Molecular Psychiatry (2003) 8, 364365

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Regulation of food intake: an old actor plays a new role

Molecular Psychiatry (2003) 8, 364365. doi:10.1038/
sj.mp.4001265

The role of insulin in the regulation of food intake is

receiving more attention. Administration of insulin in
the third ventricle of the brain and the use of animals
genetically manipulated to disrupt insulin receptors
in the central nervous system (CNS) point to the same
conclusions: when insulin reaches the arcuate nucleus, it reduces the desire for food intake.
Food intake and energy utilization are primarily
controlled by physiological mechanisms in which the
CNS takes an active part. Failure of those mechanisms
results in obesity, one of the major health problems in
Western and developing countries. The concept that
peripheral signals communicate with the CNS structures involved in the regulation of food intake was
introduced in the 1950s.1 These peripheral signals
include some that act rapidly, regulating individual
meals, and some that act more slowly controlling the
fat mass. Among the first group are cholecystokinin,2
ghrelin3 and PYY3-36.4 A description of the actions of
these short-term regulators of food intake has been
recently published.5 Regarding the slow-acting food
intake regulators, one of the key elements of the
system is the hormone, leptin, which is produced by
adipocytes. When the fat mass increases, leptin levels
also increase and by acting on the arcuate nucleus,
food intake decreases.6 The actions of leptin on the
arcuate nucleus are mediated by at least two classes of
neurons. One class expresses pro-opiomelanocortin
(POMC), a precursor of a-melanocyte stimulating
hormone (a-MSH), and cocaine and amphetamineregulated transcript (CART). Both a-MSH and CART
decrease food intake.7 Another class of neurons
expresses neuropeptide Y (NPY) and agouti-generelated peptide (AGRP). Both NPY and AGRP, increase food intake.7 Leptin suppresses the orexigenic
signals NPY and AGRP, and increases the anorexigenic peptides a-MSH and CART.6
However, leptin is not the only peripheral signal
that controls food intake. An old actor has been
recently included in this new role: insulin. Evidence
of this role has been accumulating for the last 25
years. For example, insulin receptors (IR) are expressed in classical insulin-sensitive tissues such as
the liver, muscle and fat, but also in other tissues
usually not considered as insulin-responsive, including the CNS.8 The distribution of IR in the brain is

Correspondence: GG Piroli, Laboratory of Neuroendocrinology,

The Rockefeller University, 1230 York Avenue, New York,
NY10021, USA.
E-mail: pirolig@mail.rockefeller.edu

uneven, indicating that insulin must exert some

specific effect(s) other than mediating glucose transport into neurons. In fact, neurons take glucose
through the glucose transporter GLUT 3, which has
widespread distribution in the brain and is not
regulated by insulin (however, insulin does regulate
the subcellular distribution of the insulin-sensitive
GLUT 4 and the newly described GLUT 8 in the
hippocampus, but a discussion of these events
digresses from the scope of this comment, see
Reagan9). One of the brain areas where IR are
concentrated is the hypothalamus, more specifically,
the arcuate nucleus, both in the medial (which
contains NPY-expressing neurons) and the lateral
portion (which contains POMC-expressing neurons).
Studies in which insulin was administered into the
third ventricle of the brain provided the first clues on
insulin regulation of food intake. In this context,
baboons injected i.c.v. with insulin showed a general
decrease in food intake and a significant reduction in
body weight.10 It has also been proposed that insulin
deficiency in the brain is responsible for the hyperphagia observed in type I diabetic rats. Consistently
with this idea, diabetic rats treated i.c.v. with insulin
(at a dose that did not affect plasma glucose levels)
showed a decrease in food intake. Furthermore, the
orexigenic peptide, NPY, seems to contribute to that
effect, as its expression in the arcuate nucleus
followed a pattern similar to that observed for food
intake: it was increased in diabetic rats, whereas
insulin partially reduced that increment.11
More recently, two papers have given direct
evidence of the role of CNS IR on food intake. The
first direct approach was the study by Bruning et al12
in which mice with a selective IR knockout in the
CNS (called NIRKO) were generated. The animals
showed less than 5% of IR in the brain when
compared to wild-type mice, whereas IR levels in
the rest of the body were normal. NIRKO mice
showed, 6 months after birth, an increase in adipose
mass, body weight and plasma leptin under normal
chow diet; food intake was also increased. When
animals were fed a high-fat diet, body weight was
significantly higher in NIRKO mice compared to wild
type from 14 weeks of age onwards. The obesity was
associated with insulin resistance: serum glucose
levels in fasting conditions were normal, but insulin
levels were two-fold the values of wild-type controls
and the response of blood glucose to exogenous
insulin was blunted. In addition, triglycerides were
elevated in the NIRKO mice, but cholesterol levels
were normal. Interestingly, besides the metabolic
alterations, NIRKO mice also presented reproductive
deficits with low levels of circulating luteinizing

