Leptin Resistance and Obesity

Pablo J. Enriori, Anne E. Evans, Puspha Sinnayah, and Michael A. Cowley

Abstract processes that include basal metabolism, adaptive thermo-

ENRIORI, PABLO J., ANNE E. EVANS, PUSPHA genesis, and physical activity. Adaptive thermogenesis re-
SINNAYAH, AND MICHAEL A. COWLEY. Leptin fers to an increase in heat production through futile meta-
resistance and obesity. Obesity. 2006;14(Suppl 5):254S–258S. bolic cycles in response to environmental or behavioral
The prevalence of obesity, and the human and economic changes (excess food consumption, change in the composi-
costs of the disease, creates a need for better therapeutics tion of diet, modification of ambient temperature, or a
and better understanding of the physiological processes that variety of pathogenic stimuli) (3). These thermogenic, met-
balance energy intake and energy expenditure. Leptin is the abolically futile cycles are facilitated by uncoupling pro-
primary signal from energy stores and exerts negative feed- teins (1– 4), which decouple oxidative phosphorylation from
back effects on energy intake. In common obesity, leptin ATP generation by destabilizing mitochondrial proton gra-
loses the ability to inhibit energy intake and increase energy dients.
expenditure; this is termed leptin resistance. This review In most adults, body weight is almost constant despite
discusses the evidence in support of leptin resistance in huge variations in daily food intake and energy expenditure
mouse models and humans and the possible mechanisms of (5). Therefore, complex physiological systems equilibrate
leptin resistance. energy expenditure with energy intake. Energy balance is
regulated by peripheral signals (hormones) that are inte-
Key words: proopiomelanocortin, agouti-related pep- grated in the brain centers, including the hypothalamus,
tide, arcuate nucleus, suppressor of cytokine signaling-3, brainstem, and reward centers, which in turn modulate
food intake feeding and energy expenditure (6,7). Some hormones re-
flect the long-term nutritional status of the body (including
leptin, insulin, and perhaps, adiponectin), whereas other
Introduction circulating gut hormones act acutely to initiate or terminate
Obesity is defined as an excessive proportion of body fat
a meal (such as ghrelin, peptide YY3–36, pancreatic
relative to lean body mass of sufficient magnitude to pro-
polypeptide, oxyntomodulin, glucagon-like peptides 1 and
duce adverse health consequences (1). There has been a
2, and cholecystokinin) and result in appetite stimulation or
dramatic increase in the prevalence of obesity in the world;
satiety (7). To date, we can consider leptin to be the most
⬎60% of American adults are now overweight or obese.
important peripheral signal for the balance of energy ho-
Additionally, the prevalence of obesity in children is grow-
meostasis (8).
ing dramatically, predisposing them to a host of chronic
diseases (2).

Leptin Informs the Brain of Levels of Stored

Energy In – Energy Out ⴝ Energy Stored Fat
Energy homeostasis is the balance between energy in- Leptin is secreted primarily by adipocytes and is present
take, energy expenditure, and energy storage. Maintenance in serum in direct proportion to the amount of adipose tissue
of body weight depends on the balance between energy (9 –11). The primary role of leptin is to provide the central
intake and energy expenditure. Energy intake is food intake; nervous system with a signal of energy (adipose) stores in
energy expenditure is derived from complex thermogenesis the body to enable the brain to make the adjustments nec-
essary to balance energy intake and expenditure (12). One
well-accepted role of leptin signaling is to act as a gate-
Division of Neuroscience, Oregon National Primate Research Center, Oregon Health &
Science University, Beaverton, Oregon. keeper to a range of activities that are not essential for
Address correspondence to Michael A. Cowley, Division of Neuroscience, OHSU, 505 NW immediate survival, such as reproduction.
185th Avenue, Beaverton, OR 97006.
E-mail: [email protected]
Only when leptin concentrations exceed certain thresh-
Copyright © 2006 NAASO olds are these non-essential behaviors expressed.

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Leptin Resistance and Obesity, Enriori et al.

