CDKN2C expression in adipose tissue is reduced in type II diabetes and central obesity : impact on adipocyte differentiation and lipid storage?

CDKN2C/p18 (Cyclin-Dependent Kinase Inhibitor 2C) is a cell growth regulator that controls cell cycle progression and has previously been associated with increased risk for type II diabetes (T2D) and reduced peripheral adipose tissue (AT) storage capacity. This study explored the role of CDKN2C in AT lipid and glucose metabolism in T2D. Expression of CDKN2C and other genes was analyzed by transcriptomics, or real-time PCR in subcutaneous AT (SAT) samples obtained from T2D and control subjects matched for sex, age and BMI and in paired SAT and omental AT (OAT). Functional studies included adipocyte glucose uptake and lipolysis rates, and CRISPR/Cas9 gene knockdown was performed in human preadipocytes to assess adipogenesis. CDKN2C mRNA expression in SAT and OAT was reduced in T2D and obese subjects, compared to controls. CDKN2C expression in SAT was inversely correlated with markers of hyperglycemia, insulin resistance and visceral adiposity and expression of genes in several metabolic pathways, including insulin signaling, fatty acid and carbohydrate metabolism. CDKN2C protein was mainly expressed in adipocytes compared to stromal vascular cells, and its gene and protein expression were up-regulated during adipocyte differentiation. Down-regulation of CDKN2C did not affect the percentage of differentiating cells compared to wild type cultures. However, CDKN2C knockdown cultures had significantly lower expression of differentiation markers CEBPA, ADIPOQ and FASN and transiently reduced lipid accumulation per adipocyte during differentiation. Our findings suggest that adipose CDKN2C expression might be reduced as a consequence of insulin resistance and obesity, which can further contribute to the impairment of SAT lipid storage