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Mechanisms of Leptin Action and Leptin Resistance

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The adipose tissue-derived hormone leptin acts via its receptor (LRb) in the brain to regulate energy balance and neuroendocrine function. LRb signaling via STAT3 and a number of other pathways is required for the totality of leptin action. The failure of elevated leptin levels to suppress feeding and mediate weight loss in common forms of obesity defines a state of so-called leptin resistance. A number of mechanisms, including the leptin-stimulated phosphorylation of Tyr(985) on LRb and the suppressor of cytokine signaling 3, attenuate leptin signaling and promote a cellular leptin resistance in obesity. Several unique features of the arcuate nucleus of the hypothalamus may contribute to the severity of cellular leptin resistance in this region. Other mechanisms that govern feeding behavior and food reward may also underlie the inception of obesity.
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ANRV336-PH70-23 ARI 28 December 2007 17:52
Mechanisms of Leptin
Action and Leptin
Resistance
Martin G. Myers,
1
Michael A. Cowley,
2
and Heike M
¨
unzberg
1
1
Division of Metabolism, Endocrinology and Diabetes, Department of Medicine
and Department of Molecular and Integrative Physiology, University of Michigan
Medical School, Ann Arbor, Michigan 48109; email: mgmyers@umich.edu,
hmuenzbe@umich.edu
2
Division of Neuroscience, National Primate Research Center, Oregon Health and
Sciences University, Beaverton, Oregon 97006; email: cowleym@ohsu.edu
Annu. Rev. Physiol. 2008. 70:537–56
First published online as a Review in Advance on
October 15, 2007
The Annual Review of Physiology is online at
http://physiol.annualreviews.org
This article’s doi:
10.1146/annurev.physiol.70.113006.100707
Copyright
c
2008 by Annual Reviews.
All rights reserved
0066-4278/08/0315-0537$20.00
Key Words
hypothalamus, VTA, obesity, diabetes
Abstract
The adipose tissue–derived hormone leptin acts via its receptor
(LRb) in the brain to regulate energy balance and neuroendocrine
function. LRb signaling via STAT3 and a number of other pathways
is required for the totality of leptin action. The failure of elevated
leptin levels to suppress feeding and mediate weight loss in common
forms of obesity defines a state of so-called leptin resistance. A num-
ber of mechanisms, including the leptin-stimulated phosphorylation
of Tyr
985
on LRb and the suppressor of cytokine signaling 3, attenu-
ate leptin signaling and promote a cellular leptin resistance in obesity.
Several unique features of the arcuate nucleus of the hypothalamus
may contribute to the severity of cellular leptin resistance in this
region. Other mechanisms that govern feeding behavior and food
reward may also underlie the inception of obesity.
537
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ANRV336-PH70-23 ARI 28 December 2007 17:52
LEPTIN
The adipose tissue–derived hormone leptin is
produced in proportion to fat stores. Circulat-
ing leptin serves to communicate the state of
body energy repletion to the central nervous
system (CNS) in order to suppress food intake
and permit energy expenditure (1–3). Many
of the physiological adaptations triggered by
prolonged fasting can be attenuated by exoge-
nously administered leptin, which falsely sig-
nals to the brain that energy stores are replete
(3–5). Adequate leptin levels permit energy
expenditure on the processes of reproduc-
tion, tissue remodeling, and growth and sim-
ilarly regulate the autonomic nervous system,
other elements of the endocrine system, and
the immune system (3–5). Conversely, lack
of leptin signaling due to mutation of leptin
(e.g., ob/ob mice) or the leptin receptor (LR)
(e.g., db/db mice) in rodents and humans re-
sults in increased food intake in combina-
tion with reduced energy expenditure and
a phenotype reminiscent of the neuroen-
docrine starvation response (including hy-
pothyroidism, decreased growth, infertility,
and decreased immune function) in spite of
obesity (1, 2, 6, 7).
LEPTIN RECEPTORS AND SITES
OF LEPTIN ACTION
There are multiple LR isoforms, all of which
are products of a single Lepr gene (8, 9). The
Lepr gene contains 17 common exons and sev-
eral alternatively spliced 3
exons. In mice, the
six distinct LR isoforms that have been iden-
tified are designated LRa–LRf. In all species,
LR isoforms are divisible into three classes:
secreted, short, and long. The secreted forms
are either products of alternatively spliced
mRNA species (e.g., murine LRe, which
contains only the first 14 exons of Lepr)or
proteolytic cleavage products of membrane-
bound forms of LR. These secreted forms
contain only extracellular domains that bind
circulating leptin, perhaps regulating the
concentration of free leptin (10).
Short-form LRs (LRa, LRc, LRd, and LRf
in mice) and the long-form LR (LRb in mice)
contain exons 1–17 of Lepr and therefore have
identical extracellular and transmembranedo-
mains as well as the same first 29 intracel-
lular amino acids but diverge in sequence
thereafter owing to the alternative splicing
of 3
exons. Short-form LRs contain exons
1–17 and terminate 3–11 amino acids after
the splice junction for total intracellular do-
main lengths of 32–40 amino acids. LRc-,
LRd-, and LRf-specific sequences are not well
conserved among species. However, LRa (the
most abundantly expressed isoform) is rea-
sonably well conserved, as is LRb, which has
an intracellular domain of approximately 300
residues (8, 9).
LRb is crucial for leptin action. Indeed, the
originally described db/db mice lack LRb (but
not other LR forms) as a consequence of a
mutation that causes missplicing of the LRb
mRNA; these mice closely resemble db
3J
/db
3J
mice (which are deficient in all LR isoforms)
and leptin-deficient ob/ob animals (3). The
function of short-form LRs is less clear, al-
though proposed roles include the transport
of leptin across the blood-brain barrier (BBB)
and the production of circulating LR extracel-
lular domain to complex with leptin (10, 11).
Many of the effects of leptin result from
actions in the CNS, particularly in the hy-
pothalamus, a site of high LRb mRNA expres-
sion (12–15). In the hypothalamus, leptin acts
on neurons that directly or indirectly regulate
levels of circulating hormones (e.g., thyroid
hormone, sex steroids, and growth hormone)
(12, 16, 17). Leptin action on these hypotha-
lamic neurons also regulates the activity of the
autonomic nervous system, although direct
effects of leptin on LRb-containing neurons
in the brainstem and elsewhere probably also
have an important role (18). The effects of lep-
tin on the immune system and vasculature ap-
pear to result from direct action on hematoge-
nous cells that contain LRb (5, 19). Leptin
may also regulate glucose homeostasis inde-
pendently of its effects on adiposity; leptin
regulates glycemia at least partly via the CNS,
538 Myers
·
Cowley
·
unzberg
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ANRV336-PH70-23 ARI 28 December 2007 17:52
but it may also directly regulate pancreatic β-
cells and insulin-sensitive tissues (20–24).
LEPTIN REGULATION OF
NEURAL NETWORKS AND
NEUROPHYSIOLOGY
LRb is present in several tissues; the highest
levels are in neurons of several nuclei of the
hypothalamus, including the arcuate (ARC),
dorsomedial (DMH), ventromedial (VMH),
lateral hypothalamic area (LHA), and ven-
tral premammillary (PMv) nuclei (12–14, 25).
Other sites within the brain that have been
shown to express functional LRb include the
ventral tegmental area (VTA), brainstem [in-
cluding the nucleus of the solitary tract (NTS)
and dorsal motor nucleus of the vagus], and
the periaqueductal gray matter, among others.
LRb action on two populations of ARC
neurons is particularly well characterized.