Leptin regulates food intake by binding to central nervous tivity of AgRP/NPY neurons (31) (E.E. Jobst and M.A.
system receptors and modulating the activity of neurons in Cowley, unpublished data). In contrast, leptin activates
appetite control centers in the brain (9,13). In obese leptin- POMC neurons, as shown by increased expression of
deficient mice (ob/ob), exogenous administration of leptin POMC mRNA (32), which might promote the release of the
effectively reduces hyperphagia and obesity (14). Con- ␣-MSH, a potent anorexigen at central MC4R (33). This is
versely, obese mice that are deficient in the signaling form also shown by electrophysiological recordings that show
of the leptin receptor (db/db) do not respond to leptin leptin depolarizing (i.e., activating) POMC neurons (26,34).
(14,15). As will be described later, in “common” obesity Leptin also modulates the activity of neurons in the ventro-
leptin does not cause clear effects on energy balance. medial hypothalamus (VMH) that express the transcription
steroidogenic factor-1 (SF-1) (35). Deletion of ObRb on
POMC or on VMH SF-1 neurons produces comparable
Leptin Regulates Energy Intake and obesity (27,35), showing that multiple neuronal systems can
Expenditure participate in leptin sensing and the control of body weight.
In addition to its effects on appetite, leptin also affects
energy expenditure in rodents and humans (14,16). Activa-
tion of central leptin receptors increases the activity of the
sympathetic nervous system (17,18) which stimulates en- Leptin May Modulate Endocannabinoid
ergy expenditure in adipose tissue (19 –21). Signaling
Endocannabinoids are post-synaptic regulators of presyn-
aptic activity; they act retrogradely to inhibit synaptic ac-
Leptin Acts on a Diffuse Neuronal Network, tivity. The significance of retrograde signaling used by
Including Neurons in the Arcuate Nucleus cannabinoids for modulation of energy balance is yet to be
There is considerable debate about the anatomical loci explored extensively. There is a possible link between the
through which leptin affects energy balance, but recent endocannabinoid system and leptin in the modulation of
work from many laboratories suggests that there is not a food intake. In young ob/ob mice lacking leptin, hypotha-
single locus of activity. Rather, leptin acts on a dispersed lamic 2-AG (an endogenous endocannabinoid) levels are
network of neurons, such that it can act on many anatomical elevated, and these levels are normalized by peripheral
loci that partially regulate energy balance. It is clear that intravenous leptin. Thus, hypothalamic endocannabinoids
leptin receptors (ObRb)1 are highly expressed in regions of seem to be under negative control by leptin (36), and leptin
the hypothalamus that mediate energy homeostasis (22,23). modulates the activity of lateral hypothalamic nucleus neu-
To access receptors in areas distal to circumventricular rons in an endocannabinoid-dependent manner (37).
organs, peripheral leptin is transported across the blood– Rimonabant is a cannabinoid antagonist that is being
brain barrier (24). developed for obesity. NPY is probably not involved in
The arcuate nucleus (ARH) is a major site of leptin cannabinoid effects on energy balance (36) because the
sensing, and the ARH transduces peripheral signals into appetite-suppressing effects of rimonabant are preserved in
neuronal responses (25–27). The ARH contains at least two NPY-deficient mice. There is possibly an interaction be-
key populations of neurons that have opposite actions on tween the cannabinoid and melanocortin systems, since
food intake. One population expresses anorexigenic (appe- ␣-MSH does not block feeding-induced by a cannabinoid
tite-suppressing) peptides, cocaine- and amphetamine-regu- agonist, but rimonabant reduces feeding induced by a
lated transcript and ␣-melanocyte-stimulating hormone MC4R antagonist. This suggests that cannabinoid CB1 re-
[␣-MSH; derived from the proopiomelanocortin (POMC) ceptor blockade of feeding occurs downstream of MC4R
precursor]. The other population expresses the orexigenic
(38).
(appetite-stimulating) peptides, neuropeptide Y (NPY) and
Cannabinoids might act through reward pathways to
agouti-related peptide (AgRP) (28). Neurons in the ARH
stimulate feeding. Endocannabinoids elevate extracellular
subsequently innervate various second-order hypothalamic
levels of dopamine in the shell of the nucleus accumbens
targets that express melanocortin-4 (MC4R) and NPY re-
(39), and rimonabant reduces food intake induced by injec-
ceptors (29). Leptin can modulate the activity of both
tion of a cannabinoid agonist into the nucleus accumbens
POMC and AgRP neurons. Leptin reduces the expression of
shell (40). Rimonabant may also act on the mesolimbic
NPY/AgRP mRNA (22,30) and can rapidly inhibit the ac-
dopamine “reward” circuitry (41) that provides dopamine
input to the nucleus accumbens. Cannabinoid CB1 receptors
1
Nonstandard abbreviations: ObRb, leptin receptor; ARH, arcuate nucleus; ␣MSH, ␣-me- located on afferent pathways to the ventral tegmental area
lanocyte-stimulating hormone; POMC, proopiomelanocortin; NPY, neuropeptide Y; AgRP, have been proposed to contribute to mediating activity of
agouti-related peptide; MC4R, melanocortin 4 receptor; VMH, ventromedial hypothalamus;
SF-1, steroidogenic factor-1; HFD, high-fat diet; DIO, diet-induced obesity; STAT, signal
mesolimbic dopamine neurons and thereby dopamine-in-
transducer and activator of transcription; SOCS, suppressor of cytokine signaling. duced reward behavior (42,43).

