GPR109a Signaling Alters the Hepatic Response to Fasting

Abstract

Elevated hepatic ketogenesis and gluconeogenesis are integral to the metabolic adaptation to fasting. The increase in ketone body production allows for feedback inhibition of adipose tissue lipolysis through Gαi coupled GPR109a, the β‐OH butyrate receptor. To better understand the role of this feedback we investigated the hepatic metabolic response to fasting in sibling GPR109a +/+ and −/− mice that were injected every 2 hours for 8 hours with either saline (0.1 ml/10 g body weight) or niacin (100 mg/kg in 0.1 ml saline/10 g body weight), a non‐metabolizable GPR109a agonist. In wild type mice, niacin completely eliminated the rise in serum NEFAs during a fast and significantly (p<.05) inhibited PPARα mRNA upregulation. This muted response in PPARα is important, because hepatic PPARα is integral to the upregulation of ketogenic and gluconeogenic enzymes that support the metabolic demands of fasting. Accordingly, fasting serum β‐OH‐butyrate concentrations were suppressed by niacin (p<.01), indicating sub‐maximal ketogenesis. Interestingly, GPR109a null mice do not elevate serum NEFAs and less robustly increase hepatic PPARα mRNA during a fast. Yet, fasting increases G6Pase and PEPCK mRNA expression more robustly in GPR109a null than in wildtype mice. Given that G6Pase and PEPCK expression are regulated by cAMP response elements, further studies should examine the role of hepatic GPR109a Gαi signaling in antagonizing glucagon Gαs mediated transcription of these enzymes. These studies establish that adipose lipolysis is necessary to recruit a full‐strength hepatic adaptation to fasting, and that gluconeogenesis and ketogenesis are controlled by a complex coordinated fasting response including feedback through GPR109a.