One population synthesizes neuropeptide Y
(NPY) and agouti-related peptide (AgRP),
and the other synthesizes pro-opiomel-
anocortin (POMC) (12, 15). POMC is pro-
cessed to produce α-melanocyte-stimulating
hormone (αMSH) in LRb/POMC neurons;
αMSH signals anorexia (decreased appetite)
by activating the melanocortin-4 receptor
(MC4R) and the melanocortin-3 receptor
(MC3R) (26–31). LRb stimulates the syn-
thesis of POMC, activates LRb/POMC
neurons (15, 32), and stimulates αMSH se-
cretion (33). NPY is an orexigenic (appetite-
stimulating) hormone that also suppresses
the central LRb-mediated growth and re-
productive axes (34–37). AgRP is an antag-
onist of αMSH/MC4R signaling as well as
an inhibitor (inverse agonist) of endogenous
MC4R activity (36, 38). Leptin acts via LRb to
inhibit NPY/AgRP neurons and suppress the
expression and secretion of NPY and AgRP
(15, 32, 33). Thus, LRb signaling stimulates
the production and secretion of anorectic neu-
ropeptides and reciprocally suppresses levels
of orexigenic peptides. Conversely, a decrease
or deficiency in leptin action (e.g., during star-
vation or in ob/ob and db/db mice) stimulates
appetite by the suppression of the synthesis
of anorectic neuropeptides (e.g., POMC) and
increased expression of orexigenic peptides
(e.g., NPY and AgRP).
Although we now know a great deal
about the mechanisms by which the ARC
NPY/AgRP and POMC neurons function,
numerous questions remain regarding the
contributions of each circuit to the regula-
tion of feeding in general and in response
to leptin under physiological conditions. Al-
though ablation of AgRP neurons results in
hypophagia and ablation of POMC or central
melanocortin receptors results in severe obe-
sity (27, 39), deletion of LRb from POMC
neurons or the restoration of LRb in the
ARC of db/db animals results in only mod-
est alterations in body weight (although these
manipulations robustly modulate glucose
homeostasis) (40, 41).
Furthermore, although interference with
LRb STAT3 (signal transducer and ac-
tivator of transcription 3) signaling results
in dramatic hyperphagia and obesity, dele-
tion of STAT3 in ARC neurons only mod-
estly impacts body energy homeostasis (42–
44). Thus, although melanocortins and ARC
neurons generally effect powerful appetitive
signals, they may not constitute the major-
ity of the leptin-mediated anorectic signal;
the aggregate leptin signal is likely mediated
in concert with many other populations of
LRb-expressing neurons that require further
analysis. Indeed, ARC LRb neurons comprise
only 15–20% of the total number of LRb-
expressing neurons within the CNS (25), and
other populations of LRb neurons, includ-
ing those in the VMH and VTA, clearly me-
diate important components of leptin action
(45–47).
LEPTIN RECEPTOR SIGNALING
LRb belongs to the interleukin (IL)-6 recep-
tor family of class 1 cytokine receptors, which
contain an extracellular ligand-binding do-
main, a single transmembrane domain, and
a cytoplasmic signaling domain (8, 48). Like
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ANRV336-PH70-23 ARI 28 December 2007 17:52
other cytokine receptors, LRb does not con-
tain intrinsic enzymatic activity but instead
signals via a noncovalently associated tyro-
sine kinase of the Jak kinase family ( Jak2
in the case of LRb) (49–51). Leptin bind-
ing alters the conformation of the preformed
LRb homodimer, enabling transphosphoryla-
tion and activation of the intracellular LRb-
associated Jak2 (8, 52, 53). The activated Jak2
molecule then phosphorylates other tyrosine
residues within the LRb/Jak2 complex to me-
diate downstream signaling (54, 55).
Signaling by cytokine receptors requires
a proline-rich Box 1 motif critical for Jak
kinase interaction and activation; additional,
less-conserved sequences COOH-terminal to
Box 1 (sometimes referred to as Box 2) are
also important for Jak interactions and likely
function in Jak isoform selectivity (48, 49,
51, 56). In the case of LRb, intracellular
residues 31–36 (i.e., those immediately down-
stream of the alternative splice junction fol-
lowing amino acid 29) compose Box 2 and
dictate Jak2 selectivity (51, 56). This Box 2
sequence is absent from all described short
LR isoforms—consistent with the inability of
these molecules to mediate leptin action in
db/db animals (8, 51, 54).
Tyrosine kinase–dependent signaling gen-
erally proceeds via the phosphotyrosine-
mediated recruitment of signaling proteins
that contain specialized phosphotyrosine-
binding domains (e.g., SH2 domains) (57).
Each SH2 domain isoform recognizes phos-
photyrosine in a specific amino acid con-
text. Thus, although tyrosine phosphoryla-
tion acts as a molecular switch to recruit
SH2-containing proteins, each tyrosine phos-
phorylation site recruits only specific SH2
isoforms because each isoform recognizes
specific surrounding amino acids as well as the
phosphotyrosine residue. For instance, the
SH2 domain of the latent transcription fac-
tor STAT3 binds to phosphotyrosine in the
context of a Y(P)XXQ motif (58, 59).
Understanding signaling by the LRb/Jak2
complex thus requires defining the tyrosine
phosphorylation sites on LRb and Jak2 and
the SH2 proteins that they recruit. There are
three conserved residues on the intracellular
domain of LRb: Tyr
985
,Tyr
1077
, and Tyr
1138
.
Data from our and other labs suggest that all
three of these sites are phosphorylated and
contribute to downstream leptin signaling (8,
54, 55, 60, 60a).
There are thus four tyrosine phosphoryla-
tion signaling pathways that can derive from
LRb (Figure 1): those originating directly
from Jak2 tyrosine phosphorylation sites and
those emanating from the phosphorylation of
Ty r
985
,Tyr
1077
, and Tyr
1138
of LRb. The phos-
phorylation of Tyr
985
creates a binding site for
the COOH-terminal SH2 domain of the ty-
rosine phosphatase SHP-2, leading to the ac-
tivation of the canonical p21ras ERK sig-
naling pathway in cultured cells (51, 55, 61).
Phosphorylation of Tyr
1138
recruits
STAT3 to the LRb/Jak2 complex, resulting
in the tyrosine phosphorylation and subse-
quent nuclear translocation of STAT3 to
mediate transcriptional regulation (54, 55).
Among the STAT3-regulated genes is the
SH2 domain–containing feedback inhibitor
SOCS3 (suppressor of cytokine signaling 3)
(55, 62). Following its STAT3-dependent
production during leptin stimulation, SOCS3
binds to Tyr
985
of LRb to mediate the in-
hibition of LRb STAT3 signaling (63);
SOCS3 also binds to a separate site on Jak2
(64, 65).
Ty r
1077
mediates a crucial component of
STAT5 (signal transducer and activator of
transcription 5) phosphorylation and tran-
scriptional regulation by leptin, although
Ty r
1138
also contributes to STAT5 activation
(60, 60a). Tyr
1077
does not regulate STAT3
signaling, although it may promote the in-
creased phosphorylation of LRb Tyr
985
.
