diabetes, continue to be among the most urgent health challenges in the USA. Building upon our recent discovery of a non-canonical (UCP1-independent) thermogenic mechanism in beige fat, this proposal aims to understand its biological significance and molecular mechanisms in the regulation of whole-body energy metabolism and glucose homeostasis. A better understanding of this UCP1-independent mechanism may lead to an effective therapeutic intervention for obesity and diabetes treatment even in subjects who do not possess UCP1-positive adipocytes, including elderly populations.