Effects of neuropeptides and leptin on nutrient partitioning: dysregulations in obesity.

Abstract

Body weight homeostasis is maintained via a series of complex interactions that occur between the brain (particularly the hypothalamus) and the periphery, notably via the hormone leptin, which is synthesized in and secreted from adipose tissue. Under normal conditions, a dynamic equilibrium exists between anabolic neuropeptides (orexigenic peptides), which favor food intake, decrease energy expenditure, and facilitate fat storage, and catabolic ones (anorexigenic peptides), which decrease food intake, increase energy expenditure, and facilitate the loss of fat stores. Secreted leptin, although it may have some direct peripheral effects, exerts its action principally within the brain. Following its transport through the blood-brain barrier, leptin reaches the hypothalamic area, where it binds to its long receptor isoform. After a specific signaling cascade, leptin inhibits many of the orexigenic neuropeptides while favoring many of the anorexigenic ones. Thus, leptin decreases food intake and body weight, and it increases fat oxidation and energy expenditure, ultimately favoring leanness. Lack of leptin secretion, the inability of leptin to reach the brain, or the inability of leptin to interact with hypothalamic leptin receptors, prevent leptin's effects and lead to obesity.

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Annu. Rev. Med. 2001. 52:339–51
Copyright c ? 2001 by Annual Reviews. All right reserved
EFFECTS OF NEUROPEPTIDES AND LEPTIN
ON NUTRIENT PARTITIONING: Dysregulations
in Obesity
Bernard Jeanrenaud1and Franc ¸oise Rohner-Jeanrenaud2
1Geneva University, Chemin des Piverts 6, 1226 Geneva, Switzerland;
e-mail: jeanrenaud.bf@vtx.ch;2Faculty of Medicine, Division of Endocrinology and
Diabetology and Hˆ opital Cantonal Universitaire de Gen` eve, 24 rue Micheli-du-Crest,
1211 Geneva, Switzerland
Key Words
food intake, energy partitioning, leptin resistance, fat storage, leanness
I Abstract Body weight homeostasis is maintained via a series of complex inter-
actionsthatoccurbetweenthebrain(particularlythehypothalamus)andtheperiphery,
notably via the hormone leptin, which is synthesized in and secreted from adipose
tissue. Under normal conditions, a dynamic equilibrium exists between anabolic neu-
ropeptides(orexigenicpeptides),whichfavorfoodintake,decreaseenergyexpenditure,
and facilitate fat storage, and catabolic ones (anorexigenic peptides), which decrease
food intake, increase energy expenditure, and facilitate the loss of fat stores. Secreted
leptin, although it may have some direct peripheral effects, exerts its action principally
withinthebrain. Followingitstransportthroughtheblood-brainbarrier, leptinreaches
the hypothalamic area, where it binds to its long receptor isoform. After a specific
signaling cascade, leptin inhibits many of the orexigenic neuropeptides while favoring
many of the anorexigenic ones. Thus, leptin decreases food intake and body weight,
and it increases fat oxidation and energy expenditure, ultimately favoring leanness.
Lack of leptin secretion, the inability of leptin to reach the brain, or the inability of
leptin to interact with hypothalamic leptin receptors, prevent leptin’s effects and lead
to obesity.
INTRODUCTION
Body weight homeostasis is maintained via a series of complex interactions that
occur between the brain (particularly the hypothalamus) and the periphery (1),
notably via the hormone leptin, which is synthesized in and secreted from adipose
tissue (2). Under normal conditions, a dynamic equilibrium exists between ana-
bolic and catabolic neuropeptides. Anabolic neuropeptides (orexigenic peptides)
favorfoodintake, decreaseenergyexpenditure, andfacilitatefatstorage; catabolic
ones (anorexigenic peptides) decrease food intake, increase energy expenditure,
and facilitate the loss of fat stores (3).
0066-4219/01/0218-0339$14.00
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JEANRENAUD ? ROHNER-JEANRENAUD
Secreted leptin, although it may have some direct peripheral effects, exerts its
actionprincipallywithinthebrain. Followingitstransportthroughtheblood-brain
barrier, leptin reaches the hypothalamic area, where it binds to its long receptor
isoform (ObRb). After a specific signaling cascade, leptin inhibits many of the
orexigenic neuropeptides while favoring many of the anorexigenic ones. Thus,
leptin decreases food intake and body weight, and increases fat oxidation and
energy expenditure, ultimately favoring leanness. In the ob/ob obese mice, the
ob gene of adipose tissue (the leptin gene) is mutated (2) with resulting lack of
leptinsecretionandthereforeevolutiontowardmarkedobesity.Inothergenetically
obese rodents (e.g. db/db mice, fa/fa rats) or in diet-induced obese animals
(e.g. high-fat diet), the presence of leptin receptor mutations or dysfunctions,
and/or defects in leptin transporters allowing the access of peripheral leptin into
the brain, prevent leptin from interacting with its hypothalamic receptors. This
results in a state of leptin resistance that also leads to obesity, with accompanying
hyperleptinemia related to the oversecretion of this hormone.
NEUROPEPTIDES FAVORING FOOD INTAKE
(OREXIGENIC)
Neuropeptide Y
Basic Observations
in the arcuate nucleus and released in the paraventricular nucleus, thereby stimu-
lating food intake via Y1 and/or Y5 receptors. The increase in food intake is best
observed upon infusing the peptide intracerebroventricularly (i.c.v.) in normal
rats and is accompanied by a marked increase in body weight. Central NPY in-
fusion stimulates insulin secretion by activating the vagus nerve and increases the
activity of the hypothalamo-pituitary-adrenal (HPA) axis, which results in hyper-
corticosteronemia (4,5). It reduces the activity of the efferent sympathetic nerve
that reaches energy-dissipating organs, resulting in decreased energy expenditure,
an effect ascribed to NPY-Y5-receptors (6).
When prolonged, central NPY infusion increases adipose tissue and liver
lipogenic activity, increases fat storage, decreases insulin-stimulated glucose uti-
lization, and decreases oxidation processes (4). Under physiological conditions,
the high hypothalamic NPY levels that stimulate food intake persist until adi-
pose tissue leptin is secreted, reaches the brain, and decreases hypothalamic NPY
levels, thereby exerting its negative feedback on this neuropeptide and bringing
NPY-elicited changes to an end.
Experiments have cast doubts on the physiological importance of NPY in the
regulation of food intake. In transgenic mice made deficient in NPY, the expected
decrease in both food intake and body weight fails to occur (7). Transgenic mice
lacking the NPY-Y1 or Y5 receptor actually gain more weight, not less, than the
controls(8). However,ratherthandisprovingtherelevanceofNPY,thesedatamay
indicate that the regulation of food intake and body weight is redundant, with one
orseveralpathwayscompensatingforthelackofNPY.Forexample,hypothalamic
NPY, a 36–amino acid peptide, is synthesized, in particular,

