Abstract
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 ofhyperglycemia, insulin resistanceandvisceral 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.
Highlights
Obesity is associated with insulin resistance and is an important risk factor for the development of type 2 diabetes (T2D)
CDKN2C mRNA expression in adipose tissue In subjects with T2D CDKN2C expression was down-regulated by 45% on mRNA level (p
CDKN2C mRNA expression was reduced in both subcutaneous adipose tissue (SAT) and omental AT (OAT) by 50% in overweight and by 75% in obese subjects, as compared to lean subjects (Figure 1D, F)
Summary
Obesity is associated with insulin resistance and is an important risk factor for the development of type 2 diabetes (T2D). Adipose tissue increases by a combination of increased adipocyte number (hyperplasia) or adipocyte size (hypertrophy) [1]. Increased adipocyte size is associated with metabolic impairments and adipose tissue dysfunction [2]. Independent of total body fat, increased visceral fat depots with increased waist-hip-ratio (WHR) are associated with insulin resistance, T2D, and cardiovascular disease, including hypertension and coronary heart disease [3,4,5]. Recruitment of precursor cells and differentiation of new adipocytes (adipogenesis) in the subcutaneous adipose tissue (SAT), rather than enlargement of existing adipocytes, would protect against obesity-associated metabolic complications [6]. Peroxisome Proliferator-Activated Receptor Gamma (PPAR-γ) agonists that promote adipocyte differentiation can normalise metabolic dysfunctions and reduce insulin resistance [7]
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