| First Author | Perino A | Year | 2014 |
| Journal | Sci Signal | Volume | 7 |
| Issue | 352 | Pages | ra110 |
| PubMed ID | 25406378 | Mgi Jnum | J:260009 |
| Mgi Id | MGI:6141740 | Doi | 10.1126/scisignal.2005485 |
| Citation | Perino A, et al. (2014) Combined inhibition of PI3Kbeta and PI3Kgamma reduces fat mass by enhancing alpha-MSH-dependent sympathetic drive. Sci Signal 7(352):ra110 |
| abstractText | Obesity is defined as an abnormal increase in white adipose tissue and has become a major medical burden worldwide. Signals from the brain control not only appetite but also energy expenditure, both of which contribute to body weight. We showed that genetic or pharmacological inhibition of two phosphatidylinositol 3-kinases (PI3Kbeta and PI3Kgamma) in mice reduced fat mass by promoting increased energy expenditure. This effect was accompanied by stimulation of lipolysis and the acquisition of the energy-burning characteristics of brown adipocytes by white adipocytes, a process referred to as "browning." The browning of the white adipocytes involved increased norepinephrine release from the sympathetic nervous system. We found that PI3Kbeta and PI3Kgamma together promoted a negative feedback loop downstream of the melanocortin 4 receptor in the central nervous system, which controls appetite and energy expenditure in the periphery. Analysis of mice with drug-induced sympathetic denervation suggested that these kinases controlled the sympathetic drive in the brain. Administration of inhibitors of both PI3Kbeta and PI3Kgamma to mice by intracerebroventricular delivery induced a 10% reduction in fat mass as quickly as 10 days. These results suggest that combined inhibition of PI3Kbeta and PI3Kgamma might represent a promising treatment for obesity. |
