(DCP004) CELLULAR COMMUNICATION NETWORK FACTOR 5 (CCN5) GENE DEFICIENCY CAUSES IMPROVED INSULIN SENSITIVITY AND GLUCOSE TOLERANCE IN DIET-INDUCED OBESITY IN MALE MICE

Background: Metabolic syndrome and diabetes mellitus are increasing rapidly in the last few years. Pancreas regeneration and replication of β- cells are some of the challenges that medical doctors and researchers face today. CCN5/WISP2 is a matricellular protein, the expression of which is under the regulation of Wnt signaling and IGF-1. Our initial characterization supports the notion that CCN5 promotes the proliferation and survival of pancreatic β-cells leading to metabolic benefits

METHODS AND RESULTS: To examine the e effect of endogenous CCN5 in metabolism and specifically in pancreatic islet and adipose tissue we characterized total CCN5 knockout mice and fed them either with a normal chow diet or a high-fat diet (60% kcal fat).
Contrary to previous findings, our CCN5 knockout mice, both male and female, exhibited no significant change in lean/fat mass, insulin sensitivity, or glucose tolerance when fed a chow diet, despite ~50% reductions in β-cell area and serum insulin level at 9 mo. Upon high-fat diet (HFD) feeding, CCN5 knockout mice gained similar amounts of weight as their wild-type counterparts (male 2.0 vs. 1.9-fold; female 2.7 vs. 2.4-fold) but demonstrated sexual dimorphic changes in insulin sensitivity. Interestingly, male knockout mice displayed significant improvements in insulin sensitivity and glucose tolerance, despite being equally obese as their wild-type controls. The smaller improvements in female knockout mice were not as significant. At the end of the 27 weeks of HFD, the increased levels of insulin in response to obesity, were 30-60% lower in knockout mice (both male and female) than in wild-type counterparts, also supporting improved insulin sensitivity. On the other hand, the amount of β-cell area in the pancreas is significantly decreased in CCN5 gene-deficient male mice indicating that CCN5 is required for β-cell growth.

Conclusion: Although our previous work has demonstrated that CCN5 stimulates pancreatic β-cell proliferation and survival, our assessment of the CCN5 knockout mice seems to indicate that the normal, endogenous expression of the CCN5 gene is rather detrimental to metabolic compensations against diet-induced obesity, especially in male mice. On the other hand, immunohistochemistry images indicate that CCN5 is required for β-cell growth. We are further characterizing molecular markers of -cell function and proliferation in knockout vs. wild-type mice.