The growth hormone (GH)-insulin-like growth factor (IGF-1) system is essential for optimal human growth and energy homeostasis. Deficiency of pregnancy-associated plasma protein-A2 (PAPP-A2), a protease involved in the liberation of free IGF-1, leads to problems in growth and bone density in humans and mice. Patients with PAPP-A2 deficiency also present lower body mass and mild glucose intolerance. The present study aimed to determine the influence of 1 month of high carbohydrate diet (HCHD) intake on metabolic parameters in homozygous Pappa2 knock-out (Pappa2ko/ko) mice of 8 months of age differentially affects males and females. Both male and female Pappa2ko/ko mice weighed less at baseline compared to their wild-type littermates. This was associated with a net increase in energy expenditure (EE) in both male and female Pappa2ko/ko as determined by employing metabolic cages. The higher metabolic rate accounted for weight loss despite the increase in cumulative food intake observed in Pappa2ko/ko males. Interestingly, Pappa2ko/ko males had lower locomotor activity, which suggests that the increased EE is associated with deregulation of thermogenic activity. Pappa2ko/ko females had a lower respiratory quotient (RQ, measured by vCO2/vO2 ratio), suggesting a shift towards lipid as the main source of energy utilization. HCHD consumption resulted in increased total caloric intake and body weight in males regardless of genotype, with no significant effect on RQ or locomotor activity. Female Pappa2ko/ko mice consuming the HCHD had an increase in total caloric intake. Female Pappa2ko/ko mice also had lower EE, which returned to that observed in wild-type females, and a higher RQ, indicating an increase in carbohydrate metabolism similar to that of their wild-type littermates. Glucose tolerance test (GTT) showed mild glucose intolerance in both Pappa2ko/ko males and females on a normal chow diet and glucose resistance in males and females regardless of their genotype. In summary, Pappa2ko/ko mice present a negative energy balance associated with disturbances in food intake, energy expenditure, and glucose tolerance that are sex dependent. The effects of HCHD, especially in females, opens a framework for dietary intervention in patients with PAPP-A2 deficiency.
Funding: Instituto de Salud Carlos III, Ministerio de Ciencia, Innovación y Universidades co-funded by ERDF-EU (JS: PI19/00343, JA: PI19/00166), and CIBER Obesity & Nutrition (CIBEROBN).
15 Sep 2022 - 17 Sep 2022