Brown fat burns energy to produce heat and is a promising target against obesity and its metabolic consequences. Its powerhouses, the mitochondria, are not only capable of respiration but can also actively synthesize their own fatty acids - a process whose final step is carried out by the enzyme MECR. In the first funding period we found that without MECR, mice can no longer cope with the cold and their brown fat fails, because MECR is needed to build protective lipids called plasmalogens that stabilize the mitochondria; adding these lipids back was enough to restore the cells. In this project we characterize how MECR-dependent lipids sustain thermogenesis and the crosstalk between mitochondria and other cell organelles, test plasmalogen supplementation as a possible therapy, and study common human MECR variants to define the impact on whole body metabolic health in mice and humans.