SAT045 Sexually Dimorphic Effects Of CCN5/WISP2 Overexpression On HFD-STZ Induced Diabetes And Glucose Intolerance

Disclosure: T. Alami: None. M. Zakikhani: None. V. Xega: None. J. Liu: None. Matricellular protein CCN5/WISP2 is a novel target of IGF-1 and WNT signaling within the pancreatic islets (1). Our previous works suggest that CCN5 promotes β-cell proliferation and survival via Akt/PKB and focal adhesion kinase. Last year, we reported sexually dimorphic effects of CCN5 knockout in glucose tolerance and insulin sensitivity in high-fat diet (HFD)-induced obesity, supporting a trophic role of endogenous CCN5 expression on pancreatic islets, albeit mostly in male mice (PSUN136, ENDO 2022). In order to further establish the in vivo effect of CCN5 in a gain-of-function approach, we assessed aP2-CCN5 transgenic mice which overexpress CCN5 in adipose tissues (2). These mice have increased serum level of CCN5, lean body mass and whole-body energy expenditure and hyperplastic adipose and cardiac tissues. Obese aP2-CCN5 mice remained insulin sensitive, glucose tolerant with a reduced insulin level. We first fed wild-type and transgenic mice, both male and female, a 60% HFD (Research Diets, D12492) for two weeks before administering 50 mg/kg streptozotocin (STZ) injections for 5 days, every other day. (i) In male mice, the HFD-STZ induced a steady elevation in glycemia from ∼9 to 25 mM in 7 weeks; CCN5 overexpression slowed down and curtailed the elevation to only 16 mM, and improved glucose tolerance at 48 days, suggesting a partial but significant protection from diabetes. (ii) Using the same dose of STZ, female wild-type mice exhibited only a slight elevation in glycemia from 8 to 12 mM. However, female aP2-CCN5 mice displayed a steady increase in glycemia to 18 mM and significantly impaired glucose tolerance at 16 and 48 days, suggesting rather worsening diabetes due to CCN5. In both male and female mice, there was no obvious difference in insulin sensitivity at 21 days nor in the overall weight loss caused by STZ injections. We are still analyzing the corresponding changes in serum insulin level and β-cell morphometry. Our results further support the notion that increased CCN5 level protects the β-cells, although only in male mice. The female environment, however, would abolish CCN5-induced protection. (1) Chowdhury S, Wang X, Srikant CB, Li Q, Fu M, Gong YJ, Ning G, Liu JL. IGF-I stimulates CCN5/WISP2 gene expression in pancreatic beta-cells, which promotes cell proliferation and survival against streptozotocin. Endocrinology. 2014; 155: 1629-1642. (2) Grunberg JR, Ho