ATG7-expression and chemerin secretion are co-regulated in adipocytes

Background: In obese individuals, adipocyte endocrine function is affected by altered autophagy. In a recent genome-wide association study (GWAS) genetic variants in autophagy-related gene 7 (ATG7) correlated with serum chemerin (RARRES2) concentrations. Aims: To investigate a possible interplay between chemerin and ATG7, how it may relate to autophagy-mediated adipocyte dysfunction in obesity, and the functional relevance of genetic variants in ATG7. Methods: Adipose ATG7-mRNA expression and adiposity measures were available in 100 Caucasians and 83 Native Americans. The effect of a 12-week high-calorie diet on adipose RARRES2 and ATG7-expression was investigated in mice. In 3T3L1-adipocytes, the effect of ATG7-knockdown on chemerin expression and secretion was studied. The influence of single nucleotide polymorphisms (SNPs) in linkage disequilibrium with the tag-SNP from recent GWAS on ATG7-transcription and chemerin physiology were investigated using a luciferase assay. Results: ATG7-mRNA expression in human subcutaneous adipose tissue positively correlated with BMI, fat mass, body weight (r > 0.27, P < 0.01), and measures of adipocyte cell size (r > 0.42, P < 0.02). In mice fed a high-calorie diet, adipose ATG7-expression did not parallel an increase in RARRES2-expression. ATG7-knockdown in 3T3L1-adipocytes decreased chemerin secretion by 25% (P < 0.01; CI 0.6, 0.9). Rs2606729 in ATG7 was predicted to alter ATG7-transcription and induced higher luciferase activity in vitro (P < 0.0001; CI 2.6, 24.8). Conclusions: ATG7-mRNA expression in human adipose tissue relates to measures of adiposity. ATG7 regulates chemerin secretion from adipocytes in vitro supportive of a functional interplay between ATG7 and chemerin in autophagy-mediated adipocyte dysfunction.