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Evidence from studies in rodents and in isolated adipocytes that agonists of the chemerin receptor CMKLR1 may be beneficial in the treatment of type 2 diabetes.

ABSTRACT: The literature is unclear on whether the adipokine chemerin has pro- or anti-inflammatory properties or plays any role in the aetiology of type 2 diabetes or obesity. To address these questions, and in particular the potential of agonists or antagonists of the chemerin receptor CMKLR1 in the treatment of type 2 diabetes and obesity, we studied the metabolic phenotypes of both male and female, CMKLR1 knockout and heterozygote mice. We also investigated changes in plasma chemerin levels and chemerin gene mRNA content in adipose tissue in models of obesity and diabetes, and in response to fasting or administration of the insulin sensitizing drug rosiglitazone, which also has anti-inflammatory properties. The effects of murine chemerin and specific C-terminal peptides on glucose uptake in wild-type and CMKLR1 knockout adipocytes were investigated as a possible mechanism by which chemerin affects the blood glucose concentration. Both male and female CMKLR1 knockout and heterozygote mice displayed a mild tendency to obesity and impaired glucose homeostasis, but only when they were fed on a high-fat died, rather than a standard low-fat diet. Obesity and impaired glucose homeostasis did not occur concurrently, suggesting that obesity was not the sole cause of impaired glucose homeostasis. Picomolar concentrations of chemerin and its C15- and C19-terminal peptides stimulated glucose uptake in the presence of insulin by rat and mouse wild-type epididymal adipocytes, but not by murine CMKLR1 knockout adipocytes. The insulin concentration-response curve was shifted to the left in the presence of 40 pM chemerin or its C-15 terminal peptide. The plasma chemerin level was raised in diet-induced obesity and ob/ob but not db/db mice, and was reduced by fasting and, in ob/ob mice, by treatment with rosiglitazone. These findings suggest that an agonist of CMKLR1 is more likely than an antagonist to be of value in the treatment of type 2 diabetes and to have associated anti-obesity and anti-inflammatory activities. One mechanism by which an agonist of CMKLR1 might improve glucose homeostasis is by increasing insulin-stimulated glucose uptake by adipocytes.

SUBMITTER: Wargent ET

PROVIDER: S-EPMC4327305 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Evidence from studies in rodents and in isolated adipocytes that agonists of the chemerin receptor CMKLR1 may be beneficial in the treatment of type 2 diabetes.

Wargent Edward T ET Zaibi Mohamed S MS O'Dowd Jacqueline F JF Cawthorne Michael A MA Wang Steven J SJ Arch Jonathan R S JR Stocker Claire J CJ Stocker Claire J CJ

PeerJ 20150205

The literature is unclear on whether the adipokine chemerin has pro- or anti-inflammatory properties or plays any role in the aetiology of type 2 diabetes or obesity. To address these questions, and in particular the potential of agonists or antagonists of the chemerin receptor CMKLR1 in the treatment of type 2 diabetes and obesity, we studied the metabolic phenotypes of both male and female, CMKLR1 knockout and heterozygote mice. We also investigated changes in plasma chemerin levels and chemer ...[more]

PMID: 25699203

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Project description: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.

Project description:Objective:To investigate the influences of exercise on the levels of chemerin and its receptor chemokine-like receptor (CMKLR1) in the peripheral metabolic organs of obesity and diabetes rats, and whether the mechanism is related to peroxisome proliferator activated receptor γ (PPARγ), a key modulator of glycolipid metabolism. Methods:Obesity rats induced by 8-week high fat diet (HFD) were randomly divided into obesity group (OB) and exercised obesity group (EOB) with 8 rats each group, and 40 diabetes rats established by 8-week HFD plus low dose of streptozotocin were randomly divided into 4 groups: diabetes group (DM), exercised diabetes group (EDM), exercised diabetes plus PPARγ agonist pioglitazone group (EDP), and exercised diabetes plus PPARγ antagonist GW9662 group (EDG). The rats in EOB, EDM, EDG and EDP groups participated in a 4-week moderate-intensity aerobic exercise on a treadmill with gradually increasing intensity, once a day and 6 days/week, and 30 min before each exercise EDP and EDG were administrated to the rats in EDP and EDG groups, respectively. Before and after 4-week exercise, glycolipid metabolism indexes, serum chemerin and the levels of chemerin and CMKLR1 in metabolic organs such as liver and gastrocnemius were investigated (not detecting adipose for no available perirenal adipose from DM rats). Results:(1) In addition to serum chemerin, the levels of chemerin and CMKLR1 in the liver and gastrocnemius of EOB and EDM rats were declined, accompanied with the improved glycolipid metabolism. (2) The decreased chemerin/CMKLR1 in the EDM rats were reversed by PPARγ antagonist GW9662 and further strengthened by PPARγ agonist pioglitazones. Conclusions:Besides serum chemerin, the levels of chemerin/CMKLR1 in the metabolic organs of obesity and diabetes rats were alleviated by exercise, which were likely to be associated with the improvement of glycolipid metabolism. Exercise-induced decrements of chemerin/CMKLR1 in the diabetes rats were mediated by PPARγ.

Dataset Information

Evidence from studies in rodents and in isolated adipocytes that agonists of the chemerin receptor CMKLR1 may be beneficial in the treatment of type 2 diabetes.

Publications

Evidence from studies in rodents and in isolated adipocytes that agonists of the chemerin receptor CMKLR1 may be beneficial in the treatment of type 2 diabetes.

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