Background

Fasting hyperglycemia co-morbidities (heart disease, neuropathy etc) can affect life expectancy and duration. Thus, characterizing novel peptides that ameliorate this condition may help improve quality of life. Adropin was identified by our laboratory in liver as a secreted factor that acts as nutrient sensor and regulates carbohydrate/lipid metabolism. Our previous findings indicated increased endogenous glucose production in global adropin knock-out mice, and that adropin reduced gluconeogenesis in primary cultured hepatocytes. The present study further investigated an interaction between adropin and glucagon signaling using liver-specific adropin knockout (LAdrKO) mice.

Methods

The adropin coding sequence in C57BL/6J (B6) genome was flanked by loxP-sites, with expression in hepatocytes targeted using Alb-Cre mice. A glucagon-tolerance test was performed using age-matched male LAdrKO and wild-type controls: food was removed for 1-h, and mice administered glucagon (250ug/kg BW ip). Blood glucose levels were monitored at 0, 1, 2 and 3 hours after injection (n=8/genotype/timepoint); liver, plasma were collected for gene and protein expression analysis.

Results

Surprisingly, blood glucose excursion during the glucagon tolerance test is reduced in LAdrKO (p<0.05). Several genes involved in glucose metabolism (Pck1, Gck, Fbp2) also exhibit altered responses, with elevated expression post-glucagon injection (p<0.01 or p<0.05). Plasma insulin levels are no different at baseline, but are higher after glucagon injection suggesting increases glucose production. While plasma glucagon levels are not significantly different, LAdrKO mice display enhanced activation of cAMP-dependent PKA at baseline.

Conclusions

Suppression of adropin expression in hepatocytes results in significant changes in the responses to exogenous glucagon. Adropin expressed in hepatocytes may function as a modulator of glucagon signaling.