190-LB: Dipeptidyl Peptidase-IV Promotes the Developmental Programming of Chronic Inflammatory Diseases due to Perinatal Exposure to Maternal Obesity

Perinatal exposure to maternal obesity promotes the development of chronic diseases such as cardiovascular (CVD) and metabolic diseases (T2DM) through a process known as developmental programming. The mechanisms of developmental programming are unclear. Dipeptidyl peptidase IV (DPP-4) is a pathogenic aminopeptidase that is upregulated in individuals with chronic diseases and its inhibitors are protective against T2DM and heart failure. DPP-4 can function as a membrane-anchored protein or as a soluble enzyme and can promote metainflammation and increased food intake. We found that DPP-4 enzymatic activity is upregulated over two-fold (P<0.05) in the cord blood of male offspring of women with obesity. Hence, we hypothesized that perinatal exposure to maternal obesity promotes the pathogenesis of cardiometabolic diseases through the activation of DPP-4. To test this hypothesis, we used a mouse model of maternal western style diet (WSD) feeding and found that offspring of WSD (Off-WSD) vs. regular diet (Off-RD) -fed mice have upregulated DPP-4 activity in plasma (two-fold, P<0.05) and PBMC (three-fold, P<0.05). This is concurrent with significantly impaired glucose tolerance, decreased insulin sensitivity, increased adiposity and hepatosteatosis. Systemic inhibition of DPP-4 with Sitagliptin alleviated these pathologies. Immune cells are a major source of plasma DPP-4 and we found that an allogeneic bone marrow transplantation (BMT) of Off-WSD bone marrow to lethally irradiated mice led to a significant increase in DPP-4 activity in plasma and PBMC compared to BMT with Off-RD bone marrow. This is concurrent with significantly increased adiposity, impaired glucose tolerance and decreased insulin sensitivity.

In summary, our findings suggest a pathogenic role of DPP-4, and specifically, immune-derived DPP-4, in the developmental programming of chronic inflammatory diseases due to perinatal exposure to maternal obesity.