JNK mediates serine phosphorylation of STAT3 in response to fatty acids released by lipolysis.
Overview
abstract
Adipocytes play an essential role in energy balance and metabolic health. Excess nutrients are stored within the white adipose tissue (WAT) as triglycerides. Energetic demand is communicated to the adipocyte by the sympathetic nervous system. Catecholamines released by nerve terminals in the adipose tissue promote lipolysis, a process in which triglycerides are broken down into fatty acids and glycerol. Lipolytic activation of white adipocytes is associated with an increase in the rate of oxygen consumption. This lipolysis induced respiration requires phosphorylation of signal transducer and activator of transcription 3 (STAT3) at Ser727. This study identifies c-Jun N-terminal kinase 1 (JNK1) as the kinase responsible for this critical phosphorylation event, and thus a key regulator of lipolysis-driven oxidative metabolism. We demonstrate that JNK1 is activated in response to intracellular fatty acids released during lipolysis and phosphorylates lipid droplet-associated STAT3, leading to inhibition of glycerol-3-phosphate acyltransferase 3 (GPAT3) and suppression of fatty acid re-esterification. This mechanism promotes uncoupled mitochondrial respiration, increasing energy expenditure. Inhibition of JNK1 attenuated oxidative metabolism without affecting the rate of lipolysis. The MAP kinase cascade upstream of JNK1 in lipolytic adipocytes remains unclear. Neither apoptosis signal-regulating kinase 1 (ASK1) nor mitogen-activated protein kinase kinases 4/7 (MKK4/7) appear to be required. Our findings suggest that JNK1 functions as a metabolic sensor in adipocytes, activating oxidative metabolism through STAT3 phosphorylation in response to fatty acids, with implications for energy balance and obesity-related metabolic regulation.
