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

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.

A neuroendocrine role for chemerin in hypothalamic remodelling and photoperiodic control of energy balance.

Long-term and reversible changes in body weight are typical of seasonal animals. Thyroid hormone (TH) and retinoic acid (RA) within the tanycytes and ependymal cells of the hypothalamus have been implicated in the photoperiodic response. We investigated signalling downstream of RA and how this links to the control of body weight and food intake in photoperiodic F344 rats. Chemerin, an inflammatory chemokine, with a known role in energy metabolism, was identified as a target of RA. Gene expression of chemerin (Rarres2) and its receptors were localised within the tanycytes and ependymal cells, with higher expression under long (LD) versus short (SD) photoperiod, pointing to a physiological role. The SD to LD transition (increased food intake) was mimicked by 2 weeks of ICV infusion of chemerin into rats. Chemerin also increased expression of the cytoskeletal protein vimentin, implicating hypothalamic remodelling in this response. By contrast, acute ICV bolus injection of chemerin on a 12 h:12 h photoperiod inhibited food intake and decreased body weight with associated changes in hypothalamic neuropeptides involved in growth and feeding after 24 hr. We describe the hypothalamic ventricular zone as a key site of neuroendocrine regulation, where the inflammatory signal, chemerin, links TH and RA signaling to hypothalamic remodeling.

Effects of vaspin, chemerin and omentin-1 on feeding behavior and hypothalamic peptide gene expression in the rat.

Visceral adipose tissue-derived serpin (vaspin) improves glucose tolerance and insulin sensitivity in diet-induced obese mice. Chemerin may increase insulin sensitivity in adipose tissue and seems to be associated with several key aspects of metabolic syndrome. Decreased levels of omentin-1 are associated with increasing obesity and insulin resistance. Our study aimed to investigate the effects of vaspin, chemerin and omentin-1 acute administration on feeding and hypothalamic gene expression of peptides which play a key role in feeding regulation. 35 rats were injected into the arcuate nucleus (ARC) of the hypothalamus with either saline (n=8), vaspin (1µg/kg; n=9), chemerin (8µg/kg; n=9), or omentin-1 (8µg/kg; n=9). Food intake in the following 24h was recorded, thereafter rats were sacrificed. Total RNA was extracted from hypothalami and reverse transcribed to evaluate hypothalamic gene expression of agouti-related peptide (AgRP), neuropeptide Y (NPY), orexin-A, cocaine- and amphetamine-regulated transcript (CART), corticotrophin releasing hormone (CRH) and proopiomelanocortin (POMC), by real-time reverse transcription polymerase chain reaction. Compared to vehicle, vaspin injection significantly decreased feeding, while chemerin and omentin-1 had no effect in the tested dose. Vaspin treatment significantly decreased NPY and increased POMC gene expression. Chemerin treatment led to a significant increase of both AgRP and POMC gene expression. Omentin-1 treatment did not modify gene expression of the investigated peptides. Therefore, vaspin is an adipokine triggering anorectic pathways in the hypothalamus, where reduction of NPY and increase of POMC mRNA levels mediate feeding inhibition. Chemerin and omentin-1 have no effect on feeding in the tested dose.