Endocrine Abstracts

Obesity is associated with increased and dysfunctional white adipose mass. In the past, pharmacological approaches have not yielded significant results in terms of stable weight loss. Glucagon-like peptide 1 receptor (GLP-1R) agonists (GLP-1RA) used for the treatment of type 2 diabetes have more recently been proposed as anti-obesity drugs due to their relevant effects on weight loss. Furthermore, dual agonists engaging both GLP-1R and glucagon receptor (GCGR) are under investigation for their marked effects on weight loss. However, the mechanisms underlying such effects still need to be clarified. Our group has recently demonstrated that liraglutide and GLP-1 interfere with the proliferative and differentiation ability of human adipose precursors, supporting a peripheral action of GLP-1RA on weight loss. In the present study, we investigated glucagon activity in an in vitro model of primary human adipose-derived stem cells (ASCs). Glucagon significantly inhibited ASC proliferation, in a dose and time-dependent manner, with a maximal effect at 3 days of culture (14.0%, 25.2% and 37.1% for 1-10-100 nM glucagon, respectively, P<0.005 ANOVA, n=5). When added during in vitro-induced adipogenesis, glucagon (1-10-100 nM) significantly reduced intracellular lipid accumulation evaluated by specific intracellular lipid staining (−20%, −31%, −27%, P<0.001, ANOVA, n=5) and expression of mature adipocyte markers FABP4 (−49%, 73%, 62%, P<0.001 ANOVA, n=5) and HSL (46%, 54%, 37%, P<0.001 ANOVA, n=5), respectively. Notably, the inhibitory effect of glucagon on both cell proliferation and adipogenesis was reverted by specific GLP-1R (exendin-9) and GCGR (des-His1-Glu9-glucagon (1–29)) antagonists. In conclusion, we demonstrated a direct inhibitory action of glucagon on the proliferation and differentiation ability of human adipose precursors, which seems to involve both GLP-1R and GCGR present on ASCs. In addition to the previously demonstrated lypolitic activity of glucagon on the mature adipocyte, our data suggest that the adipose stem compartment also is a target of glucagon, possibly contributing to the weight loss obtained with the dual activity molecules.