Dipeptidyl peptidase IV inhibition delays developmental programming of obesity and metabolic disease in male offspring of obese mothers

Abstract

Maternal obesity programs the offspring to metabolic diseases later in life; however, the mechanisms of programming are yet unclear, and no strategies exist for addressing its detrimental transgenerational effects. Obesity has been linked to dipeptidyl peptidase IV (DPPIV), an adipokine, and treatment of obese individuals with DPPIV inhibitors has been reported to prevent weight gain and improve metabolism. We hypothesized that DPPIV plays a role in maternal obesity-mediated programming. We measured plasma DPPIV activity in human maternal and cord blood samples from normal-weight and obese mothers at term. We found that maternal obesity increases maternal and cord blood plasma DPPIV activity but only in male offspring. Using two non-human primate models of maternal obesity, we confirmed the activation of DPPIV in the offspring of obese mothers. We then created a mouse model of maternal high-fat diet (HFD)-induced obesity, and found an early-life increase in plasma DPPIV activity in male offspring. Activation of DPPIV preceded the progression of obesity, glucose intolerance and insulin resistance in male offspring of HFD-fed mothers. We then administered sitagliptin, DPPIV inhibitor, to regular diet (RD)- and HFD-fed mothers, starting a week prior to breeding and continuing throughout pregnancy and lactation. We found that sitagliptin treatment of HFD-fed mothers delayed the progression of obesity and metabolic diseases in male offspring and had no effects on females. Our findings reveal that maternal obesity dysregulates plasma DPPIV activity in males and provide evidence that maternal inhibition of DPPIV has potential for addressing the transgenerational effects of maternal obesity.

Vitamin D Supplementation Improves Mitochondrial Function and Reduces Inflammation in Placentae of Obese Women

“…It also affects the fetus and newborn, causing congenital malformations, large- and small-for-gestational-age infants, and stillbirth. Importantly, maternal obesity leads to cardiovascular dysregulations ( 11 – 13 ) and to obesity and metabolic diseases in offspring ( 10 ). In addition, data also show that maternal obesity results in metabolic inflammation in the mother and programs inflammation in the offspring ( 14 ).…”

Incretins as a Potential Treatment Option for Gestational Diabetes Mellitus

“…The DPP family consists of enzymes such as DPP-4, fibroblast activation protein α (FAP; seprase), DPP-8, DPP-9, and prolyl carboxypeptidase (PCP; angiotensinase C) [ 46 ]. DPP-4, also known as T-cell differentiation antigen CD26, is a serine protease present in the circulation as two isoforms—a soluble protein and plasma membrane-bound [ 47 , 48 ]. The soluble isoform enables intercellular contact by cleaving protein substrates in body fluids, while the plasma membrane-bound affects intercellular communication through receptor activity [ 48 ].…”

“…Human DPP-4/CD26 has a short intracellular domain (6 amino acids), a transmembrane region, and an extracellular domain that possesses DPP activity [ 46 ]. DPP-4 expression was observed in numerous cells such as intestinal K cells, hepatocytes, adipocytes, renal brush border membranes, bone marrow cells, pancreatic cells, placental cytotrophoblasts, endothelial cells, and on the surface of lymphocytes [ 46 , 48 , 49 , 50 , 51 ].…”

“…According to the research, DPP-4 plays a role in regulating metabolism, appetite, energy expenditure, and body composition [ 48 ]. The abnormal expression and activity of DPP-4 has been observed to be associated with the occurrence of hyperglycemia and an increase in body mass index, implying that this enzyme may contribute to the development of diseases such as T2DM and obesity by mediating inflammation and insulin resistance in adipose tissue [ 48 ].…”

“…According to the research, DPP-4 plays a role in regulating metabolism, appetite, energy expenditure, and body composition [ 48 ]. The abnormal expression and activity of DPP-4 has been observed to be associated with the occurrence of hyperglycemia and an increase in body mass index, implying that this enzyme may contribute to the development of diseases such as T2DM and obesity by mediating inflammation and insulin resistance in adipose tissue [ 48 ]. Some of the other functions of DPP-4 include interactions with various proteins such as streptokinase and plasminogen, extracellular matrix components (collagen, fibronectin), and the role of binding sites for the chemokine CXCR4 receptor.…”