Jak2 tyrosine phosphorylation during LRb
stimulation may mediate some signals inde-
pendently of tyrosine phosphorylation sites
on LRb (55). The individual phosphorylation
sites on Jak2 are beginning to be enumer-
ated (66–73). Unfortunately, many more re-
main to be identified, and the binding part-
ners and signals mediated by many sites are
540 Myers
·
Cowley
·
unzberg
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ANRV336-PH70-23 ARI 28 December 2007 17:52
Figure 1
LRb signaling, feedback inhibition, and the regulation of physiology. Leptin binding to the extracellular
domain of LRb, the functional leptin receptor isoform, mediates the activation of the intracellular,
LRb-associated Jak2 tyrosine kinase, resulting in Jak2 autophosphorylation on tyrosine residues (pY) as
well as the phosphorylation of three tyrosine residues on the intracellular tail of LRb: Y
985
,Y
1077
, and
Y
1138
.pY
1138
recruits signal transducer and activator of transcription (STAT) 3, which is activated to
mediate transcriptional events, including the transcription of pro-opiomelanocortin (POMC) and the
inhibitory suppressor of cytokine signaling 3 (SOCS3) protein. pY
1077
recruits and mediates the
transcriptional activation of STAT5. pY
985
recruits the tyrosine phosphatase SHP-2 and also binds to
SOCS3 and mediates feedback inhibition of LRb signaling (dotted lines). The tyrosine phosphatase
PTP1B, although not regulated by leptin in this manner, also inhibits LRb/Jak2 signaling. The cellular
mechanisms by which LRb couples to the regulation of phosphatidylinositol 3-kinase (PI3K),
mammalian target of rapamycin (mTOR), and AMP-activated protein kinase (AMPK) pathways remain
unclear. Y
1138
-mediated STAT3 signaling by LRb (presumably via POMC and additional mechanisms) is
crucial to the regulation of anorexia and energy expenditure by leptin. Although Y
985
clearly functions to
attenuate LRb signaling in vivo, a role for Y
985
and SHP-2 in promoting leptin action has not been
defined. Leptin mediates permissive effects upon reproduction, growth, hematopoietic effects (e.g.,
immune and platelet function), and the inhibition of agouti-related protein (AgRP)/neuropeptide Y
(NPY) neurons of Y
1138
and Y
985
, perhaps via pY sites on Jak2 or via pY
1077
.
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not known, limiting our understanding of the
mechanisms by which Jak2-dependent sig-
nals are mediated. LRb stimulation mediates
the tyrosine phosphorylation of IRS proteins
and regulates the PI 3
-kinase pathway (74–
76) as well as the AMP-activated protein ki-
nase (AMPK) and mammalian target of ra-
pamycin (mTOR) pathways (77, 78), although
the molecular mechanisms by which LRb reg-
ulates these pathways remain unclear.
LRb SIGNALING VIA STAT3
MEDIATES A SUBSET OF
LEPTIN ACTIONS
Thus far, roles for two signals mediated
by LRb tyrosine phosphorylation sites—the
Ty r
1138
STAT3 pathway and the Tyr
985
SOCS3/SHP2 pathway—have been exam-
ined in leptin action in vivo (Figure 2).
We have directly addressed the contribution
of the LRb-STAT3 pathway to physiology
ARC
VMH
VTA
NTS
PVH
DMH
LHA
POA
DR
PB
Striatum
amygdala
PAG
PMv
Target areas to which LRb neurons project
(contain few or no LRb neurons)
Areas where little is known about the
projections of the LRb-expressing neurons
Components and regulators of the
mesolimbic dopamine system
Figure 2
A distributed network of LRb-expressing neurons in the CNS regulates multiple neural processes.
Shown in blue, yellow, and brown bubbles are brain regions containing significant populations of
LRb-expressing neurons. Yellow bubbles indicate areas where little is known about the projections of the
LRb-expressing neurons. Bubbles with arrows have LRb neurons with somewhat defined projection
patterns. Target areas to which LRb neurons project but that contain few or no LRb neurons are denoted
as light green bubbles. Components and regulators of the mesolimbic dopamine system are shown in
brown bubbles. ARC, arcuate nucleus; PVH, paraventricular hypothalamic nucleus; VMH, ventromedial
hypothalamic nucleus; DMH, dorsomedial hypothalamic nucleus; LHA, lateral hypothalamic area; PMv,
ventral premammilary nucleus; POA, preoptic area; VTA, ventral tegmental area; PAG, periaqueductal
gray; DR, dorsal raphe; PB, parabrachial nucleus; NTS, nucleus of the solitary tract.
542 Myers
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·
unzberg
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by studying homologously targeted knock-in
mice in which LRb is replaced by a mutant
molecule (LRb
S1138
) that contains a substitu-
tion mutation of Tyr
1138
(the STAT3 binding
site) (42). Although LRb
S1138
fails to medi-
ate STAT3 activation during leptin signaling,
this mutant regulates all other known LRb
signaling pathways. The use of the knock-
in approach ensures that the expression pat-
tern and levels of LRb
S1138
mirror those of
wild-type LRb.
Similar to db/db animals, mice homozygous
for LRb
S1138
expression (s/s) display hyperpha-
gia and decreased energy expenditure, result-
ing in profound obesity in the face of dramat-
ically increased serum leptin levels. The high
circulating leptin levels in s/s animals not only
correlate with increased adipose mass in these
mice but also indicate resistance to the en-
ergy homeostatic effects of leptin (42). Feed-
ing is similarly high in s/s and db/db mice, and
thyroid function and energy expenditure are
similarly decreased in these two mouse strains
(79).
Important differences exist between the
phenotypes of s/s mice (missing only the LRb-
STAT3 signal) and db/db mice (devoid of all
leptin signals), however (42). Whereas db/db
animals are floridly diabetic and infertile and
demonstrate decreased linear growth, s/s mice
demonstrate greatly improved glucose toler-
ance compared with db/db mice. The s/s mice
also retain fertility and demonstrate increased
linear growth as well as immune and vascular
reactivity to leptin compared with wild-type
animals (42, 79–83).
Analysis of hypothalamic neuropeptide ex-
pression reveals that, similar to db/db mice, s/s
mice have decreased POMC mRNA levels in
the hypothalamus (42). By contrast, whereas
db/db animals display dramatic induction of
hypothalamic NPY mRNA, levels of NPY
message are near normal in s/s animals. Fur-
thermore, the activity of these AgRP/NPY
neurons is appropriately suppressed in s/s, but
not db/db, animals (84). These data suggest
that LRb-STAT3 signaling is a crucial reg-
ulator of hypothalamic melanocortin action
and that dysregulated melanocortin signal-
ing (as opposed to alterations in NPY) may
contribute to the obesity of s/s animals, al-
though STAT3 presumably mediates other
leptin effects in other LRb-expressing neu-
rons. Hence, non-STAT3 LRb signals are
critical regulators of neural activity and NPY
expression in the LRb/NPY neuron.
Clearly, pathways independent of LRb
STAT3 regulate glycemic control, the func-
tion of hematopoietic and vascular cells, re-
production, growth, and NPY/AgRP neurons
in response to leptin. The phenotype of the
s/s animals does not suggest the irrelevance of
non-STAT3 pathways in other aspects of en-
ergy balance, however, and reveals only that
STAT3 signaling is important for the regu-
lation of energy homeostasis. Thus, signals
independent of Tyr
1138
STAT3 may con-
tribute to energy balance as well as to the
myriad leptin effects that are preserved in
s/s mice.
LRb Tyr
985
ATTENUATES
LEPTIN ACTION IN VIVO
To understand the contribution of LRb Tyr
985
to leptin action and inhibition in vivo, we gen-
erated mice in which LRb was homologously
replaced by a mutant containing a substitu-
tion of Tyr
985
that abrogates phosphorylation
of the site and blocks SHP-2/SOCS3 recruit-
ment (55, 61, 63, 85). Mutation of Tyr
985
in
vivo results in reduced feeding and adiposity,
decreased orexigenic ARC neuropeptide ex-
pression, and increased baseline STAT3 acti-
vation in female l/l mice—all in the face of low
leptin levels. Coupled with the increased sen-
sitivity of l/l animals to exogenous leptin, these
observations suggest that mutation of Tyr
985
blocks the activation of an inhibitory Tyr
985
-
dependent LRb signal, ultimately leading to
increased leptin sensitivity in vivo. These re-
sults suggest an important role for Tyr
985
in
the attenuation of leptin action in vivo, con-
sistent with results from cultured cells sug-
gesting an important role for Tyr
985
in the in-
hibition of LRb signaling (63, 86, 87).
