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.


K. Montaniel: None. M.S. Bucher: None. A. Maloyan: None.


National Institutes of Health; Oregon Health & Science University

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