RT Journal Article
T1 Alteration of IGF-1 bioavailability due to PAPPA2 deficiency leads to sex-specific metabolic disturbances
A1 López-Gambero, Antonio J.
A1 Vargas, Antonio
A1 Fernández-Arjona, María del Mar
A1 Rubio-Lamia, Leticia Olga
A1 De Ceglia, Marialuisa
A1 Vera-Fernández, Carlos
A1 Campillo-Calatayud, Ana
A1 Rivera-González, Patricia
A1 Rodriguez-de-Fonseca, Fernando
A1 Barrios, Vicente
A1 Chowen, Julie A.
A1 Argente, Jesús
A1 Suárez-Pérez, Juan
K1 Endocrinología
K1 Metabolismo - Aspectos endocrinos
K1 Hormonas
K1 Diferencias sexuales
K1 Homeostasis
AB Background: The growth hormone (GH)/insulin-like growth factor (IGF-1) axis determines optimal growth andaffects metabolism and energy homeostasis. Pregnancy-associated plasma protein-A2 (PAPPA2) regulatesbioactive 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.Methods: Growth and energy homeostasis were determined in male and female Pappa2ko/ko mice and controlPappa2wt/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 andenergy homeostasis were determined.Results: Pappa2ko/ko mice had reduced body weight, bone length and lipid deposition associated with higherenergy expenditure and intake. Male Pappa2ko/ko mice had mild glucose intolerance, altered bone mineralproperties and higher energy costs for locomotor activity possibly due to inefficient muscle mitochondrial activity; whereas female Pappa2ko/ko mice had enhanced fatty acid oxidation on a normal diet, but not on a HCHD. All Pappa2ko/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.Conclusion: These data reinforce the importance of the GH/IGF-1 axis in metabolic control and emphasize therelevance 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.
PB ELSEVIER
YR 2025
FD 2025-10
LK https://hdl.handle.net/10630/39930
UL https://hdl.handle.net/10630/39930
LA eng
NO Antonio J. López-Gambero, Antonio Vargas, María del Mar Fernández-Arjona, Leticia Rubio, Marialuisa de Ceglia, Carlos Vera-Fernández, Ana Campillo-Calatayud, Patricia Rivera, Fernando Rodríguez de Fonseca, Vicente Barrios, Julie A. Chowen, Jesús Argente, Juan Suárez, Alteration of IGF-1 bioavailability due to PAPPA2 deficiency leads to sex-specific metabolic disturbances, Metabolism, Volume 171, 2025, 156355, ISSN 0026-0495, https://doi.org/10.1016/j.metabol.2025.156355. (https://www.sciencedirect.com/science/article/pii/S0026049525002240)
NO Funding for open access charge: Universidad de Málaga / CBUA
DS RIUMA. Repositorio Institucional de la Universidad de Málaga
RD 19 ene 2026