Crosstalk of hypothalamic chemerin, histamine, and AMPK in diet-and olanzapine-induced obesity in rats.

Abstract

AIM\nContradiction overwhelms chemerin link to feeding behavior. Neither the chemerin central role on appetite regulation nor its relation to hypothalamic histamine and AMPK is verified.\n\n\nMAIN METHODS\nFood intake, body weight and hypothalamic biochemical changes were assessed after a single intra-cerebroventricular or intraperitoneal injection (ip) (1\u202fμg/kg or 16\u202fμg/kg, respectively) or chronic ip administration (8\u202fμg/kg/day) of chemerin for 14 or 28\u202fdays. Hypothalamic neurobiochemical changes in chemerin/histamine/AMPK induced by either 8-week high fat diet (HFD) or food restriction were also investigated. To confirm chemerin-histamine, cross talks, these neurobiochemical changes were assessed under settings of H1-receptor agonism and/or antagonism by betahistine and/or olanzapine, respectively for 3\u202fweeks.\n\n\nKEY FINDINGS\nChemerin-injected rats exhibited anorexigenic behavior in both acute and chronic studies that was associated with a decreased AMPK activity in arcuate nucleus (ARC). However, with long-term administration, chemerin anorexigenic effect gradually ceased. Contrarily to food restriction, 8-week HFD increased ARC expression of chemerin and its receptor CMKLR1 reducing food intake via an interplay of H1-receptors and AMPK activity. Blockage of H1-receptors by olanzapine disrupted chemerin signaling pathway with increased AMPK activity augmenting food intake. These changes were reversed to normal by betahistine coadministration.\n\n\nSIGNIFICANCE\nChemerin is an anorexigenic adipokine, whose dysregulation is implicated in diet, and olanzapine-induced obesity through a histamine/AMPK axis in the ARC. Hypothalamic chemerin/CMKLR1 expression is a dynamic time-dependent response to changes in body weight and/or food intake. Targeting chemerin as a novel therapeutic approach against antipsychotic- or diet-induced obesity is worth to be further delineated.