Combined inhibition of PI3Kβ and PI3Kγ reduces fat mass by enhancing α-MSH-dependent sympathetic drive

Alessia Perino, Martina Beretta, Ana Kilić, Alessandra Ghigo, Daniela Carnevale, Ivan Enrico Repetto, Laura Braccini, Dario Longo, Michaela Liebig-Gonglach, Tania Zaglia, Roberta Iacobucci, Marco Mongillo, Reinhard Wetzker, Michael Bauer, Silvio Aime, Alessandro Vercelli, Giuseppe Lembo, Alexander Pfeifer, Emilio Hirsch

Research output: Contribution to journalArticlepeer-review


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 (PI3Kβ and PI3Kγ) 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 PI3Kβ and PI3Kγ 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 PI3Kβ and PI3Kγ to mice by intracerebroventricular delivery induced a 10% reduction in fat mass as quickly as 10 days. These results suggest that combined inhibition of PI3Kβ and PI3Kγ might represent a promising treatment for obesity.

Original languageEnglish
Article numberra110
JournalScience Signaling
Issue number352
Publication statusPublished - Nov 18 2014

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology
  • Medicine(all)


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