ATGL is differentially required for adipocyte FABP4 secretionin vivoandex vivo

AbstractFatty 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 bothin vivoandin vitro. Here, we utilized adipocyte-specific deficiency of adipose triglyceride lipase (ATGL) in a mouse model (ATGLAdpKO) to evaluate the regulation of FABP4 secretion by lipolytic signals in the absence of actual lipolysisin vivo. Previously, lipolysis-induced FABP4 secretion was found to be significantly reduced upon pharmacological inhibition of ATGL, and from adipose tissue explants from ATGLAdpKOmice. Unexpectedly, upon activation beta-adrenergic receptors, ATGLAdpKOmice exhibited significantly higher levels of circulating FABP4 as compared to ATGLfl/flcontrolsin 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 ATGLAdpKOmice (ATGL/FABP4AdpKOor 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 ATGLAdpKOmice were indeed from the adipocytes. ATGLAdpKOmice 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 ATGLAdpKOmice compared to controls. Therefore, activity of a key enzymatic step of lipolysis mediated by ATGL,per se, is not required for stimulatedin vivoFABP4 secretion from adipocytes, which can be induced through sympathetic signaling.