Glucagon receptor signaling at white adipose tissue does not regulate lipolysis.

Although the physiological role of glucagon receptor signaling in the liver is well defined, the impact of glucagon receptor (Gcgr) signaling on white adipose tissue (WAT) continues to be debated. Although numerous studies propose that glucagon stimulates WAT lipolysis, we lack evidence that physiological concentrations of glucagon regulate WAT lipolysis. In turn, we performed studies in both wild-type and WAT <i>Gcgr</i> knockout mice to determine if glucagon regulates lipolysis at WAT in the mouse. We assessed the effects of fasting and acute exogenous glucagon administration in wild-type C57BL/6J and <i>Gcgr</i>^Adipocyte+/+ versus <i>Gcgr</i>^Adipocyte-/- mice. Using an ex vivo lipolysis protocol, we further examined the direct effects of glucagon on physiologically (fasted) and pharmacologically stimulated lipolysis. We found that adipocyte <i>Gcgr</i> expression did not affect fasting-induced lipolysis or hepatic lipid accumulation in lean or diet-induced obese (DIO) mice. Acute glucagon administration did not affect serum nonesterified fatty acids (NEFA), leptin, or adiponectin concentration, but did increase serum glucose and FGF21, regardless of genotype. Glucagon did not affect ex vivo lipolysis in explants from either <i>Gcgr</i>^Adipocyte+/+ or <i>Gcgr</i>^Adipocyte-/- mice. <i>Gcgr</i> expression did not affect fasting-induced or isoproterenol-stimulated lipolysis from WAT explants. Moreover, glucagon receptor signaling at WAT did not affect body weight or glucose homeostasis in lean or DIO mice. Our studies have established that physiological levels of glucagon do not regulate WAT lipolysis, either directly or indirectly. Given that glucagon receptor agonism can improve dyslipidemia and decrease hepatic lipid accumulation, it is critical to understand the tissue-specific effects of glucagon receptor action. Unlike the crucial role of hepatic glucagon receptor signaling in maintaining glucose and lipid homeostasis, we observed no metabolic consequence of WAT glucagon receptor deletion.<b>NEW &amp; NOTEWORTHY</b> It has been postulated that glucagon stimulates lipolysis and fatty acid release from white adipose tissue. We observed no metabolic effects of eliminating or activating glucagon receptor signaling at white adipose tissue.