ATGL is differentially required for adipocyte FABP4 secretionin vivoandex vivo

Fatty acid binding protein 4 (FABP4) is linked with the pathogenesis of metabolic diseases, including diabetes and cardiovascular disease in both mice and humans. It has also been demonstrated that the levels of hormonal FABP4 are strongly associated with obesity, and secretion is stimulated under conditions of fasting and lipolysis both in vivo and in vitro . Here, we utilized adipocyte-specific deficiency of adipose triglyceride lipase (ATGL) in a mouse model (ATGL AdpKO ) to evaluate the regulation of FABP4 secretion by lipolytic signals in the absence of actual lipolysis in vivo . Previously, lipolysis-induced FABP4 secretion was found to be significantly reduced upon pharmacological inhibition of ATGL, and from adipose tissue explants from ATGL AdpKO mice. Unexpectedly, upon activation beta-adrenergic receptors, ATGL AdpKO mice exhibited significantly higher levels of circulating FABP4 as compared to ATGL fl/fl controls in vivo , with no corresponding increase in non-esterified free fatty acids or glycerol, confirming the lack of lipolysis. We also generated an additional model with adipocyte-specific deletion of FABP4 in the background of ATGL AdpKO mice (ATGL/FABP4 AdpKO or DKO) to evaluate the cellular source of circulating FABP4. In these animals, there was no evidence of lipolysis-induced FABP4 secretion, indicating that the elevated FABP4 hormone levels in the ATGL AdpKO mice were indeed from the adipocytes. ATGL AdpKO mice did not exhibit an increase in insulin secretion upon stimulation of lipolysis, but had a normal insulin response to glucose injection along with increased FABP4 secretion, suggesting the elevated FABP4 secretion is not due to lack of insulin. Inhibition of sympathetic signaling during lipolysis using hexamethonium significantly reduced FABP4 secretion in ATGL AdpKO mice compared to controls. Therefore, activity of a key enzymatic step of lipolysis mediated by ATGL, per se , is not required for stimulated in vivo FABP4 secretion from adipocytes, which can be induced through sympathetic signaling.