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341
NPYandmelanocortinsarefunctionallyinterrelated,orexinsstimulatefeedingvia
NPYergic pathways, and NPY is coexpressed with agouti-related protein (AGRP),
another food-intake stimulator.
Obesity and NPY
ofobesitysyndromes(1,4),i.e.hyperinsulinemia,hypercorticism,hyperlipidemia,
increasedlipidstorageinadiposetissue,andinsulinresistance. Thesuggestionthat
increased hypothalamic NPY levels contribute to spontaneous obesity syndromes
is supported by the observations that NPY levels are elevated in ob/ob, db/db,
and fa/fa obese rodents (1). Increased NPY levels in ob/ob mice are caused
by a mutation of the adipose tissue ob (leptin) gene, which prevents secretion
of leptin from this tissue, so that leptin fails to exert its negative feedback on
hypothalamic NPY expression or levels. In the db/db and fa/fa obese rodents, the
ob gene of adipose tissue is normal, but the long-form leptin receptor is mutated
in its intracellular (db/db) or extracellular (fa/fa) domain. Although leptin is
overproduced by adipose tissue (hyperleptinemia), it cannot act centrally (leptin
resistance). Thus, hypothalamic NPY levels remain high and obesity results (9).
Chronic central NPY infusion reproduces most abnormalities
Melanin-Concentrating Hormone (MCH)
Basic Observations
It is present in many brain areas, notably in the lateral hypothalamus. Its name
derives from its ability to cause melanosome aggregation in fish skin, an action
thatisantagonizedbyα-MSH,themelanosome-dispersingfactor. However,arole
for MCH in the central regulation of food intake has been discovered: i.c.v. MCH
administration increases food intake in normal rodents (10).
MCH stimulation of food intake is transient and moderate in amplitude com-
paredwiththatproducedbyNPY(11). ThefeedingeffectofMCHiscounteracted
by α-MSH, glucagon-like peptide (GLP-1), and neurotensin (11). The physiolog-
ical role of MCH in food intake regulation has been strengthened by the discovery
of specific MCH receptors and by the observation that mice carrying a targeted
deletion of the MCH gene are hypophagic and thinner than controls.
CentralleptinadministrationdecreaseshypothalamicMCHexpressionandpre-
vents MCH-induced increase in food intake (12).
MCH is a cyclic neuropeptide comprising 19 amino acids.
Obesity and MCH
MCHadministrationfailstoproducesustainedincreasesinfoodintakeandinbody
weight gain (hence obesity). However, in the obese ob/ob mouse, hypothalamic
MCH expression is increased and may participate in the development of the obese
phenotype(10). IthasbeensuggestedthatMCHmayproduceboutsofhyperphagia
that, with time, would ultimately lead to obesity.
In contrast to what is observed with NPY, long-term central
Orexins
Basic Observations
also referred to as hypocretins (i.e. hypothalamic location, sequence analogy
Orexins (from the Greek word for appetite) A and B are

