Chemerin, a Novel Peroxisome Proliferator-activated Receptor γ (PPARγ) Target Gene That Promotes Mesenchymal Stem Cell Adipogenesis

Abstract

Chemerin is an adipocyte-secreted protein that regulates adipogenesis and the metabolic function of mature adipocytes via activation of chemokine-like receptor 1 (CMKLR1). Herein we report the interaction of peroxisome proliferator-activated receptor ␥ (PPAR␥) and chemerin in the context of adipogenesis. Knockdown of chemerin or CMKLR1 expression or antibody neutralization of secreted chemerin protein arrested adipogenic clonal expansion of bone marrow mesenchymal stem cells (BMSCs) by inducing a loss of G 2 /M cyclins (cyclin A2/B2) but not the G 1 /S cyclin D2. Forced expression of PPAR␥ in BMSCs did not completely rescue this loss of clonal expansion and adipogenesis following chemerin or CMKLR1 knockdown. However, forced expression and/or activation of PPAR␥ in BMSCs as well as non-adipogenic cell types such as NIH-3T3 embryonic fibroblasts and MCA38 colon carcinoma cells significantly induced chemerin expression and secretion. Sequence analysis revealed a putative PPAR␥ response element (PPRE) sequence within the chemerin promoter. This PPRE was able to confer PPAR␥ responsiveness on a heterologous promoter, and mutation of this sequence abolished activation of the chemerin promoter by PPAR␥. Chromatin immunoprecipitation confirmed the direct association of PPAR␥ with this PPRE. Treatment of mice with rosiglitazone elevated chemerin mRNA levels in adipose tissue and bone marrow coincident with an increase in circulating chemerin levels. Together, these findings support a fundamental role for chemerin/CMKLR1 signaling in clonal expansion during adipocyte differentiation as well as a role for PPAR␥ in regulating chemerin expression. Peroxisome proliferator-activated receptor ␥ (PPAR␥)3 is a ligand-activated transcription factor belonging to the nuclear hormone receptor gene superfamily (1, 2). This nuclear receptor is generally considered as a master regulator of adipogenesis as no other single factor is known to induce adipocyte differentiation in the absence of PPAR␥ (1-4). PPAR␥ has also been implicated in the regulation of numerous genes in the mature adipocyte, including those encoding adipocyte-derived signaling proteins (adipokines), which have a variety of hormone-like actions to regulate diverse physiological processes (5-9). Altered synthesis and secretion of adipokines have been implicated as a factor contributing to an increased risk for the development of a number of obesity-related comorbidities, including type 2 diabetes, inflammation, and cardiovascular disease (10). For example, adiponectin is a key adipokine with antiinflammatory, antiatherogenic, and insulin-sensitizing properties (11, 12). Circulating adiponectin levels are commonly decreased with obesity and insulin resistance (11,13,14). PPAR␥ is a positive regulator of adiponectin gene expression, and promotion of adiponectin synthesis and secretion by PPAR␥ agonists such as thiazolidinediones is believed to be an important aspect of the clinical benefit of this class of insulinsensitizing drugs (5).Chemerin is a secreted protein that i...

The simulated microgravity enhances multipotential differentiation capacity of bone marrow mesenchymal stem cells

“…Previous research suggested that the physiologic role of PPARc2 is to regulate development of the adipose lineage in response to endogenous lipid activators and that this factor may serve to link the process of adipocyte differentiation to systemic lipid metabolism (Muruganandan et al 2011). So we have chosen the PPARc2 as an adipogenic differentiation marker of BMSCs.…”

NOS1AP Functionally Associates with YAP To Regulate Hippo Signaling

“…A thymidine incorporation assay was used to analyze the serum-free or serum-induced proliferation of YFP-or YFP-NOS1APa-expressing cells as described previously (21,22). The incorporation of 1 Ci/ml radioactive [methyl-3 H]thymidine (Perkin-Elmer) into cellular DNA during a 15-min pulse time was quantified by liquid scintillation counting.…”

Hepatic chemerin mRNA in morbidly obese patients with nonalcoholic fatty liver disease

“…Several studies indicated altered chemerin levels or hepatic chemerin expression in chronic liver diseases of different origin, including NAFLD and chronic hepatitis C (CHC) [5,19,20,21,22,23,24,25]. Chemerin acts by binding the G protein-coupled receptor, chemokine receptor-like 1 (CMKLR1) (also known as chemerin receptor 23 (ChemR23)) [7,26], expressed by a variety of cells [26,27,28,29]. CMKLR1 was highly abundant in the liver and is expressed by primary human hepatocytes, hepatic stellate cells, Kupffer cells, and bile duct cells [30].…”