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

Abstract

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.

Evidence for Central Regulation of Glucose Metabolism

“…Indeed, hypothalamic AMPK is suppressed in response to central insulin, glucose, and leptin in mice, and stimulated in response to ICV infusion of the orexigenic agouti-related protein (15). mTOR and AMPK may in fact change in tandem to control energy status because ICV leucine administration causes decreased hypothalamic AMPK activity and increased mTOR activity in rodents (10), suggesting a complex balance between neural molecular signals. Another hypothalamic signal of nutrient status is IB kinase ␤ (IKK␤)/NFB, a mediator of inflammation normally quiescent in the hypothalamus, but activated in the setting of overnutrition (57).…”

mTORC1 signaling in energy balance and metabolic disease

“…These reports further confirmed that leucine-induced anorexia is dependent on hypothalamic mTORC1 activity and associated with the inhibition of AMPK. 17,18 Consistent with a cross-regulation between AMPK and mTORC1, the activation of these enzymes occurs in the same specific neuronal subtypes. 17 Furthermore, i.c.v.…”

“…17,18 Consistent with a cross-regulation between AMPK and mTORC1, the activation of these enzymes occurs in the same specific neuronal subtypes. 17 Furthermore, i.c.v. administration of leucine decreases mRNA levels of neuropeptide Y, [16][17][18] while increasing mRNA levels of POMC within the ARC.…”

“…17 Furthermore, i.c.v. administration of leucine decreases mRNA levels of neuropeptide Y, [16][17][18] while increasing mRNA levels of POMC within the ARC. 17,18 Recently, Blouet et al 54 have reported that intra-MBH administration of leucine reduces meal size and meal number by engaging a forebrain/hindbrain neurocircuit that activates ARC POMC neurons, paraventricular nucleus (PVN) oxytocin neurons and the nucleus of solitary tract neurons.…”

“…10,[13][14][15] The mammalian target of rapamycin (mTOR) pathway is the latest intracellular fuel-sensing mechanism to be implicated in the regulation of energy balance. [16][17][18] mTOR is a highly conserved serine-threonine kinase, which in peripheral cells is known to integrate nutrient signals with hormonal signals to control cell growth and proliferation. 19 Cellular adenosine triphosphate (ATP) levels increase mTOR activity, and the mTOR kinase itself serves as a cellular ATP sensor.…”