A Central Role for Neuronal AMP-Activated Protein Kinase (AMPK) and Mammalian Target of Rapamycin (mTOR) in High-Protein Diet–Induced Weight Loss

  1. Eduardo R. Ropelle1,
  2. José R. Pauli1,
  3. Maria Fernanda A. Fernandes1,
  4. Silvana A. Rocco1,
  5. Rodrigo M. Marin1,
  6. Joseane Morari1,
  7. Kellen K. Souza1,
  8. Marília M. Dias1,
  9. Maria C. Gomes-Marcondes2,
  10. José A.R. Gontijo1,
  11. Kleber G. Franchini1,
  12. Lício A. Velloso1,
  13. Mario J.A. Saad1 and
  14. José B.C. Carvalheira1
  1. 1Department of Internal Medicine, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
  2. 2Department of Physiology and Biophysics of State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
  1. Address correspondence and reprint requests to José B.C. Carvalheira, MD, Department of Internal Medicine, FCM–State University of Campinas (UNICAMP), 13083-970, Campinas, SP, Brazil. E-mail: carvalheirajbc{at}uol.com.br


OBJECTIVE—A high-protein diet (HPD) is known to promote the reduction of body fat, but the mechanisms underlying this change are unclear. AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) function as majors regulators of cellular metabolism that respond to changes in energy status, and recent data demonstrated that they also play a critical role in systemic energy balance. Here, we sought to determine whether the response of the AMPK and mTOR pathways could contribute to the molecular effects of an HPD.

RESEARCH DESIGN AND METHODS—Western blotting, confocal microscopy, chromatography, light microscopy, and RT-PCR assays were combined to explore the anorexigenic effects of an HPD.

RESULTS—An HPD reduced food intake and induced weight loss in both normal rats and ob/ob mice. The intracerebroventricular administration of leucine reduced food intake, and the magnitude of weight loss and reduction of food intake in a leucine-supplemented diet are similar to that achieved by HPD in normal rats and in ob/ob mice, suggesting that leucine is a major component of the effects of an HPD. Leucine and HPD decrease AMPK and increase mTOR activity in the hypothalamus, leading to inhibition of neuropeptide Y and stimulation of pro-opiomelanocortin expression. Consistent with a cross-regulation between AMPK and mTOR to control food intake, our data show that the activation of these enzymes occurs in the same specific neuronal subtypes.

CONCLUSIONS—These findings provide support for the hypothesis that AMPK and mTOR interact in the hypothalamus to regulate feeding during HPD in a leucine-dependent manner.


  • Published ahead of print at http://diabetes.diabetesjournals.org on 5 December 2007. DOI: 10.2337/db07-0573.

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Received April 26, 2007.
    • Accepted November 16, 2007.
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  1. Diabetes vol. 57 no. 3 594-605
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