Antagonistic regulation of Drosophila mitochondrial uncoupling protein UCP4b by cold and BMP signaling

Regulation of energy metabolism and response to cold are intimately linked in mammals. Central to these two processes are the mitochondrial uncoupling proteins (UCPs), which by promoting proton leakage across the inner mitochondrial membrane lead to the generation of heat instead of ATP synthesis. In addition to heat generation, UCPs also influence energy storage and can protect against obesity and diabetes. Cold-blooded animals like flies also contain UCPs that protect from cold, however their regulations are poorly understood. We find that Drosophila UCP4b is induced by cold in a cell-intrinsic manner and protects against cold and obesity in fly models. Mechanistically, cold regulates UCP4b expression through calcium signaling and Spargel (Srl), the Drosophila ortholog of mammalian PGC1α. To the opposite, MAD, acting downstream of the BMP branch of the TGFβ signaling pathway, represses UCP4b expression independently of cold. Interestingly, the two mechanisms of UCP4b regulation are integrated as MAD binding to the UCP4b promoter is displaced by cold in a Srl-dependent manner. We discuss the similarities between the regulation of mammalian and Drosophila UCPs. ### Competing Interest Statement The authors have declared no competing interest.