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JEANRENAUD ? ROHNER-JEANRENAUD
to secretin). Orexin A (33 amino acids) and orexin B (28 amino acids) bind to
specific receptors. The acute stimulatory effect of central administration of orexin
on food intake is much weaker than that of NPY, and somewhat weaker than that
of MCH. Orexin A is more potent than orexin B.
Like NPY, orexin A has some centrally elicited effects that are mediated by an
activation of the parasympathetic nervous system (e.g. the stimulation of gastric
acid secretion), favoring anabolic processes. Other qualitative similarities to NPY
are that orexin A favors insulin output (13) and that both orexins stimulate the
secretion of corticosterone (14).
Leptin administration produces a diminution of orexin A levels in the lateral
hypothalamus, thereby canceling its effect.
Obesity and Orexins
food intake, it does not cause obesity in rats, making the role of orexins in obe-
sity syndromes uncertain at present. Orexin cells are anatomically located in the
hypothalamus, but their widespread projections suggest that orexins have other
physiopathological roles yet to be defined.
Although chronic orexin A treatment increases daytime
Opioids
Basic Observations
regulation of ingestive behavior via the now cloned receptor subtypes kappa, mu,
and delta. The central administration of opioid agonists stimulates food intake,
favorsfataswellassucroseingestion,andincreasesbodyweightgain. Thecentral
administration of opioid antagonists does the reverse, decreasing food intake and
body weight (15,16).
Anotherreceptor,homologoustotheopioidreceptorsbutnotbindinganyopioid
peptides, has been cloned and named opioid receptor-like-1 (ORL-1). It is present
withinthecentralnervoussystem,notablythehypothalamus(17). Theendogenous
ligandforthisopioid-likeorphanreceptoriscallednociceptin(becauseitincreases
pain responsiveness). It is an 18–amino acid peptide that has a marked affinity for
ORL-1. The nociceptin/ORL-1 combination constitutes a new peptidergic system
within the central nervous system. When given centrally, nociceptin stimulates
food intake in normal rats (17).
The opioids have long been known to play a role in the
ObesityandOpioids
the hyperphagia and obesity of the Zucker (fa/fa) rat (18). Also, the susceptibility
to obesity induced by a high-fat diet in the rat is strain dependent (19) and may
depend on the sensitivity to opioids, with increased sensitivity favoring increased
fat intake and thus leading to obesity.
The likely importance of the opioid system in obesity is illustrated by the
observation that the peripheral administration of compounds with potent opioid-
antagonisticactivitytoobeseratsresultsinrapid, marked, andsustaineddecreases
in food intake and body weight gain.
Ithasbeensuggestedthatendogenousopioidscontributeto

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343
NEUROPEPTIDES INHIBITING FOOD INTAKE
(ANOREXIGENIC)
Cocaine- and Amphetamine-Regulated Transcript (CART)
Basic Observations
arecentlydiscoveredhypothalamicpeptidethatinhibitsfoodintake. Intherat, the
CARTgeneencodestwosplicedmRNAvariantsthatpredicttwodifferentproteins
of116or129aminoacidresidues(20). Thematurepeptidecontainsseveralcleav-
age sites and CART may be post-transcriptionally processed into long and short
fragments. The short-form CART (amino acids 42–89 of the whole molecule)
is found in rat hypothalamus and in humans (20). CART has histochemical rela-
tionships with hypothalamic NPY, MCH, and orexins that indicate a role in the
regulation of energy balance (21). Acute i.c.v. CART administration to normal
rats produces a dose-dependent decrease in food intake (22). It potently inhibits
NPY-induced food intake (22) and activates hypothalamic c-fos. CART appears
to have a “tonic” inhibitory influence on food intake: Treatment of rats with anti-
CART antiserum results in increased food intake (22). CART is upregulated by
leptin (22).
Cocaine- and amphetamine-regulated transcript (CART) is
Obesity and CART
rat (22). Hypothalamic CART expression is also low in the leptin-deficient ob/ob
mouseandisincreasedbychronicperipheralleptinadministrationtotheseanimals,
a rise paralleled by a decrease in body weight (22). Thus, failure of leptin to act
centrally (as in the fa/fa rat), or to be secreted from adipose tissue (as in the
ob/ob mouse), results in low levels of CART that may be responsible for lack of
food-intake inhibition and hence hyperphagia (22).
Incontrast, inobesityinducedbyahigh-fatdiet, leptinhassubstantialaccessto
the brain. It acts to some degree within the hypothalamus (leptin receptors being
partlyfunctional),andhypothalamicCARTlevelsofhigh-fat–obeseratsarehigher
thanthoseofcontrols(23). ThishighCARTexpressionappearstolimitthedegree
of this type of obesity syndrome. Indeed, high-fat-diet–obese rats have a normal
food intake and their obesity is less marked than that of ob/ob or fa/fa rodents.
When central CART levels are further increased in high-fat-diet–obese rats by the
chronic i.c.v. administration of the peptide, their food intake and body weight are
markedlydecreased,theirinsulinemiaandhyperleptinemiaarereduced,theirlipid
oxidation is enhanced, and fat storage stops.
CART expression is reduced in the genetically obese fa/fa
Corticotropin-Releasing Hormone (CRH)
Basic Observations
pituitary-adrenal(HPA)axis,corticotropin-releasinghormone(CRH),a41–amino
acid peptide, functions as a central effector that brings about a state of negative
energybalanceandweightloss.ThisisduetotheabilityofcentralCRHtodecrease
In addition to its role as controller of the hypothalamo-