PSUN136 CCN5/WISP2 gene deficiency improves insulin sensitivity and glucose tolerance in diet-induced obesity, especially in male mice

Abstract

Abstract 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 [1]. Recently, the effects of CCN5 gene deficiency and ectopic, transgenic overexpression of CCN5 have been established. A systemic deficiency of CCN5 gene expression caused adipocyte hypertrophy, increased adipogenesis, and lipid accumulation, resulting in insulin resistance and glucose intolerance which are further exacerbated upon high-fat diet (HFD) feeding [2]. On the other hand, an adipocyte-specific and systemic overexpression of CCN5 caused an increase in lean body mass, improved insulin sensitivity, hyperplasia of cardiomyocytes and increased heart mass but decreased fasting glucose levels [3]. CCN5 is clearly a regulator of adipocyte proliferation and maturation, affecting lean/fat mass ratio and insulin sensitivity. In order to consolidate those findings and further establish the metabolic roles played by endogenous CCN5, we characterized CCN5 knockout mice fed in chow diet or 60% HFD. Unlike being reported [2], however, CCN5 knockout mice in our hands, both male and female, exhibited no significant change in lean/fat mass, insulin sensitivity, nor glucose tolerance when fed a chow diet, despite 2-5-fold elevations in serum insulin concentration. Upon 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 serum 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. 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 normal, endogenous expression of CCN5/WISP2 gene is rather detrimental to metabolic compensations against diet-induced obesity, especially in male mice. These observations are not only unexpected but also contradicts to a previous report [2]. We are further characterizing potential changes in pancreatic islet morphometry and molecular markers of beta-cell function, in knockout vs. wild-type mice after HFD feeding.