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

• Published in: Translational research : the journal of laboratory and clinical medicine Vol. 242; pp. 105 - 121
• Main Authors: Pereira, MARIA J., VRANIC, MILICA, KAMBLE, PRASAD G., JERNOW, HENNING, KRISTÓFI, ROBIN, HOLBIKOVA, EMA, SKRTIC, STANKO, KULLBERG, JOEL, SVENSSON, MARIA K., HETTY, SUSANNE, ERIKSSON, JAN W.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-04-2022
• Subjects: Adipocytes - metabolism; ADIPOQ=Adiponectin; Adipose Tissue - metabolism; AT=Adipose tissue; CDKN2C=Cyclin-Dependent Kinase Inhibitor 2C; CEBPA=CCAAT Enhancer Binding Protein Alpha; Cyclin-Dependent Kinase Inhibitor p18 - metabolism; Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - metabolism; Endocrinology and Diabetes; Endokrinologi och diabetes; FASN=Fatty Acid Synthase; GWAS=Genome-wide association study; Humans; Insulin Resistance; Lipids; MRI=Magnetic resonance imaging; OAT=Omental adipose tissue; Obesity - genetics; Obesity - metabolism; Obesity, Abdominal; PPARG=Peroxisome Proliferator-Activated Receptor Gamma; RNP=Ribonucleoprotein; SAT=Subcutaneous adipose tissue; sgRNA=Single-guide RNA; SVF=Stromal vascular fraction; T2D=Type II diabetes; VAT=Visceral adipose tissue; WHR=Waist-hip ratio; sgRNA=Single-guide RNA; SAT=Subcutaneous adipose tissue; OAT=Omental adipose tissue; T2D=Type II diabetes; VAT=Visceral adipose tissue; ADIPOQ=Adiponectin; RNP=Ribonucleoprotein; WHR=Waist-hip ratio; AT=Adipose tissue; MRI=Magnetic resonance imaging; CDKN2C=Cyclin-Dependent Kinase Inhibitor 2C; CEBPA=CCAAT Enhancer Binding Protein Alpha; FASN=Fatty Acid Synthase; SVF=Stromal vascular fraction; PPARG=Peroxisome Proliferator-Activated Receptor Gamma; GWAS=Genome-wide association study
• ISSN: 1931-5244; 1878-1810; 1878-1810
• DOI: 10.1016/j.trsl.2021.12.003

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 also in paired SAT and omental AT (OAT) samples. Functional studies included adipocyte glucose uptake and lipolysis rates. CRISPR/Cas9 CDKN2C 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 measures of hyperglycemia, insulin resistance and visceral adiposity and positively correlated with expression of genes in several metabolic pathways, including insulin signaling and fatty acid and carbohydrate metabolism. CDKN2C protein was mainly expressed in adipocytes compared to stromal vascular cells, and its gene and protein expression was up-regulated during adipocyte differentiation. Knockdown 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, and this can further contribute to impairment of SAT lipid storage.