DGAT-driven futile lipid cycling has a pronounced, yet concealed, thermogenic function

Thermoregulation is an essential yet incompletely understood homeostatic process in mammals. UCP1-mediated thermogenesis, while efficient, is dispensable, suggesting the existence of alternative mechanisms. Using a pharmacogenetic approach, we show that the adipose tissue futile lipid cycling (FLC) contributes to UCP1-independent thermogenesis, with DGATs being involved in the regulation of FLC. The loss of DGAT-driven FLC-mediated thermogenesis is compensated for by the hierarchical recruitment of alternative mechanisms such as shivering and enhanced lipid catabolism mediated by AMPK activation. Consistently, pharmacological inhibition of muscle shivering or AMPK in FLC-deficient mice leads to an acute reduction in energy expenditure and hypothermia. These findings demonstrate a substantial thermogenic potential of FLC and suggest previously unappreciated flexibility and adaptability in regulating the core body temperature through adaptive changes in adipocyte metabolism. • DGATi efficiently blocks basal and iso-stimulated lipolysis and redirects FA to FAO • Terminal FLC deficiency does not compromise cold tolerance in mice • AMPK activation remodels iWAT of TKO mice toward higher FA catabolism • AMPK activation and shivering perform compensatory thermogenesis in TKO mice Through comprehensive phenotyping of complex mouse models and in vitro studies, the authors uncovered that futile lipid cycling has a sizable thermogenic output. However, in its absence, alternative mechanisms, including AMPK-driven catabolism and overt shivering, efficiently compensate for the thermogenic loss, thus concealing the true magnitude of FLC-driven thermogenesis.