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Leptin resistance:
the failure of high
levels of leptin in
obese individuals to
suppress feeding and
prevent or mitigate
obesity
Because Tyr
985
of LRb recruits both
SHP-2 and SOCS3 (63, 87, 88), the failure
of LRb
L985
to recruit either of these proteins
may theoretically underlie the lean, leptin-
sensitive phenotype of l/l mice. Many data
from cultured cells and animals support a
primary role for SOCS3 in the inhibition
of LRb signaling, however, suggesting that
SOCS3 (rather than SHP-2) mediates Tyr
985
-
dependent inhibition of LRb (61–63, 83,
89–91).
The phenotype of l/l mice also suggests
that SHP-2 may not be required for the reg-
ulation of growth or reproduction by leptin
and does not mediate essential anorectic sig-
nals. This finding contrasts with the obesity
and impaired neuroendocrine function in an-
imals with deletion of SHP-2 in the forebrain
(91), consistent with the notion that disrup-
tion of SHP-2 alters signaling by numerous
factors other than leptin and in a wide va-
riety of neuronal populations (92, 93). The
loss of SHP-2 recruitment by leptin in l/l an-
imals may result in a diminution of anorec-
tic function that is obscured by the enhance-
ment of overall LRb signaling owing to the
concomitant loss of inhibitory signals, how-
ever. Collectively, these findings suggest that
LRb Tyr
1138
- and Tyr
985
-independent signals
likely contribute to the regulation of growth,
reproduction, and glucose homeostasis by lep-
tin (42). These signals may include the LRb
Ty r
1077
/STAT5 pathway or signals mediated
by the LRb-associated Jak2 independently of
LRb tyrosine phosphorylation (3, 60, 74). Ad-
ditionally, some possible downstream path-
ways include the PI 3
-kinase, mTOR, and
AMPK pathways, although we cannot rule out
the possibility that other uncharacterized sig-
nals may also participate.
LEPTIN RESISTANCE IN
OBESITY
An absolute deficit of leptin does not under-
lie most cases of obesity: Indeed, most obese
individuals exhibit elevated circulating leptin
levels commensurate with their adipose mass
(94–96). The apparent conundrum that this
observation implies (why do elevated leptin
levels not act to decrease feeding and thus
prevent obesity?) has given rise to the no-
tion of the existence of physiological leptin
resistance. Simply put, the failure of high lev-
els of leptin to suppress feeding and decrease
body weight/adiposity to prevent or mitigate
obesity suggests a relative resistance to the
catabolic effects of leptin action in obesity.
A number of mechanisms have been pro-
posed to explain leptin resistance; these in-
clude alterations in the transport of leptin
across the BBB, alterations in cellular LRb sig-
naling, perturbations in developmental pro-
gramming, and others (97–99; 101). Indeed,
each of these mechanisms may contribute to
the totality of leptin resistance. Although the
absolute lack or genetic alteration of LRb
does not underlie most leptin resistance (95,
100), the preponderance of data confirm that
alterations in cellular LRb signaling, espe-
cially in the ARC, play a crucial role in leptin
resistance (98, 101, 102).
LRb SIGNAL ATTENUATION
AND EVIDENCE FOR CELLULAR
LEPTIN RESISTANCE
IN OBESITY
The concept of leptin resistance is analogous
to the syndrome of insulin resistance, in which
elevated levels of insulin are required to me-
diate adequate glucose disposal and metabolic
control. In the case of insulin resistance, a
number of intracellular pathways contribute
to the attenuation of insulin signaling in
insulin-responsive tissues such as muscle and
liver (103). Indeed, diet-induced obese (DIO)
animals (in which consumption of a palatable,
calorically dense diet promotes obesity) are
leptin resistant, displaying decreased anorec-
tic response and decreased amplitude of max-
imal LRb signaling in the hypothalamus in
response to high-dose leptin treatment, as evi-
denced by decreased STAT3 phosphorylation
and neuropeptide release compared with con-
trols (33, 98, 101, 102). Furthermore, maximal
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leptin-stimulated neuropeptide release is im-
paired in explanted tissues from DIO mice,
demonstrating the preservation of impaired
leptin signaling outside of the physiological
milieu of DIO mice (33).
Others and we have therefore undertaken
to define the cellular mechanisms that con-
tribute to the attenuation of LRb signaling,
with the idea that these mechanisms may con-
tribute to a cellular leptin resistance similar
to the insulin signaling defects in insulin re-
sistance (98). As noted above, SOCS3 binds
to LRb Tyr
985
and Jak2 to impair LRb sig-
naling in cultured cells (63). Additionally, in
mice, decreasing SOCS3 expression in the
whole body or deleting SOCS3 in neurons
increases the amplitude of LRb signaling, re-
sulting in animals that are leaner than wild
types at baseline and that are resistant to DIO
(90, 104). As detailed above, LRb Tyr
985
also
mediates the attenuation of LRb signaling in
cultured cells, and mutation of this residue
in l/l mice results in augmented leptin sen-
sitivity, leanness, and resistance to DIO (63,
85, 87, 88). Thus, Tyr
985
and SOCS3 atten-
uate LRb signaling and contribute to leptin
resistance.
The tyrosine phosphatase PTP1B dephos-
phorylates Jak2 to diminish LRb signaling in
cultured cells, and whole-body or neuron-
specific deletion of PTP1B increases lean-
ness and leptin sensitivity (105–107). Neural
PTP1B expression or activity is not altered
by leptin or adiposity, however, suggesting
that, although PTP1B physiologically atten-
uates leptin action and thus may represent an
important therapeutic target, it may not un-
derlie altered leptin signaling in obesity. In-
deed, although neuronal deletion of PTP1B
renders animals lean and leptin sensitive, the
effect of PTP1B on adiposity is independent
of DIO (that is, the increased leanness of neu-
ronal PTP1B knockout mice relative to con-
trols does not differ by diet) (105).
Leptin (which is increased in obesity) itself
stimulates the phosphorylation of LRb Tyr
985
to limit LRb signaling (63, 85, 87, 88), and
SOCS3 expression increases in response to
leptin and is elevated in the hypothalami of
obese animals (62, 102, 108, 109). In addition
to leptin, other cytokines promote SOCS3 ac-
cumulation. Thus, increased activity in any of
these metabolic and inflammatory pathways
has the potential to impair LRb signaling, and
the convergence of all these signaling systems
upon SOCS3 mirrors some of the phenotypes
that comprise the metabolic syndrome. Thus,
Ty r
985
and SOCS3 contribute to cellular lep-
tin resistance, specifically in states of obesity,
and leptin/obesity activate these feedback sig-
nals to attenuate LRb signaling at high lep-
tin levels, as found in obesity. This is not
to say that increased leptin and/or obesity
block LRb signaling to such an extent that
LRb activity at these elevated circulating lev-
els falls below that observed in lean controls
with lower leptin levels, however. Rather, each
increase in circulating leptin levels yields a
smaller and smaller increase in LRb signaling
over the baseline observed at low leptin levels
(Figure 3). Indeed, DIO mice with several-
fold increases in circulating leptin levels
demonstrate only slightly increased baseline
LRb signaling compared with normal, chow-
fed mice (but this would presumably support
some continued increase in Tyr
985
phospho-
rylation and SOCS3 expression) (85). Thus,
baseline LRb signaling in DIO mice, although
modestly increased, is not proportional to
their degree of hyperleptinemia. This LRb
signal attenuation is also evident by the sub-
stantially reduced response to acute high-dose
leptin administration (33, 85, 101).
