Alteration of IGF-1 bioavailability due to PAPPA2 deficiency leads to sex-specific metabolic disturbances
Metabolism. 2025-10-01; 171: 156355
DOI: 10.1016/j.metabol.2025.156355
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https://www.bordeaux-neurocampus.fr/12140
López-Gambero AJ(1), Vargas A(2), Del Mar Fernández-Arjona M(3), Rubio L(4), de Ceglia M(5), Vera-Fernández C(6), Campillo-Calatayud A(7), Rivera P(8), Rodríguez de Fonseca F(3), Barrios V(9), Chowen JA(10), Argente J(11), Suárez J(12).
Author information:
(1)Biomedical Research Institute of Malaga (IBIMA)-BIONAND Platform, Málaga
29590, Spain; UGC Neurology, Regional University Hospital of Malaga, Málaga
29010, Spain; University of Bordeaux, INSERM, Neurocentre Magendie, U1215,
Bordeaux 33000, France. Electronic address: .
(2)Biomedical Research Institute of Malaga (IBIMA)-BIONAND Platform, Málaga
29590, Spain.
(3)Biomedical Research Institute of Malaga (IBIMA)-BIONAND Platform, Málaga
29590, Spain; UGC Neurology, Regional University Hospital of Malaga, Málaga
29010, Spain.
(4)Biomedical Research Institute of Malaga (IBIMA)-BIONAND Platform, Málaga
29590, Spain; Department of Human Anatomy, Legal Medicine and Science History,
School of Medicine, University of Malaga, Málaga 29071, Spain.
(5)Biomedical Research Institute of Malaga (IBIMA)-BIONAND Platform, Málaga
29590, Spain; UGC Mental Health, Regional University Hospital of Malaga, Málaga
29010, Spain.
(6)Department of Psychobiology, School of Psychology, National University for
Distance Learning (UNED), Madrid, Spain.
(7)Departments of Pediatrics & Pediatric Endocrinology, Hospital Infantil
Universitario Niño Jesús, Madrid 28009, Spain.
(8)Biomedical Research Institute of Malaga (IBIMA)-BIONAND Platform, Málaga
29590, Spain; Department of Human Anatomy, Legal Medicine and Science History,
School of Medicine, University of Malaga, Málaga 29071, Spain; UGC Mental
Health, Regional University Hospital of Malaga, Málaga 29010, Spain.
(9)Departments of Pediatrics & Pediatric Endocrinology, Hospital Infantil
Universitario Niño Jesús, Madrid 28009, Spain; La Princesa Research Institute,
Madrid 28009, Spain; Centro de Investigación Biomédica en Red Fisiología de la
Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid 28029,
Spain.
(10)Departments of Pediatrics & Pediatric Endocrinology, Hospital Infantil
Universitario Niño Jesús, Madrid 28009, Spain; La Princesa Research Institute,
Madrid 28009, Spain; Centro de Investigación Biomédica en Red Fisiología de la
Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid 28029,
Spain; IMDEA Food Institute, CEI UAM & CSIC, Madrid 28049, Spain.
(11)Departments of Pediatrics & Pediatric Endocrinology, Hospital Infantil
Universitario Niño Jesús, Madrid 28009, Spain; La Princesa Research Institute,
Madrid 28009, Spain; Centro de Investigación Biomédica en Red Fisiología de la
Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid 28029,
Spain; IMDEA Food Institute, CEI UAM & CSIC, Madrid 28049, Spain; Department of
Pediatrics, Universidad Autónoma de Madrid, Madrid 28049, Spain.
(12)Biomedical Research Institute of Malaga (IBIMA)-BIONAND Platform, Málaga
29590, Spain; Department of Human Anatomy, Legal Medicine and Science History,
School of Medicine, University of Malaga, Málaga 29071, Spain. Electronic
address: .
BACKGROUND: 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.
METHODS: Growth and energy homeostasis were determined in male and female
Pappa2ko/ko mice and control Pappa2wt/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.
RESULTS: Pappa2ko/ko mice had reduced body weight, bone length and lipid
deposition associated with higher energy expenditure and intake. Male
Pappa2ko/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 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 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.
Copyright © 2025 The Author(s). Published by Elsevier Inc. All rights reserved.
DOI: 10.1016/j.metabol.2025.156355
PMID: 40695421 [Indexed for MEDLINE]
Conflict of interest statement: Declaration of competing interest The authors
declare that they have no known competing financial interests or personal
relationships that could have appeared to influence the work reported in this
paper.