A Novel Hypothalamic Action of Adropin: Regulation of Fluid Homeostasis

Abstract

Adropin, a recently described endogenous peptide encoded by the Energy Homeostasis Associated (Enho) gene, has been reported to be abundantly produced in the liver, smooth muscle and brain. While clinical and transgenic studies have identified adropin as a potent peripheral regulator of energy homeostasis, little is known about its action within the CNS. Therefore, the purpose of our study was to investigate a potential hypothalamic site of action to regulate ingestive behaviors. Male Sprague‐Dawley rats (200–250g) bearing an indwelling cannula in the right lateral ventricle were placed in metabolic cages with free access to lab chow and water (lights out 1800–0600h). During a two‐day habituation period, body weight and ad libitum water and food intakes were recorded. On the day of the experiment, rats were given a 2μl i.c.v. injection of vehicle or vehicle containing 0.3nmol, 1nmol, or 3nmol adropin at 1730h. Cumulative water and food intake was recorded in 30‐minute intervals until 1930h and again the next day at 0800h. While exogenous adropin had only a modest effect on food intake, we observed a profound inhibitory action on anticipatory water intake. Furthermore, after overnight water deprivation male rats administered 3nmol adropin i.c.v. exhibited significantly reduced water intake compared to vehicle treated controls. Importantly, using a deductive ligand receptor matching strategy (AJP 303:R941, 2012) we have identified a putative receptor for adropin. To demonstrate a functional relationship between our candidate receptor and adropin, rats were pretreated with i.c.v. injections of siRNA targeted against either eGFP as a control or our candidate receptor, followed by overnight dehydration and treatment with 3nmol adropin i.c.v. Cumulative water intake was recorded over the next four hours. Compromise of the endogenous candidate receptor significantly abrogated the adropin‐induced inhibition in dehydration‐stimulated water intake. Not only are these studies the first to demonstrate physiologic relevance of adropin as a central regulator of fluid homeostasis, but they provide compelling evidence that the adropin receptor is a formerly orphaned, G protein‐coupled receptor.Support or Funding InformationNIH RO1 HL121456