IMPE Abstracts

The growth hormone (GH)-insulin-like growth factor (IGF-1) axis determines growth during different stages of life. Mutations resulting in deficiency of pregnancy-associated plasma protein-A2 (PAPP-A2), a protease involved in the release of free IGF-1, leads to problems in growth, reduced bone density and body mass and mild glucose intolerance. To better understand the physiological role of PAPP-A2, we analyzed the metabolic status and lipid metabolism in a mouse model of homozygous PAPP-A2 gene knock-out (Pappa2ko/ko) in males and females to assess sex-specific differences. As IGF-1 availability affects glucose tolerance, 8-month-old wild-type (WT) and Pappa2ko/ko mice were fed a normal chow diet or a high-carbohydrate diet (HCHD) for 1 month to explore possible changes in glucose and whole-body metabolism. Energy expenditure (EE), respiratory exchange rate (RER) and locomotor activity were evaluated in metabolic cages. Expression of inflammatory and neuropeptide markers in the hypothalamus and lipogenesis/lipolysis pathways in the liver were determined. Fatty acid content in the liver was assessed by total fat extraction and oil red O staining. Pappa2ko/ko males and females had higher net EE accounting for lower basal body weight compared to their WT littermates. Pappa2ko/ko males had lower locomotor activity, suggesting the increased EE is associated with modifications in thermogenic activity. HCHD increased total caloric intake and body weight in males regardless of genotype. Pappa2ko/ko females had a lower RER, suggesting a shift towards β-oxidation and the HCHD increased their caloric intake. Female Pappa2ko/ko mice also had a reduced EE that normalized with HCHD and higher RER, indicating increased carbohydrate metabolism. Glucose tolerance testing (GTT) showed mild glucose intolerance in Pappa2ko/ko males and females on a normal diet and glucose resistance in both sexes regardless of their genotype. Alterations in orexigenic (Npy, Agrp) and anorexigenic (Pomc, Cartpt) gene expression and susceptibility to inflammation in the hypothalamus were observed in Pappa2ko/ko mice. Total fat content in the liver was decreased in male and female Pappa2ko/ko mice, confirming a preference for lipids as the main source of energy. Expression of lipogenic enzymes was increased and lipolysis enzymes decreased in Pappa2ko/ko mice, suggesting a compensatory mechanism for reduced accumulation of fatty acids in liver. In summary, Pappa2ko/ko mice present a negative energy balance associated with disturbances in hypothalamic control of food intake, energy expenditure, hepatic lipid metabolism and glucose tolerance, which are sex dependent. Female-specific effects of HCHD opens a window for dietary intervention in patients with PAPP-A2 deficiency.