White adipose tissue browning preserves UCP1-dependent nonshivering thermogenesis upon brown-adipocyte specific lipase-deficiency

Abstract

Intracellular fatty acids (FAs) activate and fuel non-shivering thermogenesis (NST) via uncoupling protein 1 (UCP1). Adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL) control FA availability. Since mice lacking ATGL in brown adipose tissue (BAT) exhibit intact recruitable adrenergic thermogenesis, we hypothesized that HSL-mediated FA release is sufficient to activate UCP1-dependent NST. We demonstrate that mice with inducible brown adipocyte-specific loss of ATGL and HSL (iBDKO) exhibit normal recruitable adrenergic thermogenesis upon prolonged cold exposure. Mechanistically, we show that BAT thermogenic capacity is impaired in cold-adapted iBDKO mice due to diminished mitochondrial numbers. Increased browning of white adipose tissue (WAT) in iBDKO mice indicates a shift in thermogenesis from BAT to WAT. Consistently, the loss of ATGL and HSL in BAT and WAT disrupts thermogenesis in both depots, resulting in blunted UCP1-dependent NST. Our study highlights the metabolic adaptability of adipose tissue and the critical role of intracellular lipolysis in regulating thermogenesis.