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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

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: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.

Project description:The chemokine chemerin is a novel adipokine involved in the regulation of energy metabolism but also female reproductive functions in mammals. Its effects on male fertility are less studied. Here, we investigated the involvement of chemerin in chicken male reproduction. Indeed, the improvement of the sperm of roosters is a challenge for the breeders since the sperm quantity and quality have largely decreased for several years. By using specific chicken antibodies, here we show that chemerin and its main receptor CMKLR1 (chemokine-like receptor 1) are expressed within the chicken testis with the lowest expression in adults as compared to the embryo or postnatal stages. Chemerin and CMKLR1 are present in all testicular cells, including Leydig, Sertoli, and germinal cells. Using in vitro testis explants, we observed that recombinant chicken chemerin through CMKLR1 inhibits hCG (human chorionic gonadotropin) stimulated testosterone production and this was associated to lower 3?HSD (3beta-hydroxysteroid dehydrogenase) and StAR (steroidogenic acute regulatory protein) expression and MAPK ERK2 (Mitogen-Activated Protein Kinase Extracellular signal-regulated kinase 2) phosphorylation. Furthermore, we demonstrate that chemerin in seminal plasma is lower than in blood plasma, but it is negatively correlated with the percentage of motility and the spermatozoa concentration in vivo in roosters. In vitro, we show that recombinant chicken chemerin reduces sperm mass and individual motility in roosters, and this effect is abolished when sperm is pre-incubated with an anti-CMKLR1 antibody. Moreover, we demonstrate that fresh chicken sperm treated with chemerin and used for artificial insemination (AI) in hen presented a lower efficiency in terms of eggs fertility for the four first days after AI. Taken together, seminal chemerin levels are negatively associated with the rooster fertility, and chemerin produced locally by the testis or male tract could negatively affect in vivo sperm quality and testosterone production through CMKLR1.

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.

Similar Datasets

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