ESPE Abstracts (2019) 92 RFC14.1

PAPP-A2 Deficiency Results in Sex-Dependent Modifications in Hypothalamic Regulation of Energy Homeostasis

Patricia Rivera1, Antonio Vargas2, Javier Bonsón2, Julian Christians3, Fernando Rodríguez de Fonseca2, Julie Chowen1,4,5,6, Juan Suárez2, Jesús Argente1,4,5,6

1Department of Pediatrics & Pediatric Endocrinology, Hospital Infantil Universitario Niño Jesús, Universidad Autónoma de Madrid, Madrid, Spain. 2Instituto de Investigación Biomédica de Málaga (IBIMA), UGC Salud Mental, Universidad de Málaga, Hospital Universitario Regional de Málaga, Málaga, Spain. 3 Simon Fraser University. Department of Biological Sciences, Burnaby, Canada. 4Hospital de la Princesa Research Institute, Madrid, Spain. 5Centro de Investigación Biomédica en Red de Fisiopatologia de la Obesidad y Nutriciòn (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain. 6IMDEA Food Institute, CEI UAM + CSIC, Madrid, Spain

Pregnancy associated plasma protein (PAPP)-A2 is an insulin-like growth factor (IGF) binding protein (BP) protease that regulates IGF-1 availability affecting postnatal growth. Mutations in human PAPP-A2 cause short stature and changes in bone size and mineral density. The present study aimed to characterize the effects of constitutive Pappa2 gene deletion on hypothalamic regulation of energy homeostasis in adult male and female mice. In addition to being shorter, Pappa2 knock-out (ko/ko) mice of both sexes weigh significantly less than their wild type (WT) controls. However, only male Pappa2ko/ko mice were found to eat less (P<0.01) than same-sex controls during adulthood. Male Pappa2ko/ko mice were also found to have an increase in energy expenditure (P<0.05) compared to their controls. These sex differences in affection of energy intake-output are most likely related to changes in hypothalamic factors controlling energy homeostasis as they were also modified in a sex-dependent manner. In Pappa2ko/ko males the mRNA levels of the satiety-related factors leptin receptor (LEPR), cocaine- and amphetamine-regulated transcript (CART) and proopiomelanocortin (POMC), as well as factors that stimulate appetite neuropeptide Y (NPY) and Agouti-related peptide (AgRP) were elevated in the hypothalamus. These changes in Pappa2ko/ko male hypothalamus were accompanied by elevated mRNA levels of leptin in epididymal white adipose tissue (eWAT). In contrast, in Pappa2ko/ko females the expression of the insulin receptor (INSR), CART and POMC were reduced in the hypothalamus and the expression of leptin and the thermogenic factor uncoupling protein 1 (UCP1) were reduced in eWAT.

In conclusion, energy homeostasis is affected in Pappa2ko/ko mice in a sex-specific manner. However, how a reduction in IGF availability due to PAPP-A2 deficiency modulates the development and functioning of hypothalamic metabolic circuits remains to be determined.

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