ABSTRACT
Although various function of chemerin have been suggested, its physiological role remains to be elucidated. Here we show that chemerin-deficient mice are glucose intolerant irrespective of exhibiting reduced macrophage accumulation in adipose tissue. The glucose intolerance was mainly due to increased hepatic glucose production and impaired insulin secretion. Chemerin and its receptor ChemR23 were expressed in ß-cell. Studies using isolated islets and perfused pancreas revealed impaired glucose-dependent insulin secretion (GSIS) in chemerin-deficient mice. Conversely, chemerin transgenic mice revealed enhanced GSIS and improved glucose tolerance. Expression of MafA, a pivotal transcriptional factor for ß-cell function, was downregulated in chemerin-deficient islets and a chemerin-ablated ß-cell line and rescue of MafA expression restored GSIS, indicating that chemerin regulates ß-cell function via maintaining MafA expression. These results indicate that chemerin regulates ß-cell function and plays an important role in glucose homeostasis in a tissue-dependent manner.
Subject(s)
Chemotactic Factors/physiology , Insulin-Secreting Cells/physiology , Intercellular Signaling Peptides and Proteins/physiology , Adipose Tissue/pathology , Adipose Tissue/physiopathology , Animals , Cell Line , Chemokines , Chemotactic Factors/antagonists & inhibitors , Chemotactic Factors/deficiency , Chemotactic Factors/genetics , Diet, High-Fat/adverse effects , Gene Knockdown Techniques , Glucose Tolerance Test , Insulin/metabolism , Insulin Secretion , Insulin-Secreting Cells/metabolism , Intercellular Signaling Peptides and Proteins/deficiency , Intercellular Signaling Peptides and Proteins/genetics , Macrophages/pathology , Maf Transcription Factors, Large/genetics , Maf Transcription Factors, Large/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Receptors, Chemokine , Receptors, G-Protein-Coupled/antagonists & inhibitors , Receptors, G-Protein-Coupled/genetics , Receptors, G-Protein-Coupled/metabolismABSTRACT
To explore a novel adipokine, we screened adipocyte differentiation-related gene and found that TIG2/chemerin was strongly induced during the adipocyte differentiation. Chemerin was secreted by the mature 3T3-L1 adipocytes and expressed abundantly in adipose tissue in vivo as recently described. Intriguingly, the expression of chemerin was differently regulated in the liver and adipose tissue in db/db mice. In addition, serum chemerin concentration was decreased in db/db mice. Chemerin and its receptor/ChemR23 were expressed in mature adipocytes, suggesting its function in autocrine/paracrine fashion. Finally, chemerin potentiated insulin-stimulated glucose uptake concomitant with enhanced insulin signaling in the 3T3-L1 adipocytes. These data establish that chemerin is a novel adipokine that regulates adipocyte function.
Subject(s)
Adipocytes/metabolism , Chemotactic Factors/metabolism , Glucose/metabolism , Insulin/metabolism , Intercellular Signaling Peptides and Proteins/metabolism , Signal Transduction , 3T3-L1 Cells , Adipocytes/cytology , Adipocytes/drug effects , Adipose Tissue/drug effects , Adipose Tissue/metabolism , Animals , Antibody Specificity/drug effects , COS Cells , Cell Differentiation/drug effects , Chemokines , Chemotactic Factors/genetics , Chemotactic Factors/pharmacology , Chlorocebus aethiops , Culture Media , Gene Expression Profiling , Gene Expression Regulation/drug effects , Humans , Intercellular Signaling Peptides and Proteins/genetics , Intercellular Signaling Peptides and Proteins/pharmacology , Liver/drug effects , Liver/metabolism , Male , Mice , Mice, Inbred C57BL , Signal Transduction/drug effectsABSTRACT
Accumulating evidence suggests an association between obesity and adipose tissue inflammation. Chemokines are involved in the regulation of inflammation status. Chemokine (C-X-C motif) ligand 14 (CXCL14) is known to be a chemoattractant for monocyte and dendritic cells. Recently, it was reported that CXCL14-deficient mice show resistance to high-fat diet-induced obesity. In this study, we identified CXCL14 as a growth hormone (GH)-induced gene in HepG2 hepatoma cells. Substantial in vivo expression of CXCL14 was detected in the adipose tissue and liver. Its expression and secretion were strikingly increased by insulin administration and high-fat diet. Intriguingly, incubation of 3T3-L1 adipocytes with CXCL14 stimulated insulin-dependent glucose uptake. Further, this effect was associated with enhanced insulin signaling. CXCL14 enhanced the insulin-induced tyrosine phosphorylation of insulin receptors and insulin receptor substrate-1. These results suggest that CXCL14 plays a causal role in high-fat diet-induced obesity.