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Leptin Resistance and Obesity, Enriori et al.

Leptin Resistance We can speculate that “physiological” leptin signaling

Most obese humans and rodents do not have low circu- attempts to limit body weight, even in obese states, but that
lating leptin. In contrast, they usually have very high plasma other factors are opposing this. In modern society, we might
leptin concentrations. However, this endogenous hyperlep- suggest that hedonic cues to overconsume are one such
tinemia may not reduce appetite or increase energy expen- factor. The effects of leptin are more obvious in a controlled
diture. There are only rare examples of single-gene muta- dietary paradigm, because the background influence of vari-
tions that are responsible for obesity in humans, and the able diet is absent. This interpretation suggests the question:
majority of “common” obesity is thought to be a conse- “Is obesity caused by increased hedonic and cortical cues to
quence of polygenic interaction with the environment (44). over-eat, which overwhelm the normal counter-regulatory
This state has been termed “leptin resistance.” Several responses to increased obesity?” As an additional compli-
mechanisms may contribute to leptin resistance. The two cation, we might hypothesize that in some situations leptin
hypotheses that have received the most attention are that signaling can cause desensitization, perhaps when levels are
circulating leptin fails to reach its targets in the brain (45) or elevated for a significant period of time, and that only after
that there is a failure of components of the intracellular leptin signaling is reduced for a period (such as after a long
ObRb signaling cascade (46). hypocaloric diet) can the system resensitize. A pertinent
Some strains of mice fed a high-fat diet (HFD) exhibit clinical example of this phenomenon is the use of gonado-
increased body adiposity and many other characteristics of tropin-releasing hormone agonists to down-regulate the re-
human obesity, and they show leptin resistance in some productive axis and androgen levels in men undergoing
paradigms. Diet-induced obesity (DIO) has proved to be an treatment for prostatic tumors (52).
excellent system to explore how leptin functions and iden-
tify how leptin signaling becomes compromised in obesity.
The development of obesity and leptin resistance in Conclusion
Whether leptin resistance occurs in humans remains open
C57BL/6J mice on HFD can be divided into three stages. In
to debate; however, there is very good evidence that it does
the early stage, mice on HFD gain weight (fat tissue) but
occur in animal model systems. If we can conclusively
maintain an adequate response to the anorectic effect of
identify the specific neuronal pathways that become leptin
peripheral leptin injection. In the middle stage, mice on
resistant in obese states, engaging these circuits may repre-
HFD show peripheral leptin insensitivity, expressed by
sent a therapeutic strategy to bypass insensitivity to endog-
changes in food intake and body weight or by lack of
enous leptin. Such a strategy would produce the same co-
activation of signal transducer and activator of transcription
ordinated actions on energy intake and energy expenditure
(STAT)-3, however these mice retain the capacity to re-
that are normally regulated by leptin which could help obese
spond to central leptin injection. Finally, there is a late state
patients decrease adiposity or comply with a low-calorie
in which mice develop central leptin resistance (47– 49) and
diet.
do not show changes in food intake and body weight or
activation of STAT-3 in response to icv leptin.
Recently, Munzberg et al. (50) showed that the expres- Acknowledgments
sion of p-STAT in cells of the ARH was selectively reduced We thank Sonja K. Billes for helpful review of this
in leptin-treated DIO mice but not in the VMH or dorso- manuscript. This study was supported by NIH Grants
medial hypothalamus, suggesting that the ARH is a major RR0163 and DK 62202.
site of leptin resistance. Increased suppressor of cytokine
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