Glucagon receptor signaling at white adipose tissue does not regulate lipolysis

Abstract

Although 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. In turn, we performed studies in both wildtype and WAT Gcgr 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 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. We found that adipocyte 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 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.

Evaluation of commercially available glucagon receptor antibodies and glucagon receptor expression

“…It has been suggested that glucagon increases blood flow, lipolysis, glucose uptake and oxygen consumption in white and BAT 29 – 31 . Studies in mouse and humans have not revealed a lipolytic effect of glucagon 27 , 32 whereas this may occur in rats 33 . In the present study we found GCGR staining of preadipocytes and BAT, while no WAT was stained, using antibody no.…”

“…There are ongoing controversies about GCGR expression in adipose tissue 27 . Localization of the GCGR has been reported for both white and BAT 5 , 28 , predominantly based on the identification of GCGR mRNA transcripts 1 , 4 .…”

Distinct physiological characteristics and altered glucagon signaling in GHRH knockout mice: Implications for longevity

“…In GHdeficient mice however, brown adipose tissue is considerably more metabolically active as mRNA transcripts for key thermogenic and lipolytic genes are significantly elevated, and brown adipose tissue removal normalizes many metabolic features in these mice (Darcy et al, 2016). Increased sensitivity for glucagon in brown adipose or white adipose tissue may also explain the heightened light-cycle lipid oxidation rate we observed, as glucagon receptor activity appears to be dispensable for white-adipose lipolysis (Vasileva et al, 2022), however, the enhanced metabolic rate of brown adipose or white adipose tissue (Darcy et al, 2020) in GH-deficient mice may render physiological relevance to this pathway. Indeed, further study is necessary to determine if glucagon receptor action in adipose tissue is relevant in these animals.…”

Unveiling the dynamics of acetylation and phosphorylation in SGBS and 3T3-L1 adipogenesis

“… 59 Even though the glucagon receptor was found expressed in adipocytes from rat 60 and human liposarcoma, 61 physiological levels of glucagon did not show an effect on lipolysis in murine WAT. 62 Thus, hepatic glucagon signaling is relying on phosphorylation to mediate fed-state appropriate blood glucose levels, only with peripheral mechanisms acting in adipocytes. Although overall trends in the phosphoproteome agree between SGBS and 3T3-L1 cells, the species and cell line-specific differences seem more pronounced than for the adipocytes acetylomes.…”