AI Article Synopsis

  • - Related Overgrowth Syndrome (PROS) is a genetic disorder linked to mutations that disrupt normal growth and metabolic functions, with significant implications for adipose (fat) tissue and endocrine systems.
  • - Researchers developed a mouse model simulating the disorder's symptoms, revealing how specific mutations lead to insulin resistance, abnormal liver function, and a metabolic shift similar to cancer cells.
  • - The study found that the drug alpelisib can effectively reduce adipose tissue overgrowth and correct metabolic dysfunctions in both the mouse models and in human patients.

Article Abstract

-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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9733923PMC
http://dx.doi.org/10.1126/sciadv.ade7823DOI Listing

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