A central role for neuronal AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) in high-protein diet-induced weight loss.
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.



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



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.



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.
Ropelle
Eduardo R
ER
Department of Internal Medicine, State University of Campinas (UNICAMP), 13083-970, Campinas, São Paulo, Brazil.
Pauli
José R
JR
Fernandes
Maria Fernanda A
MF
Rocco
Silvana A
SA
Marin
Rodrigo M
RM
Morari
Joseane
J
Souza
Kellen K
KK
Dias
Marília M
MM
Gomes-Marcondes
Maria C
MC
Gontijo
José A R
JA
Franchini
Kleber G
KG
Velloso
Lício A
LA
Saad
Mario J A
MJ
Carvalheira
José B C
JB
D055372:AMP-Activated Protein Kinases; D000818:Animals; D001823:Body Composition; D004044:Dietary Proteins / Q000494:pharmacology*; D019587:Dietary Supplements; D004435:Eating / Q000187:drug effects; D007930:Leucine / Q000494:pharmacology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D008820:Mice, Obese; D009097:Multienzyme Complexes / Q000378:metabolism*; D009474:Neurons / Q000201:enzymology*; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D058570:TOR Serine-Threonine Kinases; D013997:Time Factors; D015431:Weight Loss / Q000187:drug effects*
D004044:Dietary Proteins; D009097:Multienzyme Complexes; D011494:Protein Kinases; C546843:mTOR protein, mouse; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D007930:Leucine