ABSTRACT
Rising temperatures resulting from climate change will increase the incidence of heat stress, negatively impacting the labor force and food animal production. Heat stress elevates circulating ß-OH butyrate, which induces vasodilation through GPR109a. Interestingly, both heat stress and intraperitoneal ß-OH butyrate administration induce hypophagia. Thus, we aimed to investigate the role of ß-OH butyrate in heat stress hypophagia in mice. We found that niacin, a ß-OH butyrate mimetic that cannot be oxidized to generate ATP, also reduces food intake. Interestingly, the depression in food intake as a result of 8-h intraperitoneal niacin or 48-h heat exposure did not result from changes in hypothalamic expression of orexigenic or anorexigenic signals (AgRP, NPY, or POMC). Genetically eliminating GPR109a expression did not prevent the hypophagic response to heat exposure, intraperitoneal ß-OH butyrate (5.7 mmol/kg), or niacin (0.8 mmol/kg). Hepatic vagotomy eliminated the hypophagic response to ß-OH butyrate and niacin but did not affect the hypophagic response to heat exposure. We subsequently hypothesized that the hypophagic response to heat stress may depend on direct effects of ß-OH butyrate at the central nervous system: ß-OH butyrate induced hormonal changes (hyperinsulinemia, hypercorticosteronemia, and hyperleptinemia), or gene expression changes. To test these possibilities, we blocked expression of hepatic hydroxyl methyl glutaryl CoA synthase II (HMGCS2) to prevent hepatic ß-OH butyrate synthesis. Mice that lack HMGCS2 maintain a hypophagic response to heat stress. Herein, we establish that the hypophagia of heat stress is independent of GPR109a, the hepatic vagus afferent nerve, and hepatic ketone body synthesis.
Subject(s)
3-Hydroxybutyric Acid/pharmacology , Eating , Heat Stress Disorders/pathology , Hot Temperature/adverse effects , Receptors, G-Protein-Coupled/metabolism , Receptors, Nicotinic/metabolism , Animals , Ketone Bodies/biosynthesis , Liver/innervation , Liver/physiology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Niacin/pharmacology , Receptors, G-Protein-Coupled/agonists , Receptors, G-Protein-Coupled/genetics , Receptors, Nicotinic/genetics , Vagus Nerve/physiology , Vitamin B Complex/pharmacologyABSTRACT
Non-alcoholic fatty liver disease can result in changes to drug metabolism and disposition potentiating adverse drug reactions. Furthermore, arsenite exposure during development compounds the severity of diet-induced fatty liver disease. This study examines the effects of arsenite potentiated diet-induced fatty liver disease on hepatic transport in male mice. Changes were detected for Mrp2/3/4 hepatic transporter gene expression as well as for Oatp1a4/2b1/1b2. Plasma concentrations of Mrp and Oatp substrates were increased in arsenic exposure groups compared with diet-only controls. In addition, murine embryonic hepatocytes and adult primary hepatocytes show significantly altered transporter expression after exposure to arsenite alone: a previously unreported phenomenon. These data indicate that developmental exposure to arsenite leads to changes in hepatic transport which could increase the risk for ADRs during fatty liver disease.
