Glucagon is an essential regulator of glucose and lipid metabolism that also promotes weight loss. We have shown that GCGR signaling increases fatty acid oxidation (FAOx) in primary hepatocytes and reduces liver triglycerides in DIO mice; however, the mechanisms underlying this aspect of glucagon biology remains unclear. Investigation of downstream GCGR targets elucidated potent and previously unknown regulation of liver leptin receptor (Lepr) expression. Intriguingly, we found GCGR agonism induces hepatic Lepr expression in vivo and in vitro. Liver leptin signaling is known to increase FAOx and decrease liver triglycerides, similar to glucagon action. Therefore, we hypothesized that glucagon increases hepatic LEPR, which is necessary for glucagon-mediated reversal of hepatic steatosis. Administration of the selective GCGR agonist IUB288 in both lean and diet-induced obese (DIO) mice increases both total hepatic Lepr (p<0.001) expression and the signaling isoform Lepr-b (p<0.05) in acute and chronic settings. In addition, Lepr-b increased in IUB288 treated primary hepatocytes (p<0.05), suggesting cell-autonomous regulation. Further, GCGR activation potentiates leptin-stimulated phosphorylation of AMPK (Thr172) in a dose-dependent manner, suggesting an increase in hepatic leptin sensitivity. Mice deficient for the hepatic leptin receptor (LeprΔliver) displayed increased hepatic triglycerides on a chow diet alone (p<0.001), which persisted in a DIO state, with no differences in body weight or composition. Surprisingly, chronic administration of IUB288 in DIO WT and LeprΔliver mice resulted in similar reductions of liver triglycerides. Glucagon also reduces plasma lipids during oral lipid challenge. Similar to liver triglycerides, there were no differences in response to IUB288 between WT and LeprΔliver mice. Together these data suggest that although hepatic glucagon and leptin signaling have similar lipid targets, these appear to be two distinct pathways.


S. Nason: None. T. Kim: None. J.P. Antipenko: None. B. Finan: Employee; Self; Novo Nordisk A/S. R. DiMarchi: Employee; Self; Novo Nordisk Inc. K.M. Habegger: Consultant; Self; Glyscend, Inc., Novo Nordisk Inc. Research Support; Self; Glyscend, Inc. Stock/Shareholder; Self; Glyscend, Inc.


National Institutes of Health (T32HL1053491, R011DK112934-01)

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