The chemerin-CMKLR1 axis is functionally important for central regulation of energy homeostasis

Yun, H, Dumbell, R ORCID: https://orcid.org/0000-0002-8805-3777, Hanna, K, Bowen, J, McLean, SL, Kantamneni, S, Pors, K, Wu, Q-F and Helfer, G, 2022. The chemerin-CMKLR1 axis is functionally important for central regulation of energy homeostasis. Frontiers in Physiology, 13: 897105. ISSN 1664-042X

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Abstract

Chemerin is an adipokine involved in inflammation, adipogenesis, angiogenesis and energy metabolism, and has been hypothesized as a link between obesity and type II diabetes. In humans affected by obesity, chemerin gene expression in peripheral tissues and circulating levels are elevated. In mice, plasma levels of chemerin are upregulated by high-fat feeding and gain and loss of function studies show an association of chemerin with body weight, food intake and glucose homeostasis. Therefore, chemerin is an important blood-borne mediator that, amongst its other functions, controls appetite and body weight. Almost all studies of chemerin to date have focused on its release from adipose tissue and its effects on peripheral tissues with the central effects largely overlooked. To demonstrate a central role of chemerin, we manipulated chemerin signaling in the hypothalamus, a brain region associated with appetite regulation, using pharmacological and genetic manipulation approaches. Firstly, the selective chemerin receptor CMKLR1 antagonist α-NETA was administered i.c.v. to rats to test for an acute physiological effect. Secondly, we designed a short-hairpin-RNA (shRNA) lentivirus construct targeting expression of CMKLR1. This shRNA construct, or a control construct was injected bilaterally into the arcuate nucleus of male Sprague Dawley rats on high-fat diet (45%). After surgery, rats were maintained on high-fat diet for 2 weeks and then switched to chow diet for a further 2 weeks. We found a significant weight loss acutely and inhibition of weight gain chronically. This difference became apparent after diet switch in arcuate nucleus-CMKLR1 knockdown rats. This was not accompanied by a difference in blood glucose levels. Interestingly, appetite-regulating neuropeptides remained unaltered, however, we found a significant reduction of the inflammatory marker TNF-α suggesting reduced expression of CMKLR1 protects from high-fat diet induced neuroinflammation. In white and brown adipose tissue, mRNA expression of chemerin, its receptors and markers of adipogenesis, lipogenesis and brown adipocyte activation remained unchanged confirming that the effects are driven by the brain. Our behavioral analyses suggest that knockdown of CMKLR1 had an impact on object recognition. Our data demonstrate that CMKLR1 is functionally important for the central effects of chemerin on body weight regulation and neuroinflammation.

Item Type:	Journal article
Publication Title:	Frontiers in Physiology
Creators:	Yun, H., Dumbell, R., Hanna, K., Bowen, J., McLean, S.L., Kantamneni, S., Pors, K., Wu, Q.-F. and Helfer, G.
Publisher:	Frontiers Media
Date:	2 May 2022
Volume:	13
ISSN:	1664-042X
Identifiers:	Number Type 10.3389/fphys.2022.897105 DOI 1549453 Other
Rights:	Copyright © 2022 Yun, Dumbell, Hanna, Bowen, McLean, Kantamneni, Pors, Wu and Helfer. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Divisions:	Schools > School of Science and Technology
Record created by:	Laura Ward
Date Added:	26 May 2022 12:53
Last Modified:	06 Jun 2022 09:22
URI:	https://irep.ntu.ac.uk/id/eprint/46372

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