Editors' ChoiceObesity

Of obese mice and monkeys: Protective effects of PI3K inhibition

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Science Translational Medicine  15 Apr 2015:
Vol. 7, Issue 283, pp. 283ec61
DOI: 10.1126/scitranslmed.aab2768

In some countries, more than 30% of people are obese, which increases their risk to develop comorbidities such as metabolic syndrome and nonalcoholic fatty liver disease (NAFLD). Molecular pathways involved in regulating body weight are thus a natural target for metabolic research. The phosphatidylinositol 3-kinase (PI3K) signaling cascade, which is down-regulated with caloric restriction, is one such key pathway that may be amenable to pharmacological intervention.

Ortega-Molina et al. have previously reported that a genetic reduction in PI3K signaling in mice protects against obesity and metabolic syndrome. Now, the investigators evaluate the metabolic effects of pharmacological inhibition of PI3K signaling in mice and extend their research to obese rhesus monkeys. They found that short-term, high doses of pharmacological inhibitors of PI3K (CNIO-PI3Ki and GDC-0941) decreased body weight as well as fat accumulation around the heart and lung and within the liver of obese mice. Although body weight remained higher than standard diet–fed controls, long-term (>2.5 months) low daily doses of CNIO-PI3Ki in high-fat diet–induced obese mice reduced body weight and increased energy expenditure, despite no changes in food intake. This low-dose treatment strategy reversed hepatic steatosis—of note because there are no currently approved pharmaceutical therapies for NAFLD. Moreover, fasting glucose levels normalized after 5 months of treatment. In a separate experiment, the PI3K inhibitor slowed weight gain and glucose intolerance in lean mice given a high-fat diet. Last, although results were not as robust as in the mouse studies, a 12-week trial of daily oral CNIO-PI3Ki intake by obese rhesus monkeys moderately decreased trunk fat gain and trended towards lowering fasting glucose levels, with no evidence of drug toxicity. There is no substitute for good, old-fashioned nutrition and exercise; however, these studies provide strong preclinical data for the development of pharmacological inhibitors of the PI3K pathway for the treatment of human obesity.

A. Ortega-Molina et al., Pharmacological inhibition of PI3K reduces adiposity and metabolic syndrome in obese mice and rhesus monkeys. Cell Metab. 21, 558–570 (2015). [Abstract]

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