Glucagon Receptor Signaling at White Adipose Tissue Does Not Regulate Lipolysis
ObjectiveAlthough the physiologic role of glucagon receptor signaling in the liver is well defined, the impact of glucagon receptor (Gcgr) signaling at white adipose tissue (WAT) continues to be debated. While numerous studies propose glucagon stimulates WAT lipolysis, we lack evidence that physiological concentrations of glucagon regulate WAT lipolysis. Glucagon receptor antagonists are proposed as a treatment to lower blood glucose in people with type 2 diabetes, yet concerns on how these treatments may affect lipid homeostasis have led to questions regarding the potential safety and efficacy of such therapeutics. Tight regulation of adipose tissue lipolysis is critical for whole body lipid homeostasis. In turn, we used WAT Gcgr knockout mice to determine if glucagon regulates lipolysis at WAT in the mouse. MethodsWe assessed the effects of fasting and acute exogenous glucagon administration in wildtype C57BL/6J and Gcgr Adipocyte+/+ vs GcgrAdipocyte-/- mice. Using an ex vivo lipolysis protocol, we further examined the direct effects of glucagon on physiologically (fasted) and pharmacologically stimulated lipolysis. ResultsAdipocyte Gcgr 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 non-esterified 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 Gcgr Adipocyte+/+ or GcgrAdipocyte-/- mice. Gcgr expression did not affect fasting-induced or isoproterenol-stimulated lipolysis from WAT explants. Moreover, glucagon receptor signaling at WAT does not affect body weight or glucose homeostasis in lean or DIO mice. ConclusionsWe have established that glucagon does not regulate WAT lipolysis, either directly or indirectly. 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.