PIK3CA gain-of-function mutation in adipose tissue induces metabolic reprogramming with Warburg-like effect and severe endocrine disruption

-related overgrowth syndrome (PROS) is a genetic disorder caused by somatic mosaic gain-of-function mutations of . Clinical presentation of patients is diverse and associated with endocrine disruption. Adipose tissue is frequently involved, but its role in disease development and progression has not...

Full description

Saved in:
Bibliographic Details
Published in:Science advances 2022-12, Vol.8 (49), p.eade7823-eade7823
Main Authors: Ladraa, Sophia, Zerbib, Lola, Bayard, Charles, Fraissenon, Antoine, Venot, Quitterie, Morin, Gabriel, Garneau, Alexandre P, Isnard, Pierre, Chapelle, Célia, Hoguin, Clément, Fraitag, Sylvie, Duong, Jean-Paul, Guibaud, Laurent, Besançon, Alix, Kaltenbach, Sophie, Villarese, Patrick, Asnafi, Vahid, Broissand, Christine, Goudin, Nicolas, Dussiot, Michael, Nemazanyy, Ivan, Viel, Thomas, Autret, Gwennhael, Cruciani-Guglielmacci, Céline, Denom, Jessica, Bruneau, Julie, Tavitian, Bertrand, Legendre, Christophe, Dairou, Julien, Lacorte, Jean-Marc, Levy, Pacifique, Pende, Mario, Polak, Michel, Canaud, Guillaume
Format: Article
Language:English
Subjects:
Adipose Tissue - metabolism
Animals
Biochemistry
Biomedicine and Life Sciences
Class I Phosphatidylinositol 3-Kinases - genetics
Class I Phosphatidylinositol 3-Kinases - metabolism
Gain of Function Mutation - genetics
Life Sciences
Mice
Mutation
Phenotype
SciAdv r-articles
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:-related overgrowth syndrome (PROS) is a genetic disorder caused by somatic mosaic gain-of-function mutations of . Clinical presentation of patients is diverse and associated with endocrine disruption. Adipose tissue is frequently involved, but its role in disease development and progression has not been elucidated. Here, we created a mouse model of -related adipose tissue overgrowth that recapitulates patient phenotype. We demonstrate that mutation leads to GLUT4 membrane accumulation with a negative feedback loop on insulin secretion, a burst of liver IGFBP1 synthesis with IGF-1 sequestration, and low circulating levels. Mouse phenotype was mainly driven through AKT2. We also observed that mutation induces metabolic reprogramming with Warburg-like effect and protein and lipid synthesis, hallmarks of cancer cells, in vitro, in vivo, and in patients. We lastly show that alpelisib is efficient at preventing and improving -adipose tissue overgrowth and reversing metabolomic anomalies in both animal models and patients.
ISSN:2375-2548
2375-2548
DOI:10.1126/sciadv.ade7823