The Chemerin-CMKLR1 Axis is Functionally important for Central Regulation of Energy Homeostasis

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.

Chemerin Forms: Their Generation and Activity

“…Photoperiodicity also affects chemerin expression in the rat hypothalamus where long days increase chemerin expression compared to short days, suggesting that this could influence energy balance and body weight [ 64 ]. This has been confirmed in rat experiments in which a shRNA that reduces chem1 mRNA was injected into the arcuate nucleus of the hypothalamus in rats, resulting in acute weight loss and the chronic inhibition of weight gain [ 65 ]. These data suggest that chemerin via chem1 exerts its effects on energy homeostasis via central regulation as well as in the periphery [ 66 , 67 ].…”

The role of chemerin in the regulation of cGAS‐STING pathway in gestational diabetes mellitus placenta

“…15 While it is still debated how chemerin controls insulin sensitivity and glucose homeostasis through its receptors. 16 In our previous research, DsbA-L protein expression was found to be moderately upregulated with raised chemerin concentration. 17 Nevertheless, it is unclear how chemerin interacts with DsbA-L and whether chemerin has any influence on the cGAS-STING pathway.…”

“…Adipokine chemerin, encoded by retinoic acid receptor responder 2 ( RARRES2 ) gene, is also a multifaceted biomolecule which is involved in GDM 15 . While it is still debated how chemerin controls insulin sensitivity and glucose homeostasis through its receptors 16 . In our previous research, DsbA‐L protein expression was found to be moderately upregulated with raised chemerin concentration 17 .…”

The Hidden Role of Non-Canonical Amyloid β Isoforms in Alzheimer’s Disease

“…Chemokine-like receptor 1 ( CMKLR1 ) is a G-protein-coupled receptor that is mainly expressed in white adipose tissue and immune cells such as microglia, macrophages, and dendritic cells [ 390 ]. CMKLR1 interacts with endogenous ligands such as the adipokine Chemerin, and helps to modulate metabolic processes and cell proliferation, especially during glucose processing, adipogenesis, and angiogenesis [ 390 ].…”

“…Chemokine-like receptor 1 ( CMKLR1 ) is a G-protein-coupled receptor that is mainly expressed in white adipose tissue and immune cells such as microglia, macrophages, and dendritic cells [ 390 ]. CMKLR1 interacts with endogenous ligands such as the adipokine Chemerin, and helps to modulate metabolic processes and cell proliferation, especially during glucose processing, adipogenesis, and angiogenesis [ 390 ]. In immune cells, CMKLR1 induces chemotaxis and pro-inflammatory cascades, but is also involved in anti-inflammatory signaling through interactions with pro-resolving ligands such as Resolvin E1 [ 391 ].…”