THE ARCUATE NUCLEUS AS A
CRUCIAL SITE OF CELLULAR
LEPTIN RESISTANCE
The cellular leptin resistance phenotype of
DIO animals is most prominently detected
in the ARC relative to other hypothalamic
sites (33, 102). Furthermore, the increased
expression of SOCS3 in seasonally obese ro-
dents is localized to the ARC (108, 109). This
ARC specificity of cellular leptin resistance
and increased SOCS3 expression raises the
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ANRV336-PH70-23 ARI 28 December 2007 17:52
question of how the ARC differs from other
hypothalamic sites. Potentially increased ac-
cess of leptin and other factors from the
circulation into the ARC relative to other
hypothalamic sites (where leptin access is lim-
ited by transport mechanisms across the BBB)
may represent one such mechanism. Indeed,
this notion finds support in our recent data
demonstrating that endogenous circulating
leptin (in untreated, ad libitum–fed mice) pro-
motes increased LRb signaling in ARC neu-
rons compared with LRb neurons in other
sites (109a). Indeed, the time course of LRb
signaling is delayed in non-ARC neurons rela-
[Leptin]
Leptin action
Normal
No F-Inh
F-Inh
Overweight
Adequate:
normal
neuroendocrine
function
Inadequate: reduced
neuroendocrine function
Max
Underweight Obese
Membrane potential
a
b
Hypothetical AgRP neuron
[Leptin]
Normal
Obese
AP threshold
Ghrelin
F-Inh
No F-Inh
Loss of ghrelin’s
ability to initiate AP
Overweight
tive to ARC neurons in response to peripheral
leptin administration but is similar between
hypothalamic sites after central leptin admin-
istration (which circumvents the BBB) (109a).
This result is consistent with differential ac-
cess of the ARC LRb neurons to circulating
leptin (as opposed to intrinsic differences in
the leptin responsiveness of the LRb neurons
among sites).
−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−
Figure 3
Theoretical functional consequences of the
attenuation of leptin action in obesity. (a) Shown is
a theoretical graph of how leptin action on body
weight (e.g., via STAT3 phosphorylation) and on
the reproductive axis (via an unknown signaling
pathway) varies with leptin concentration in the
presence or absence of feedback inhibition (F-Inh)
mechanisms that attenuate leptin action in
proportion to leptin levels and/or adiposity. At low
leptin levels, at which the effect of F-Inh is
minimal, the curves for F-Inh and no F-Inh
overlie. The lines diverge as leptin and F-Inh
increase. With increasing concentrations of
endogenous circulating leptin in the case of F-Inh,
leptin action increases modestly. The amplitude of
the leptin signal in response to a single large dose
of leptin (seen at max) is attenuated in animals with
increased baseline leptin levels (at which F-Inh
levels are high before the leptin dose is given)
compared with animals with low baseline levels of
leptin and low F-Inh; the latter group of animals
should demonstrate a response analogous to the
maximum of the no F-Inh line. (b) Mechanism by
which the presence of F-Inh enables the detection
of energy flux via hormones such as ghrelin in the
face of high leptin levels. Taken is the hypothetical
case for a leptin-inhibited, ghrelin-activated
agouti-related protein (AgRP) neuron. Curves for
the effect of leptin on the membrane potential are
shown for various leptin levels for the cases of no
F-Inh (dark blue) and F-Inh (blue). Also shown is
the effect for this theoretical neuron of a high
physiological dose of ghrelin, which relatively
depolarizes the neuron ( gray arrow) and shifts the
leptin curves (red ) as shown. When there is no
F-Inh, ghrelin is incapable of depolarizing the
theoretical neuron to the point of action potential
(AP) generation (AP threshold) at high levels of
leptin, whereas the attenuation of leptin action by
F-Inh mechanisms at chronically high leptin levels
permits the detection of ghrelin/energy flux even
in the face of high leptin levels.
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Furthermore, peripheral application of the
BBB-impermeant retrograde neuronal tracer
fluorogold reveals a substantial population of
highly leptin-sensitive LRb neurons that di-
rectly contact the circulation in the ARC, but
not elsewhere in the hypothalamus (109a).
Hence, a population of ARC LRb neurons
is directly exposed to circulating leptin levels
and poised to respond more sensitively to cir-
culating leptin (and other factors) compared
with LRb neurons at other sites. These ARC
LRb neurons may be more prone to the devel-
opment of cellular leptin resistance than other
LRb neurons owing to their increased expo-
sure to high leptin levels or to other potential
circulating mediators of cellular leptin resis-
tance in obesity.
WHEREFORE CELLULAR
LEPTIN RESISTANCE?
We are faced with the challenge of ex-
plaining the need for and the physiological
consequences of feedback mechanisms that
limit LRb signaling in hyperleptinemic/obese
states. For some organisms, such as seasonal
mammals, there is a periodic need to increase
energy stores, and thus these feedback mech-
anisms may work in concert with other pro-
cesses that increase energy intake to promote
seasonal energy storage. For nonseasonal ani-
mals, such as humans, another potential expla-
nation for feedback inhibition of LRb signal-
ing arises from the need to sense not only the
content of body energy stores but also the flux
of energy, as detailed for the case of reproduc-
tion in On Fertile Ground: A Natural History of
Reproduction (109b). Even when energy stores
are relatively high (resulting in high circulat-
ing leptin levels), it is important to evaluate
the rate of energy expenditure (energy flux)
to determine if the organism is in a positive or
a negative energy balance and thus enable the
organism to further increase or maintain food
consumption despite already elevated energy
stores. Specific instances in which expendi-
ture may be high and caloric intake must be
increased (even in the face of normal energy
stores) include pregnancy, lactation, and in-
tensive exercise. Indicators of high energy flux
that must be sensed even if circulating levels
indicate significant energy stores include falls
in leptin levels (even within the high end of
the normal physiological range) as well as op-
posing and short-term acting factors like the
gut hormone ghrelin. However, in a system in
which increases in circulating leptin levels lin-
early amplify LRb signaling (leptin rises and
falls in direct proportion to energy stores at
all levels of adiposity), it is difficult to detect
alterations in energy flux at high leptin lev-
els because very elevated LRb signaling could
overwhelm opposing signals like ghrelin
(Figure 3). In contrast, the presence of a
leptin-stimulated feedback mechanism pre-
vents unlimited leptin action during hyper-
leptinemia. Thus, this system protects the
ability to detect alterations in energy flux by
ensuring that signals like ghrelin are not over-
whelmed at relatively high leptin levels if neg-
ative energy balance exists.
In addition to mediators of cellular leptin
resistance, such as Tyr
985
and SOCS3, other
mechanisms of cellular leptin resistance and
any mechanism of leptin resistance that is in-
creased by adiposity or leptin levels (including
alterations in BBB leptin transport) should act
in this manner.
OTHER POTENTIAL
MECHANISMS OF LEPTIN
RESISTANCE
Although cellular leptin resistance is physio-
logically relevant and even desirable to permit
the detection of energy flux in states in which
increased adipose stores exist, such mecha-
nisms that require leptin or increased adipos-
ity to initiate leptin resistance cannot underlie
the inception of obesity but can only con-
tribute to its stability. For example, mice that
are put on a high-fat diet to induce DIO be-
gin with a perfectly acting LRb signaling sys-
tem. The diet, rather than alteration of the
LRb system itself, must trigger the increased
energy intake, although the developing
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ANRV336-PH70-23 ARI 28 December 2007 17:52
feedback inhibition/cellular leptin resistance
exacerbate and stabilize the ensuing increase
in body weight. Although genetic variabil-
ity in factors that attenuate LRb signaling
(e.g., PTP1B, SOCS3) may underlie a cellu-
lar leptin resistance that causes obesity, there
is clearly a strong environmental component
to obesity, as evidenced by the rapidly increas-
ing rates of obesity in industrialized countries
today. Some evidence exists for developmen-
tal alterations in neural and other systems that
may underlie some propensity to obesity, but
the ready availability of palatable, calorically
dense food (the basis for DIO in experimen-
tal animals) clearly plays a dominant role. In-
deed, the obesity and cellular leptin resistance
of DIO animals are reversed by replacing the
palatable calorie-dense chow used to promote
obesity with standard chow (33).
Although some of the obesogenic effects
of tasty foods may be due to their nutrient
content, the hedonic or rewarding proper-
ties of these foods also contribute (110, 111).
