Endocrine Abstracts

Chemerin is a newly discovered chemoattractant adipokine and is a natural ligand for the G protein coupled receptor CMKLR1. Its role in the regulation of energy metabolism and inflammation makes it a promising candidate for urgently needed pharmacological treatment strategies for obesity. To demonstrate a central role of chemerin, we manipulated chemerin signalling in the arcuate nucleus, a specific hypothalamic region associated with appetite regulation. We designed a short-hairpin-RNA (shRNA) lentivirus construct targeting expression of Cmklr1 and tested for efficiency to reduce expression of this receptor mRNA in vitro in characterised mouse NPY-AgRP hypothalamic cell lines. This shRNA construct or a control construct was injected bilaterally into the arcuate nucleus of adult Sprague Dawley rats on high-fat diet (45 % fat; n = 8 / group). After surgery, these rats were maintained on high fat diet for 2 weeks and then switched to chow diet for a further 2 weeks. The novel object recognition test was performed at 2 and 4 weeks following surgery. The rats were humanely killed at 28 days following surgery and tissues were collected (hypothalamus, white adipose tissue, brown adipose tissue, blood). We found a significant inhibition of weight gain of arcuate nucleus-Cmklr1 knockdown rats 28 days after injection, and this difference became apparent after the diet switch. Interestingly, this was not accompanied by a difference in blood glucose levels. Our behavioural analyses suggest that knockdown of Cmklr1 had an impact on object recognition. We investigated mRNA expression of neuropeptides and chemerin receptors in the hypothalamus, and mRNA expression of chemerin, its receptors, and markers of adipogenesis, lipogenesis and brown adipocyte activation in adipose tissues. Together our data demonstrate that Cmklr1 is functionally important for the central effects of chemerin on body weight regulation and implicate the chemerin-CMKLR1 axis in regulation of whole body metabolism and cognition.