Fatty acids promote uncoupled respiration via the ATP/ADP carrier in white adipocytes.

Adipocytes store energy as triglycerides, while mobilizing energy when needed via lipolysis. Triglyceride lipolysis releases fatty acids and glycerol into the circulation to fuel other tissues. However, a significant fraction of fatty acids released by lipolysis are retained within the white adipose tissue and handled by adipocytes. While some of these retained fatty acids are re-esterified in white adipocytes, the a substantial amount undergo oxidative metabolism via a pathway regulated by the nongenomic effects of STAT3. Here we report that fatty acids promote uncoupled oxidative metabolism in white adipocytes via the ATP/ADP carrier, contributing to thermogenesis and cold tolerance in obese thermoneutral-adapted mice, independent of brown adipose tissue and muscle activity. Our results suggest that uncoupled respiration in white adipocytes significantly contributes to whole-body energy expenditure and could be a promising target for obesity treatment.