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How much leucine we eat and leucine in our brain area
associated with
eating, the hypothalamus, may have different effects on how
much we eat.

Science 1 September 2006:313 (5791) 1236-8

Letters

Role of Leucine in Regulating Food Intake

"In their recent Report "Hypothalamic mTOR signaling
regulates food
intake" (12 May, p. 927), D. Cota et al. detail the
metabolic mechanisms
controlling food intake and show that increased hypothalamic
availability of
the branched-chain amino acid (BCAA) leucine acts as a
potent signal that
reduces food intake by promoting mTOR signaling in rats.
Cota et al. further
suggest that low leucine levels in peripheral tissues may
curtail protein
synthesis while stimulating food intake in the brain.

"Although very interesting, these experimental data
appear to conflict
with clinical data. The amino acid leucine has been used for
decades to
treat hepatic encephalopathy, to increase muscle protein
synthesis, and to
improve appetite (1). Although usually supplemented with the
other BCAAs
(valine and isoleucine), leucine typically accounts for
about 50% of the
given dose of BCAAs. When supplemented, leucine effectively
competes with
the neutral amino acids for crossing the blood-brain
barrier, and its
supplementation in humans yields increased leucine brain
levels and reduced
concentrations of the competitors. These changes in brain
neurochemistry are
not associated with reduced food intake, but rather with
enhanced appetite
and protein synthesis. In cancer patients, BCAA
supplementation that
provides 7 g/day of leucine rapidly improves food intake (2)
and enhances
protein synthesis (3). Similar results are seen in
malnourished uremic
patients undergoing hemodialysis (4) and in patients with
liver cirrhosis
(5). We therefore believe that BCAA, particularly leucine
supplementation,
remains a useful and clinically relevant tool to improve
food intake and
enhance protein synthesis in patients suffering from chronic
diseases, at
least at the doses used in clinical trials. It remains to be
ascertained
whether higher leucine doses that have not been given in
clinical trials
would be perceived by the brain as toxic, thus prompting a
reduction of food
intake by means of increased mTOR signaling.
Alessandro Laviano et al"

Response

"Laviano and colleagues question whether the mTOR
system that we
describe in the hypothalamus is sensitive to nutrient
supplementation of the
diet, and they cite examples in which leucine has
supplemented the diet to
encourage weight gain during pathological conditions. We
used healthy rats
of normal weight to investigate the physiological role of
hypothalamic mTOR
in the regulation of food intake. Thus, our model does not
address the role
that central nervous system (CNS) mTOR may play in chronic
diseases
associated with malnutrition and weight loss.

The contradiction between evidence that supplemental
leucine in the
diet causes weight gain and our findings that CNS
administration causes
weight loss raises three key issues. First, there is a
difference between
adipose and lean tissue mass. The cited examples are
clinical syndromes
associated with substantial loss of muscle mass, and the
supplementation is
designed to promote muscle gain. Whether such manipulations
increase
appetite and independently increase adipose mass is less
clear. Second, mTOR
activity is regulated in numerous cell types in the
periphery and is
associated with numerous aspects of cellular function,
including cell growth
(1, 2). Consequently, it is not surprising that leucine
supplementation
increases peripheral mTOR activity and leads to an overall
anabolic action.
Indeed, mice deficient in the downstream target of mTOR,
S6K1, are smaller
overall than their wild-type controls (3). This is not the
only example of a
system that is anabolic in its peripheral action and
catabolic in its CNS
action. Insulin administration in the periphery can produce
rapid increases
in adipose mass, given that available fuel is sequestered in
adipose tissue
(4, 5). Conversely, CNS insulin administration reduces food
intake and leads
to adipose tissue depletion (6, 7). Third, although it is
clear that
branched-chain amino acids such as leucine can enter the
CNS, the
determinants of their levels in the specific circuits we
describe is
unclear. Furthermore, these amino acids are critical to the
synthesis of a
number of important neurotransmitters, and altering their
rate of entry may
complicate their effect on food intake and body weight."

" All three of these issues provide notable barriers to
the rapid
application of our findings to the treatment of obesity. Our
work represents
the initial steps of a lengthy process whereby
fuel-sensitive pathways in
neurons that contribute to the regulation of energy balance
might be
therapeutically exploited. Dietary changes may ultimately
provide a way to
manipulate these hypothalalmic circuits for therapeutic
benefit, but much
more work is necessary to identify specific means to do so.
Daniela Cota et al"