A Novel Role for Vasopressin in Fructose-Induced Metabolic Syndrome

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Vasopressin is classically considered as the antidiuretic hormone that mediates water reabsorption from the kidney and urinary concentration as a protection from dehydration. While it is known to increase blood pressure, increase serum glucose, and block fat oxidation, vasopressin is usually not considered as a mediator of obesity and metabolic syndrome. However, recent studies demonstrate that serum copeptin (a stable biomarker of vasopressin) is elevated in subjects with metabolic syndrome. Furthermore, our preliminary data indicate that dietary fructose increases vasopressin levels and that fructose-induced metabolic syndrome is mediated by the activation of vasopressin 1b (V1b) receptor and the down-regulation of vasopressin 1a (V1a) receptor in the liver. Based on these observations, we hypothesize that vasopressin plays a key deleterious role in driving fructose-induced obesity and metabolic syndrome. We propose three aims to test this hypothesis. Aim 1 will characterize the mechanisms whereby physiological and clinically relevant amounts of fructose stimulate vasopressin release and action including the determination of the onset of expression of vasopressin following fructose exposure, the determination of whether it is a direct or calorie-dependent effect and if it is mediated by the metabolism of fructose in the liver and/or in vasopressin-producing neurons of the hypothalamus. We will also characterize the molecular mechanisms for fructose induced production, transport, storage and release of vasopressin using hypothalamo-neurohypophyseal system (HNS) explants. Aim 2 will test whether vasopressin plays an important deleterious role in fructose-induced metabolic syndrome by two opposing approaches: by providing increased water intake (using hydrated gel) to suppress serum vasopressin levels, and by chronic infusion of vasopressin with osmotic pumps. This aim will also determine if the deleterious effect of vasopressin is mediated by its action on the V1b receptor using both V1b-/- mice and a V1b specific antagonist. We will also characterize the role of FGF21 in V1b-mediated fructose-induced metabolic syndrome. Aim 3 will test the hypothesis that hepatic V1a receptors are important in counter-regulating the deleterious effects from V1b activation by downregulating fructokinase metabolism, by a series of cell culture and animal studies including V1a forced expression and characterizing the response of V1a/V1b double knockout mice. In summary, the strength of our proposal is that we will identify new and clinically relevant mechanisms whereby fructose induces vasopressin release, the specific role of vasopressin in fructose-induced metabolic syndrome, and the opposite function of the V1a and V1b receptors in this process. Our studies will provide new insights into the mechanisms driving metabolic syndrome, and especially the interaction of water, vasopressin and fructose in this process.