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

Abstract

Aim: Contradiction overwhelms chemerin link to feeding behavior. Neither the chemerin central role on appetite regulation nor its relation to hypothalamic histamine and AMPK is verified.

Main methods: Food intake, body weight and hypothalamic biochemical changes were assessed after a single intra-cerebroventricular or intraperitoneal injection (ip) (1 μg/kg or 16 μg/kg, respectively) or chronic ip administration (8 μg/kg/day) of chemerin for 14 or 28 days. 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 crosstalk, these neurobiochemical changes were assessed under settings of H₁-receptor agonism and/or antagonism by betahistine and/or olanzapine, respectively for 3 weeks.

Key findings: Chemerin-injected rats exhibited anorexigenic behavior in both acute and chronic studies that was associated with a decreased AMPK activity in the 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 an increased AMPK activity, augmenting food intake. These changes were reversed to normal by betahistine coadministration.

Significance: Chemerin 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.

Keywords: Antipsychotics; Appetite; Arcuate nucleus; CMKLR1; H(1)-receptors.