IMPE2023 Free Communications GH and IGFs 1 (4 abstracts)
Treatment with recombinant murine Pappa2, GH or IGF-1 modifies hepatic energy metabolism in a mouse model of Pappa2 deficiency
María del Mar Fernández-Arjona 1 , Leticia Rubio 12 , Antonio López-Gambero 1,3 , Antonio Vargas 1 , Carlos Vera-Fernández 1 , Patricia Rivera 1,4 , Fernando Rodríguez de Fonseca 1,4 , Julie A. Chowen 5,6,7 , Jesús Argente 5,6,7,8 & Juan Suárez 1,2
1Instituto de Investigación Biomédica de Málaga-IBIMA, Málaga, Spain. 2Department of Anatomy, and Forensic and Legal Medicine, Universidad de Málaga, Málaga, Spain. 3Universidad de Málaga, Andalucia Tech, Departamento de Biología Celular, Genética y Fisiología, Málaga, Spain. 4UGC Salud Mental, Universidad de Málaga, Hospital Universitario Regional de Málaga, Málaga, Spain. 5Hospital Infantil Universitario Niño Jesús, Departamento de Endocrinología, Madrid, Spain. 6CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Madrid, Spain. 7IMDEA Food Institute, Madrid, Spain. 8Universidad Autónoma de Madrid, Madrid, Spain
Human growth is regulated by the growth hormone (GH)/insulin-like growth factor (IGF) axis, which also plays an essential role in energy homeostasis. GH regulates hepatic expression of IGF-1 and modulators of IGF bioavailability, including specific IGF-binding proteins (IGFBPs) and the acid-labile subunit (ALS) that bind IGFs to form binary and ternary complexes, respectively, to increase the half-life of IGF in the circulation. When these complexes reach target tissues specific proteases, including the proteolytic plasma pregnancy-associated protein A2 (PAPPA2), cleave the IGFBPs such that the free IGF-1 can then activate its receptor to initiate both proliferative and anabolic signaling pathways. Thus, both growth and metabolism are affected in patients that lack PAPPA2. The present study aimed to determine the effects of daily administration (from PND5 to PND35) of recombinant murine (rm) PAPPA2 compared to rmGH and rmIGF-1, using saline administration (sham) as a reference group, on the liver in homozygous knock-out (ko/ko) PAPPA2 mice of both sexes. The expression of genes involved in the GH/IGF-1 axis, including hormone receptors and IGFBP3, was evaluated in the liver of both Pappa2ko/ko and wild-type (Pappa2wt/wt) mice. Total protein and the phosphorylation levels of the main kinases involved in glucogenogenesis and lipogenesis were also evaluated. Treatment with rmPAPPA2, as well as rmGH and rmIGF1, decreased the gene expression of GH and the IGF-1 receptor in the liver, as well as that of IGFBP3, IGF-ALS, and the PAPPA2 inhibitor stanniocalcin (STC)1, in a treatment-, sex-and genotype-dependent manner (mainly in Pappa2ko/ko females). However, the increase in liver IGF-1 gene expression was dependent only on treatment. Treatment also decreased phosphorylation of PI3K, Akt, mTOR, ERK2, STAT5, together with an increase in AMPKα phosphorylation as determined by western blotting, in a treatment-and sex-dependent manner. We suggest that changes in the activity of these kinases could lead to a modification in the metabolism of both glucose and lipids in the liver. In summary, daily administration of rmPAPPA2 from PND5 to PND35 produces changes in the activation of anabolic pathways in the liver of Pappa2ko/ko mice with respect to Pappa2wt/wt mice and sham Pappa2ko/ko mice.
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