Serum Chemerin Levels Vary with Time of Day and Are Modified by Obesity and Tumor Necrosis Factor-α

Chemerin is an adipokine with important regulatory roles in adipogenesis. In humans, serum total chemerin (i.e. prochemerin plus chemerin) levels are positively associated with body mass index and metabolic syndrome. However, the mechanisms that increase serum chemerin concentration are unknown. We hypothesized that chronic low-grade inflammation that occurs in obesity promotes chemerin production by adipocytes. Consistent with this, TNF alpha treatment of 3T3-L1 adipocytes increased bioactive chemerin levels in the cell media as detected using a CMKLR1 cell-based bio-assay. This effect was blocked by the protein synthesis inhibitor cycloheximide and protein secretion inhibitor brefeldin A, indicating that TNF alpha may enhance prochemerin synthesis and secretion from adipocytes. In vivo, TNF alpha produced a time-dependent increase in serum total chemerin and bioactive chemerin. Bioactive chemerin was produced by primary mouse adipocytes and hepatocytes. Only primary adipocyte-derived chemerin was responsive to TNF alpha regulation implicating adipocytes as a potential source of elevated serum chemerin after TNF alpha exposure in vivo. In lean mice, serum total chemerin levels oscillated with peak levels occurring during daytime and trough levels at night. Comparatively, leptin-and leptin receptor-deficient obese mice, which have elevated adipose tissue expression of TNF alpha, displayed elevated serum total chemerin levels with an enhanced oscillatory pattern. In summary, our novel results identified TNF alpha as a positive regulator of adipocyte-derived chemerin. We corroborate the finding of elevated chemerin in obese humans by identifying elevated serum levels of total chemerin in two obese mouse models with a corresponding alteration in the rhythmic pattern of serum chemerin levels. (Endocrinology 151: 2590-2602, 2010)