Attenuated Response of hCD39 Overexpressing Transgenic Mice to High‐fat Diet‐induced Obesity and Glucose Intolerance

Abstract

CD39 (ENTPD1) is an ecto‐nucleotidase that scavenges extracellular nucleotides, and thus terminates P2 receptor signaling. Previously we reported that genetic deletion ATP/UTP‐activated P2Y2 receptor confers significant protection against high‐fat diet (HFD)‐induced obesity and insulin resistance (IR). In order to understand the role of extracellular nucleotides in diet‐induced obesity and IR, we subjected wild type C57/Bl6 (WT) and syngeneic transgenic (TG) mice overexpressing human CD39 (hCD39) to either regular diet (10% of calories as fat; n = 5/genotype) or HFD (60% calories as fat; n = 7/genotype) feeding for 18 weeks with free access to drinking water and food. Body weights (BW), food and water consumption and urine output were measured every two weeks. Glucose tolerance test (GTT) was performed during 15th week. At the end of the experimental period all mice were humanely euthanized. Both genotypes showed significant increases in BW over time, and reached comparable mean BW toward the end of the study. However, until week 14, the slope of gain in BW was higher in WT vs. TG mice. No significant differences were found in daily food intake between the two groups. And there were no signs of steatorrhea, indicating no malabsorption of fat. Significant increases in the amount of brown and white adipose tissues were recorded in both groups, although the increases were not comparable. Liver and kidney weights, when adjusted to BW, are modestly, but significantly higher in HFD‐fed TG mice vs. WT mice. Glucose tolerance was significantly better in HFD‐fed TG vs. WT mice. Our results demonstrate that scavenging of extracellular nucleotides has the potential to delay the onset of diet‐induced obesity and glucose intolerance, and open potential avenues for the development of new therapies for obesity and insulin resistance.Support or Funding InformationDept. of Veterans Affairs (BKK) & PRIA Foundation (SCR)