Leptin regulates the perception of the reward-
ing value of palatable food (as well as that of
other addictive substances, such as drugs of
abuse) (112–115).
Leptin regulates a broadly distributed net-
work of LRb-expressing neurons in the brain
to orchestrate an array of neural processes
(Figure 2). Some of the neural mechanisms by
which leptin may control food reward are be-
ginning to be elucidated via the investigation
of the interaction of leptin with the mesolim-
bic dopamine (DA) system. The core of the
mesolimbic DA system lies in a set of DA neu-
rons in the ventral tegmental area that project
forward to innervate the striatum (nucleus ac-
cumbens, caudate/putamen), amygdala, and
prefrontal cortex (111). It is by acting upon
this system that drugs of abuse generally ex-
ert their reinforcing effects, and the activity
of this system is clearly important to medi-
ate the incentive salience of food and other
natural rewards. Although ARC LRb neurons
do not project to the VTA and there is little
evidence for the modulation of the mesolim-
bic circuitry by NPY or melanocortin action,
a number of research groups have demon-
strated the presence of LRb-expressing VTA
DA neurons and proven the ability of lep-
tin to alter the physiology of this system (45,
47, 116, 117). Additionally, feeding and leptin
modulate the reward associated with intracra-
nial self-stimulation specifically in the LHA,
which is mediated by the mesolimbic reward
circuitry (116, 118). Indeed, we have iden-
tified a novel population of LRb-expressing
neurons in the LHA that project to the VTA
to regulate the mesolimbic DA system. Thus,
leptin acts via multiple ARC-independent sys-
tems to control the VTA and the mesolimbic
DA system at its inception in the VTA, and
these sites of leptin action likely regulate the
incentive salience of food.
How then is the action of leptin to regulate
the perception of food reward overwhelmed
to promote obesity in the face of plentiful
tasty food? Leptin is only one of many in-
puts into the mesolimbic DA system and other
neural pathways that regulate the perception
of food reward, and physiological leptin lev-
els may not be able to suppress the myriad
other signals that compel us to consume tasty
food. Although leptin may reasonably inhibit
the drive to overeat foods with only modestly
rewarding properties, leptin may be insuffi-
cient to effectively compete with the reward-
ing properties of more palatable treats because
these more-rewarding foods engage powerful
neural responses that oppose leptin within the
mesolimbic DA system and elsewhere.
Indeed, endogenous (and exogenous)
cannabinoids modulate the mesolimbic DA
system and exert powerful anorectic signals.
The finding that inhibitors of endocannabi-
noid action promote weight loss speaks to the
importance of this system in energy balance
(119). Furthermore, although leptin regulates
the production of endogenous cannabinoids
to some extent, many other factors, including
stress, also contribute to their regulation.
Where does this leave us in terms of lep-
tin resistance, cellular leptin resistance, the
problem of plentiful calorie-dense foods, and
therapeutic alternatives? First, many lines of
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ANRV336-PH70-23 ARI 28 December 2007 17:52
evidence suggest that, even if cellular leptin
resistance or other obesity-induced mecha-
nisms of leptin resistance may not be the ini-
tiating insult in obesity, it clearly contributes
to the ability to become and remain obese,
and the blockade of processes that mediate
leptin signal attenuation remains an attractive
potential therapeutic modality. Furthermore,
the investigation of the leptin signaling sys-
tem has led us to a more detailed and general
understanding of the regulatory mechanisms
of food intake, including the melanocortin
or the mesolimbic VTA/DA system, that can
be considered general tools in the regula-
tion of feeding that are employed by several
peptides (e.g., leptin, ghrelin, serotonin, neu-
rotensin, etc.). A more detailed understand-
ing of the widely distributed network of LRb
neurons in several poorly investigated CNS
sites and the neural mechanisms by which
leptin and other cues (nutritional, taste, etc.)
regulate the perception of food reward will
likely reveal additional potential therapeutic
targets.
DISCLOSURE STATEMENT
M.G.M. and H.M. are not aware of any biases that might be perceived as affecting the objectivity
of this review.
M.A.C. is Chief Scientific Officer of, and owns stock in, Orexigen Therapeutics, Inc.,
a company that is developing pharmaceutical approaches to treat obesity and is developing
combination therapies that attempt to bypass leptin resistance. The work described in this
manuscript was not supported by Orexigen Therapeutics. Oregon Health and Sciences Uni-
versity (OHSU) and M.A.C. have a significant financial interest in Orexigen Therapeutics,
which may have a commercial interest in the results of this research and technology; this po-
tential conflict has been reviewed and managed by the OHSU Conflict of Interest in Research
Committee and the Integrity Program Oversight Council.
In the past M.A.C. has received grant support from the NIH (RR 0163, DK 62202), Oregon
National Primate Research Center, and Orexigen Therapeutics. In the past M.A.C. has re-
ceived compensation from Orexigen Therapeutics, Novo Nordisk, Merck & Co., Semaphore
Pharmaceuticals, Konovo Inc., 7TM Pharma, Ipsen, and Amylin Pharmaceuticals.
LITERATURE CITED
1. Friedman JM, Halaas JL. 1998. Leptin and the regulation of body weight in mammals.
Nature 395:763–70
2. Elmquist JK, Maratos-Flier E, Saper CB, Flier JS. 1998. Unraveling the central nervous
system pathways underlying responses to leptin. Nat. Neurosci. 1:445–49
3. Bates SH, Myers MG Jr. 2003. The role of leptin receptor signaling in feeding and
neuroendocrine function. Trends Endocrinol. Metab. 14:447–52
4. Ahima RS, Prabakaran D, Mantzoros CS, Qu D, Lowell BB, et al. 1996. Role of leptin
in the neuroendocrine response to fasting. Nature 382:250–52
5. Lord GM, Matarese G, Howard JK, Baker RJ, Bloom SR, Lechler RI. 1998. Leptin
modulates the T-cell immune response and reverses starvation-induced immunosup-
pression. Nature 394:897–901
6. Montague CT, Farooqi IS, Whitehead JP, Soos MS, Rau H, et al. 1997. Congenital
leptin deficiency is associated with severe early onset obesity in humans. Nature 387:903–
8
www.annualreviews.org
Mechanisms of Leptin Action and Leptin Resistance 549
Annu. Rev. Physiol. 2008.70:537-556. Downloaded from www.annualreviews.org
by Universita degli Studi di Roma Tor Vergata on 10/14/10. For personal use only.
ANRV336-PH70-23 ARI 28 December 2007 17:52
7. Clement K, Vaisse C, Lahlou N, Cabrol S, Pelloux V, et al. 1998. A mutation in the
human leptin receptor gene causes obesity and pituitary dysfunction. Nature 392:398–
401
8. Tartaglia LA. 1997. The leptin receptor. J. Biol. Chem. 272:6093–96
9. Chua SC Jr, Koutras IK, Han L, Liu SM, Kay J, et al. 1997. Fine structure of the murine
leptin receptor gene: Splice site suppression is required to form two alternatively spliced
transcripts. Genomics 45:264–70
10. Ge H, Huang L, Pourbahrami T, Li C. 2002. Generation of soluble leptin receptor
by ectodomain shedding of membrane-spanning receptors in vitro and in vivo. J. Biol.
Chem. 277:45898–903
11. Uotani S, Bjørbæk C, Tornoe J, Flier JS. 1999. Functional properties of leptin receptor
isoforms: internalization and degradation of leptin and ligand-induced receptor down-
regulation. Diabetes 48:279–86
12. Elmquist JK, Elias CF, Saper CB. 1999. From lesions to leptin: hypothalamic control
of food intake and body weight. Neuron 22:221–32
13. Elmquist JK, Bjørbæk C, Ahima RS, Flier JS, Saper CB. 1998. Distributions of leptin
receptor mRNA isoforms in the rat brain. J. Comp. Neurol. 395:535–47
14. Baskin DG, Schwartz MW, Seeley RJ, Woods SC, Porte D Jr, et al. 1999. Leptin
receptor long-form splice-variant protein expression in neuron cell bodies of the brain
and colocalization with neuropeptide Y mRNA in the arcuate nucleus. J. Histochem.
