title: 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: Tumor Suppression Group, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
authors: Ana
authors: A
authors: Ortega-Molina
authors: Tumor Suppression Group, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
authors: Elena
authors: E
authors: Lopez-Guadamillas
authors: Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, NIH, Baltimore, MD 21224, USA.
authors: Julie A
authors: JA
authors: Mattison
authors: Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, NIH, Baltimore, MD 21224, USA.
authors: Sarah J
authors: SJ
authors: Mitchell
authors: Tumor Suppression Group, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
authors: Maribel
authors: M
authors: Muñoz-Martin
authors: Tumor Suppression Group, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
authors: Gema
authors: G
authors: Iglesias
authors: Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, NIH, Baltimore, MD 21224, USA.
authors: Vincent M
authors: VM
authors: Gutierrez
authors: Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, NIH, Baltimore, MD 21224, USA; SoBran, Inc., Burtonsville, MD 20866, USA.
authors: Kelli L
authors: KL
authors: Vaughan
authors: Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, NIH, Baltimore, MD 21224, USA; SoBran, Inc., Burtonsville, MD 20866, USA.
authors: Mark D
authors: MD
authors: Szarowicz
authors: Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela 15782, Spain.
authors: Ismael
authors: I
authors: González-García
authors: Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela 15782, Spain.
authors: Miguel
authors: M
authors: López
authors: Experimental Therapeutics Programme, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
authors: David
authors: D
authors: Cebrián
authors: Experimental Therapeutics Programme, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
authors: Sonia
authors: S
authors: Martinez
authors: Experimental Therapeutics Programme, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
authors: Joaquin
authors: J
authors: Pastor
authors: Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, NIH, Baltimore, MD 21224, USA.
authors: Rafael
authors: R
authors: de Cabo
authors: Tumor Suppression Group, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain. Electronic address: mserrano@cnio.es.
authors: Manuel
authors: M
authors: Serrano
mesh_terms: D050154:Adiposity / Q000187:drug effects* / Q000502:physiology; D000818:Animals; D006652:Histological Techniques; D007093:Imidazoles / Q000494:pharmacology*; D015151:Immunoblotting; D007191:Indazoles / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008253:Macaca mulatta; D013058:Mass Spectrometry; D024821:Metabolic Syndrome / Q000188:drug therapy*; D008820:Mice, Obese; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011719:Pyrazines / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: C532162:2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine; C000604163:CNIO-PI3Ki compound; D007093:Imidazoles; D007191:Indazoles; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011719:Pyrazines; D013449:Sulfonamides