The protein p85α is a regulatory subunit of phosphoinositide 3-kinases (PI3Ks). Some class I PI3K isoforms are involved in different levels of metabolic control as well as in systemic dysfunctions associated with obesity. The lack of p85α induces an increased insulin sensitivity in mice. Gomez-Hernandez and colleagues generated a mouse model lacking p85α in brown adipose tissue (BAT). Their data strongly suggest that under a high-fat diet, the loss of p85α in BAT improves thermogenic functionality and induces obesity resistance by increased insulin sensitivity and a nonfatty liver.