Pharmacological inhibition of PI3K reduces adiposity and metabolic syndrome in obese mice and rhesus monkeys.

Abstract

Genetic inhibition of PI3K signaling increases energy expenditure, protects from obesity and metabolic syndrome, and extends longevity. Here, we show that two pharmacological inhibitors of PI3K, CNIO-PI3Ki and GDC-0941, decrease the adiposity of obese mice without affecting their lean mass. Long-term treatment of obese mice with low doses of CNIO-PI3Ki reduces body weight until reaching a balance that is stable for months as long as the treatment continues. CNIO-PI3Ki treatment also ameliorates liver steatosis and decreases glucose serum levels. The above observations have been recapitulated in independent laboratories and using different oral formulations of CNIO-PI3Ki. Finally, daily oral treatment of obese rhesus monkeys for 3 months with low doses of CNIO-PI3Ki decreased their adiposity and lowered their serum glucose levels, in the absence of detectable toxicities. Therefore, pharmacological inhibition of PI3K is an effective and safe anti-obesity intervention that could reverse the negative effects of metabolic syndrome in humans.

• Authors: Ana Ortega-Molina, Elena Lopez-Guadamillas, Julie A Mattison, Sarah J Mitchell, Maribel Muñoz-Martin, Gema Iglesias, Vincent M Gutierrez, Kelli L Vaughan, Mark D Szarowicz, Ismael González-García, Miguel López, David Cebrián, Sonia Martinez, Joaquin Pastor, Rafael de Cabo, Manuel Serrano
• Journal: Cell metabolism (Cell Metab) Vol. 21 Issue 4 Pg. 558-70 (Apr 07 2015) ISSN: 1932-7420 [Electronic] United States
• PMID: 25817535 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• 2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine
• CNIO-PI3Ki compound
• Imidazoles
• Indazoles
• Phosphoinositide-3 Kinase Inhibitors
• Pyrazines
• Sulfonamides

Topics

• Adiposity (drug effects, physiology)
• Animals
• Histological Techniques
• Imidazoles (pharmacology)
• Immunoblotting
• Indazoles (pharmacology)
• Liver (drug effects, pathology)
• Macaca mulatta
• Mass Spectrometry
• Metabolic Syndrome (drug therapy)
• Mice, Obese
• Phosphoinositide-3 Kinase Inhibitors
• Pyrazines (pharmacology)
• Sulfonamides (pharmacology)