Endocrine Abstracts

Introduction: Adipose tissue-derived peptides, known as adipokines, act as key regulators of metabolic homeostasis, but little information is available on adipokine-mediated cross-talk with β-cells via islet GPCR interactions, nor whether this is altered in obesity. The expression profile of islet GPCR peptide ligand mRNAs in visceral adipose tissue from lean and diet-induced obese mice was therefore defined and the functional effects of Ccl4 on β-cells were characterised.

Methods: 155 islet GPCR ligand mRNAs were quantified by RT-qPCR in epididymal adipose tissue retrieved from 24-week-old C57BL/6 male mice fed either control (CD:10% fat) or high-fat diet (HFD:60% fat) for 16 weeks. The effects of Ccl4 on cell viability, proliferation and apoptosis in MIN6 β-cells were investigated using standard assays.

Results: 45 and 40 islet GPCR peptide ligand mRNAs were detectable in CD and HFD adipose tissue, respectively, and Ccl4 mRNA expression was significantly upregulated by HFD (11.13-fold increase vs control, P < 0.001, n = 5). Ccl4 (10-100ng/mL) did not significantly affect β-cell viability (% viable: control: 97.2±1.2; +10ng/ml Ccl4: 90.6±3.7; +50ng/ml Ccl4: 88.9±6.1; +100 ng/ml Ccl4: 85.2±6.0; ns, n = 4). Ccl4 stimulated concentration-dependent protective effects against palmitate-induced β-cell apoptosis (caspase-3/7 activities, % control: –palmitate: 100±6.2; +palmitate: 291.5±14.3; +10 ng/ml Ccl4: 222.7±13.6; +50ng/ml Ccl4: 197.5±12.7; +100ng/ml Ccl4: 195.1±9.7; P < 0.0001, n = 3) and protective effects were also observed in the presence of cytokines (caspase-3/7 activities, % control: –cytokines: 100±7.9; +cytokines: 595.2±37.0; +10ng/ml Ccl4: 502.8±18.0; +50ng/ml Ccl4: 497.8±19.5; +100ng/ml Ccl4: 469.1±24.5; P < 0.01, n = 3). Ccl4 significantly reduced serum-stimulated β-cell proliferation (BrdU incorporation, % control: 0% FBS: 100.0±4.9; 10% FBS: 176.1±6.5; +10ng/ml Ccl4: 162.0±7.9; +50ng/ml Ccl4: 156.7±9.5; +100ng/ml Ccl4: 129.8±5.3; P < 0.0001, n = 3).

Discussion: Visceral fat Ccl4 mRNA expression is significantly increased in obesity. Ccl4 exerts concentration-dependent anti-apoptotic and anti-proliferative actions at β-cells, providing evidence of adipokine-mediated regulation of β-cell function in obesity.