Cytochem. 47:353–62
15. Schwartz MW, Woods SC, Porte D Jr, Seeley RJ, Baskin DG. 2000. Central nervous
system control of food intake. Nature 404:661–71
16. Inui A. 1999. Feeding and body-weight regulation by hypothalamic neuropeptides—
mediation of the actions of leptin. Trends Neurosci. 22:62–67
17. Huo L, M
¨
unzberg H, Nillni EA, Bjørbæk C. 2004. Role of signal transducer and ac-
tivator of transcription 3 in regulation of hypothalamic trh gene expression by leptin.
Endocrinology 145:2516–23
18. Elmquist JK, Ahima RS, Maratos-Flier E, Flier JS, Saper CB. 1997. Leptin activates
neurons in ventrobasal hypothalamus and brainstem. Endocrinology 138:839–42
19. Bodary PF, Westrick RJ, Wickenheiser KJ, Shen Y, Eitzman DT. 2002. Effect of leptin
on arterial thrombosis following vascular injury in mice. JAMA 287:1706–9
20. Liu L, Karkanias GB, Morales JC, Hawkins M, Barzilai N, et al. 1998. Intracere-
broventricular leptin regulates hepatic but not peripheral glucose fluxes. J. Biol. Chem.
273:31160–67
21. Kulkarni RN, Wang ZL, Wang RM, Hurley JD, Smith DM, et al. 1997. Leptin rapidly
suppresses insulin release from insulinoma cells, rat and human islets and, in vivo, in
mice. J. Clin. Invest. 100:2729–36
22. Burcelin R, Kamohara S, Li J, Tannenbaum GS, Charron MJ, Friedman JM. 1999. Acute
intravenuous leptin infusion increases glucose turnover but not skeletal muscle glucose
uptake in ob/ob mice. Diabetes 48:1264–69
23. Kieffer TJ, Heller RS, Leech CA, Holz GG, Habener JF. 1997. Leptin suppression of
insulin secretion by the activation of ATP-sensitive K
+
channels in pancreatic beta-cells.
Diabetes 46:1087–93
24. Covey SD, Wideman RD, McDonald C, Unniappan S, Huynh F, et al. 2006. The
pancreatic beta cell is a key site for mediating the effects of leptin on glucose homeostasis.
Cell Metab. 4:291–302
25. Leshan RL, Bjornholm M, M
¨
unzberg H, Myers MG Jr. 2006. Leptin receptor signaling
and action in the central nervous system. Obesity 14(Suppl. 5):208S–12S
550 Myers
·
Cowley
·
unzberg
Annu. Rev. Physiol. 2008.70:537-556. Downloaded from www.annualreviews.org
by Universita degli Studi di Roma Tor Vergata on 10/14/10. For personal use only.
ANRV336-PH70-23 ARI 28 December 2007 17:52
26. Huszar D, Lynch CA, Fairchild-Huntress V, Dunmore JH, Fang Q, et al. 1997. Targeted
disruption of the melanocortin-4 receptor results in obesity in mice. Cell 88:131–41
27. Butler AA, Cone RD. 2002. The melanocortin receptors: lessons from knockout models.
Neuropeptides 36:77–84
28. Marsh DJ, Hollopeter G, Huszar D, Laufer R, Yagaloff KA, et al. 1999. Response of
melanocortin-4 receptor-deficient mice to anorectic and orexigenic peptides. Nat. Genet.
21:119–22
29. Ste ML, Miura GI, Marsh DJ, Yagaloff K, Palmiter RD. 2000. A metabolic defect
promotes obesity in mice lacking melanocortin-4 receptors. Proc. Natl. Acad. Sci. USA
97:12339–44
30. Butler AA, Kesterson RA, Khong K, Cullen MJ, Pelleymounter MA, et al. 2000. A
unique metabolic syndrome causes obesity in the melanocortin-3 receptor-deficient
mouse. Endocrinology 141:3518–21
31. Chen AS, Marsh DJ, Trumbauer ME, Frazier EG, Guan XM, et al. 2000. Inactivation
of the mouse melanocortin-3 receptor results in increased fat mass and reduced lean
body mass. Nat. Genet. 26:97–102
32. Cowley MA, Smart JL, Rubinstein M, Cerdan MG, Diano S, et al. 2001. Leptin activates
anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature
411:480–84
33. Enriori PJ, Evans AE, Sinnayah P, Jobst EE, Tonelli-Lemos L, et al. 2007. Diet-induced
obesity causes severe but reversible leptin resistance in arcuate melanocortin neurons.
Cell Metab. 5:181–94
34. Erickson JC, Hollopeter G, Palmiter RD. 1996. Attenuation of the obesity syndrome
of ob/ob mice by the loss of neuropeptide Y. Science 274:1704–7
35. Clark JT, Kalra PS, Kalra SP. 1985. Neuropeptide Y stimulates feeding but inhibits
sexual behavior in rats. Endocrinology 117:2435–42
36. Schwartz MW. 2006. Central nervous system regulation of food intake. Obesity 14(Suppl.
1):1S–8S
37. Smith MS, Grove KL. 2002. Integration of the regulation of reproductive function and
energy balance: lactation as a model. Front. Neuroendocrinol. 23:225–56
38. Ollmann MM, Wilson BD, Yang YK, Kerns JA, Chen Y, et al. 1997. Antagonism of
central melanocortin receptors in vitro and in vivo by agouti-related protein. Science
278:135–38
39. MacNeil DJ, Howard AD, Guan X, Fong TM, Nargund RP, et al. 2002. The role of
melanocortins in body weight regulation: opportunities for the treatment of obesity.
Eur. J. Pharmacol. 450:93–109
40. Balthasar N, Coppari R, McMinn J, Liu SM, Lee CE, et al. 2004. Leptin receptor
signaling in POMC neurons is required for normal body weight homeostasis. Neuron
42:983–91
41. Morton GJ, Niswender KD, Rhodes CJ, Myers MG Jr, Blevins JT, et al. 2003. Arcu-
ate nucleus-specific leptin receptor gene therapy attenuates the obesity phenotype of
Koletsky (fa
k
/fa
k
) rats. Endocrinology 144:2016–24
42. Bates SH, Stearns WH, Schubert M, Tso AWK, Wang Y, et al. 2003. STAT3 signaling is
required for leptin regulation of energy balance but not reproduction. Nature 421:856–
59
43. Kaelin CB, Gong L, Xu AW, Yao F, Hockman K, et al. 2006. Signal transducer and
activator of transcription (Stat) binding sites but not Stat3 are required for fasting-
induced transcription of agouti-related protein messenger ribonucleic acid. Mol. En-
docrinol. 20:2591–602
www.annualreviews.org
Mechanisms of Leptin Action and Leptin Resistance 551
Annu. Rev. Physiol. 2008.70:537-556. Downloaded from www.annualreviews.org
by Universita degli Studi di Roma Tor Vergata on 10/14/10. For personal use only.