News & Commentary

hormone. In summary, the study indicated that brainspecific disruption of the IR alters the normal
regulation of energy homeostasis by causing hyperphagia, obesity and peripheral insulin resistance. An
additional observation is that obesity is present in the
NIRKO mice despite the elevated levels of leptin in
blood, linking the lack of IR in the brain with CNS
resistance to leptin.12
Results presented in a more recent paper by Obici
et al13 support and extend the conclusions of the
NIRKO mice study. The authors used a different
approach, consisting of a treatment with an IR
antisense oligonucleotide, which was administered
i.c.v. for 7 days; control rats received a scrambled
oligonucleotide. In this case, IR were decreased only
in areas surrounding the third ventricle, namely the
medial arcuate nucleus and the habenular nucleus,
but not in areas located at a certain distance from the
ventricle, as other hypothalamic nuclei (ventrolateral
region of the arcuate nucleus, ventromedial nucleus
and dorsomedial nucleus), the hippocampus and the
olfactory cortex. Targeting IR at such specific areas
previously described to be relevant to food intake and
only during the treatment has an important advantage
over the NIRKO mice: an altered insulin signaling
during development of the brain could have been
responsible for the biological consequences of IR
knockout if it is considered that insulin exerts effects
on neuronal growth and differentiation.14 The animals treated with the antisense oligonucleotide
showed a rapid onset of hyperphagia and a marked
increase in fat mass, which was accompanied by an
elevation in circulating leptin levels. The mechanism
of action of insulin in the regulation of food intake
seems to involve the expression of the orexigenic
peptides, NPY and AGRP, as mRNAs for these factors
were increased in the arcuate nucleus of rats treated
with the IR antisense oligonucleotide. Confirming
results obtained with NIRKO mice, rats receiving the
antisense therapy presented a peripheral insulin
resistance when subjected to hyperinsulinemiceuglycemic clamps, as the rate of glucose infusion
required to maintain the plasma glucose at basal
levels was lower than in control rats. While peripheral glucose uptake did not change with the treat-

ment, insulin decreased glucose production to a

lower extent in treated animals than in controls. This
means that hepatic insulin action was impaired in
rats with selective attenuation of hypothalamic IR
expression.13
Perspectives: Taken together, the evidence indicates
that insulin, acting through IR located in the medial
arcuate nucleus, contributes to regulate food intake in
conjunction with leptin. However, some topics
remain to be elucidated. One of them is the hepatic
insulin resistance observed after central depletion of
IR (What mechanism(s) are involved in this effect?).
We also know that in type II diabetes and obesity,
insulin resistance and weight gain are common
features, as it happened to rats or mice with decreased
IR expression in the CNS. Is a similar reduction in
hypothalamic IR the main cause of those human
diseases? Studies with human tissue will help to
clarify the role of CNS IR in the susceptibility to
obesity and diabetes mellitus.

365

Acknowledgements
This work was supported by NIH, CONICET (Consejo
Nacional de Investigaciones Cientficas y Tecnicas,
Argentina) and Universidad de Buenos Aires.
GG Piroli
Laboratory of Neuroendocrinology,
The Rockefeller University, 1230 York Avenue,
New York, NY10021, USA

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Molecular Psychiatry