JNK1 mediates serine phosphorylation of STAT3 in response to fatty acids released by lipolysis.
Academic Article
Overview
abstract
Adipocytes play a central role in energy balance and metabolic health by storing excess nutrients as triglycerides in white adipose tissue (WAT). During physiological stress, sympathetic activation triggers lipolysis, releasing fatty acids and glycerol to meet systemic energy demands. Lipolytic activation in white adipocytes also increases their rate of oxygen consumption. Phosphorylation of signal transducer and activator of transcription 3 (STAT3) at Ser727 is a key regulatory event in lipolysis-driven respiration. Here, we identify c-Jun N-terminal kinase 1 (JNK1) as the kinase responsible for this essential phosphorylation event and a key regulator of oxidative metabolism in lipolytic adipocytes. We show that fatty acids produced by lipolysis activate JNK, which phosphorylates lipid droplet-associated STAT3, leading to inhibition of glycerol-3-phosphate acyltransferase 3 (GPAT3) and suppression of fatty acid re-esterification. This shift in lipid handling promotes mitochondrial uncoupling and increases energy expenditure. Pharmacological inhibition of JNK1 markedly reduced lipolysis-driven respiration without altering the rate of lipolysis. The critical role of JNK1 in promoting respiration in lipolytic adipocytes was verified using genetic knockdown studies. Notably, canonical upstream MAP kinase kinases were not required for JNK1 activation, suggesting a noncanonical pathway that senses acute increases in intracellular fatty acid levels. Together, these findings identify JNK1 as a metabolic sensor linking intracellular fatty acid levels to STAT3-mediated oxidative metabolism in adipocytes, with potential implications for energy balance and metabolic disease.
