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The growth hormone (GH)/insulin-like growth factor (IGF-1) axis determines optimal growth and affects metabolism and energy homeostasis. Pregnancy-associated plasma protein-A2 (PAPPA2) regulates bioactive IGF-1 availability and patients with PAPPA2 deficiency have impaired growth and glucose metabolism. This axis is altered in metabolic disturbances such as obesity and anorexia nervosa in a sex-specific manner, but the mechanisms involved are not completely understood. Here we evaluated how Pappa2 deficiency affects energy homeostasis, focusing on male and female differences.

Growth and energy homeostasis were determined in male and female Pappa2^ko/ko mice and control Pappa2^wt/wt littermates, as well as their response to recombinant human (rh)PAPPA2, rhIGF-1 and rhIBFBP5. Effects of a high-carbohydrate diet (HCHD) on glucose tolerance, fuel partitioning, de novo lipogenesis and energy homeostasis were determined.

Pappa2^ko/ko mice had reduced body weight, bone length and lipid deposition associated with higher energy expenditure and intake. Male Pappa2^ko/ko mice had mild glucose intolerance, altered bone mineral properties and higher energy costs for locomotor activity possibly due to inefficient muscle mitochondrial activity; whereas female Pappa2^ko/ko mice had enhanced fatty acid oxidation on a normal diet, but not on a HCHD. All Pappa2^ko/ko mice had lower hepatic fat deposition associated with lower IGF-1 activity in the liver, while fatty acid metabolism dysregulation in adipose tissue was found only in females.

These data reinforce the importance of the GH/IGF-1 axis in metabolic control and emphasize the relevance of its fine-tuned control by Pappa2. Moreover, the differences between sexes in metabolic imbalances underscore the relevance of sex-specific strategies for treatment of metabolic imbalances.