Amino acids and leptin use mammalian target of rapomycin (mTOR) pathway to control feeding circuits in the brain
By Melissa Lee Phillips | May 12, 2006
The mammalian target of rapomycin (mTOR) signaling pathway appears to regulate an organism's food intake, according to a paper in this week's Science. The authors suggest that aberrant mTOR signaling in the brain may contribute to excessive eating associated with obesity and diabetes.
"It provides the first clear evidence that this mTOR signaling pathway is not only present in the key areas of the central nervous system but also that it plays an important role as a sensing mechanism in order to control food intake," André Marette of the University of Laval in Québec, who was not involved in the study, told The Scientist.
The mTOR protein is a highly conserved kinase that senses changes in cellular energy status and regulates cell growth and proliferation. Elevated mTOR activity in the body's periphery had previously been linked with obesity, diabetes, and cancer. But its role in the central nervous system was unclear, said study first author Daniela Cota of the University of Cincinnati.
Cota and her colleagues found that activated mTOR and one of its downstream targets are expressed in a key feeding region of the rat hypothalamus called the arcuate nucleus. mTOR in the arcuate nucleus colocalized with neurons expressing neuropeptide Y and proopiomelanocortin, both known to be regulated by leptin and involved in food intake.
The researchers next examined how two downstream targets of mTOR were affected by the rats' energy status. When the animals didn't eat for 48 hours, phosphorylation of these targets decreased significantly in the hypothalamus. Animals that were fed after fasting, however, showed increased levels of hypothalamic mTOR activity.
The authors then treated rats with leucine, a branched-chain amino acid known to upregulate peripheral mTOR signaling. Injecting leucine into the brain caused anorexia and weight loss in the rats. When the scientists pre-treated the rats with the specific mTOR inhibitor rapamycin, however, leucine's effects disappeared, suggesting that inhibiting mTOR activity prevented the anorexia and weight loss normally induced by leucine.
This is the first study to "clearly show how amino acids can be sensed and how then this message can be processed and can inform the brain" about nutrient availability in the body, Cota told The Scientist.
The researchers also found evidence that the hormone leptin regulates feeding through the mTOR pathway. Leptin is released from fat cells and influences feeding by telling hypothalamic neurons how much fat the body has stored. Increased leptin signaling normally produces anorexia and weight loss in animals. Cota and her co-workers found that leptin treatment activates mTOR signaling and that inhibiting this signaling with rapamycin attentuates leptin's ability to reduce appetite and induce weight loss.
Normally, experiments with inhibitors -- epecially if just one inhibitor is used -- give questionable results, said Joseph Avruch of Harvard Medical School, who was not an author. "But this particular inhibitor is perhaps the most specific inhibitor of any protein kinase known at this point. So that makes the behavioral responses pretty convincing."
Further work will be needed to solidify mTOR's role as a central fuel sensor, said Sue Ritter of Washington State University in Pullman, also not involved in the study. It's still possible that mTOR is not itself a sensor but is "just reflecting activity of the cells," Ritter said. However, she added, "one of the strengths of the paper is that they are relating this potential mechanism of fuel sensing to particular cells in the hypothalamus with demonstrated roles in control of feeding."
The next step, according to Marette, is to show that the mTOR signaling pathway is abnormally regulated in states like obesity or diabetes. According to Cota's results, when normal organisms have plenty of nutrients and fat, mTOR activity increases, which then "shuts off food intake in order to maintain the balance," Marette said. In obesity, however, this "shut off" command doesn't take place, he said. "I'm really curious to know what would happen to this mTOR signaling pathway in states of chronic imbalance such as obesity."
Melissa Lee Phillips
Links within this article
D. Cota et al., "Hypothalamic mTOR signaling regulates food intake," Science, May 12, 2006.
S. Blackman, "The enormity of obesity," The Scientist, May 24, 2004.
A. Rinaldi, "Diabetes and cancer: an unexpected link," The Scientist, September 25, 2003.
E. Jacinto, M.N. Hall, "Tor signalling in bugs, brain and brawn," Nature Reviews Molecular Cell Biology, February 2003.
L. Khamzina et al., "Increased activation of the mammalian target of rapamycin pathway in liver and skeletal muscle of obese rats: possible involvement in obesity-linked insulin resistance," Endocrinology, March 2005.
D. Secko, "Sensitizing cancer through mTOR," The Scientist, March 15, 2004.
K. Rahmouni, W.G. Haynes, "Leptin signaling pathways in the central nervous system: interactions between neuropeptide Y and melanocortins," Bioessays, December 2001.
C.G. Proud, "Regulation of mammalian translation factors by nutrients," European Journal of Biochemistry, November 2002.
More transmissible cancers in clams; first human trial for Zika vaccine a go; Great Barrier Reef bleaching; neuronal diversity; mosquito bites enhance viral infection; news from the American Society for Microbiology annual meeting