ANRV336-PH70-23 ARI 28 December 2007 17:52
44. Xu AW, Ste-Marie L, Kaelin CB, Barsh GS. 2007. Inactivation of signal transducer and
activator of transcription 3 in proopiomelanocortin (Pomc) neurons causes decreased
Pomc expression, mild obesity, and defects in compensatory refeeding. Endocrinology
148:72–80
45. Hommel JD, Trinko R, Sears RM, Georgescu D, Liu ZW, et al. 2006. Leptin receptor
signaling in midbrain dopamine neurons regulates feeding. Neuron 51:801–10
46. Dhillon H, Zigman JM, Ye C, Lee CE, McGovern RA, et al. 2006. Leptin directly
activates SF1 neurons in the VMH, and this action by leptin is required for normal
body-weight homeostasis. Neuron 49:191–203
47. Fulton S, Pissios P, Manchon RP, Stiles L, Frank L, et al. 2006. Leptin regulation of
the mesoaccumbens dopamine pathway. Neuron 51:811–22
48. Taga T, Kishimoto T. 1997. gp130 and the interleukin-6 family of cytokines. Annu. Rev.
Immunol. 15:797–819
49. Ihle JN, Kerr IM. 1995. Jaks and Stats in signaling by the cytokine receptor superfamily.
Trends Genet. 11:69–74
50. Taniguchi T. 1995. Cytokine signaling through nonreceptor protein tyrosine kinases.
Science 268:251–55
51. Kloek C, Haq AK, Dunn SL, Lavery HJ, Banks AS, Myers MG Jr. 2002. Regulation of
Jak kinases by intracellular leptin receptor sequences. J. Biol. Chem. 277:41547–55
52. Devos R, Guisez Y, Van der Heyden J, White DW, Kalai M, et al. 1997. Ligand-
independent dimerization of the extracellular domain of the leptin receptor and deter-
mination of the stoichiometry of leptin binding. J. Biol. Chem. 272:18304–10
53. Couturier C, Jockers R. 2003. Activation of the leptin receptor by a ligand-induced
conformational change of constitutive receptor dimers. J. Biol. Chem. 278:26604–11
54. White DW, Kuropatwinski KK, Devos R, Baumann H, Tartaglia LA. 1997. Leptin
receptor (OB-R) signaling. J. Biol. Chem. 272:4065–71
55. Banks AS, Davis SM, Bates SH, Myers MG Jr. 2000. Activation of downstream signals
by the long form of the leptin receptor. J. Biol. Chem. 275:14563–72
56. Bahrenberg G, Behrmann I, Barthel A, Hekerman P, Heinrich PC, et al. 2002. Identi-
fication of the critical sequence elements in the cytoplasmic domain of leptin receptor
isoforms required for Janus kinase/signal transducer and activator of transcription acti-
vation by receptor heterodimers. Mol. Endocrinol. 16:859–72
57. Koch CA, Anderson DJ, Moran MF, Ellis CA, Pawson T. 1991. SH2 and SH3 domains:
elements that control interactions of cytoplasmic signaling proteins. Science 252:668–74
58. Songyang Z, Shoelson SE, Chaudhuri M, Gish GD, Pawson T, et al. 1993. SH2 domains
recognize specific phosphopeptide sequences. Cell 72:767–78
59. Haan S, Hemmann U, Hassiepen U, Schaper F, Schneider-Mergener J, et al. 1999.
Characterization and binding specificity of the monomeric STAT3-SH2 domain. J.
Biol. Chem. 274:1342–48
60. Hekerman P, Zeidler J, Bamberg-Lemper S, Knobelspies H, Lavens D, et al. 2005.
Pleiotropy of leptin receptor signalling is defined by distinct roles of the intracellular
tyrosines. FEBS J. 272:109–19
60a. Gong Y, Ishida-Takahashi R, Villanueva EC, Fingar DC, M
¨
unzberg H, Myers MG Jr.
2007. The long form of the leptin receptor regulates STAT5 and ribosomal protein S6
by alternate mechanisms. J. Biol. Chem. 282:31019–27
61. Bjørbæk C, Buchholz RM, Davis SM, Bates SH, Pierroz DD, et al. 2001. Divergent
roles of SHP-2 in ERK activation by leptin receptors. J. Biol. Chem. 276:4747–55
62. Bjørbæk C, Elmquist JK, Frantz JD, Shoelson SE, Flier JS. 1998. Identification of
SOCS-3 as a potential mediator of central leptin resistance. Mol. Cell 1:619–25
552 Myers
·
Cowley
·
unzberg
Annu. Rev. Physiol. 2008.70:537-556. Downloaded from www.annualreviews.org
by Universita degli Studi di Roma Tor Vergata on 10/14/10. For personal use only.
ANRV336-PH70-23 ARI 28 December 2007 17:52
63. Bjørbæk C, Lavery HJ, Bates SH, Olson RK, Davis SM, et al. 2000. SOCS3 mediates
feedback inhibition of the leptin receptor via Tyr985. J. Biol. Chem. 275:40649–57
64. Sasaki A, Yasukawa H, Shouda T, Kitamura T, Dikic I, Yoshimura A. 2000. CIS3/SOCS-
3 suppresses erythropoietin (EPO) signaling by binding the EPO receptor and JAK2. J.
Biol. Chem. 275:29338–47
65. Sasaki A, Yasukawa H, Suzuki A, Kamizono S, Syoda T, et al. 1999. Cytokine-inducible
SH2 protein-3 (CIS3/SOCS3) inhibits Janus tyrosine kinase by binding through the
N-terminal kinase inhibitory region as well as SH2 domain. Genes Cells 4:339–51
66. Feng J, Witthuhn BA, Matsuda T, Kohlhuber F, Kerr IM, Ihle JN. 1997. Activation
of Jak2 catalytic activity requires phosphorylation of Y
1007
in the kinase activation loop.
Mol. Cell Biol. 17:2497–501
67. Carpino N, Kobayashi R, Zang H, Takahashi Y, Jou ST, et al. 2002. Identification, cDNA
cloning, and targeted deletion of p70, a novel, ubiquitously expressed SH3 domain-
containing protein. Mol. Cell Biol. 22:7491–500
68. Argetsinger LS, Kouadio JL, Steen H, Stensballe A, Jensen ON, Carter-Su C. 2004.
Autophosphorylation of JAK2 on tyrosines 221 and 570 regulates its activity. Mol. Cell
Biol. 24:4955–67
69. Feener EP, Rosario F, Dunn SL, Stancheva Z, Myers MG Jr. 2004. Tyrosine phosphory-
lation of Jak2 in the JH2 domain inhibits cytokine signaling. Mol. Cell Biol. 24(11):4968–
78
70. Kurzer JH, Argetsinger LS, Zhou YJ, Kouadio JL, O’Shea JJ, Carter-Su C. 2004. Tyro-
sine 813 is a site of JAK2 autophosphorylation critical for activation of JAK2 by SH2-Bβ.
Mol. Cell Biol. 24:4557–70
71. Funakoshi-Tago M, Pelletier S, Matsuda T, Parganas E, Ihle JN. 2006. Receptor specific
downregulation of cytokine signaling by autophosphorylation in the FERM domain of
Jak2. EMBO J. 25:4763–72
72. Matsuda T, Feng J, Witthuhn BA, Sekine Y, Ihle JN. 2004. Determination of the
transphosphorylation sites of Jak2 kinase. Biochem. Biophys. Res. Commun. 325:586–94
73. Ishida-Takahashi R, Rosario F, Gong Y, Kopp K, Stancheva Z, et al. 2006. Phosphory-
lation of Jak2 on Ser
523
inhibits Jak2-dependent leptin receptor signaling. Mol. Cell Biol.
26:4063–73
74. Niswender KD, Morton GJ, Stearns WH, Rhodes CJ, Myers MG Jr, Schwartz MW.
2001. Intracellular signalling: key enzyme in leptin-induced anorexia. Nature 413:794–
95
75. Xu AW, Kaelin CB, Takeda K, Akira S, Schwartz MW, Barsh GS. 2005. PI3K integrates
the action of insulin and leptin on hypothalamic neurons. J. Clin. Invest. 115:951–58
76. Plum L, Ma X, Hampel B, Balthasar N, Coppari R, et al. 2006. Enhanced PIP
3
signaling
in POMC neurons causes K
ATP
channel activation and leads to diet-sensitive obesity. J.
Clin. Invest. 116:1886–901
77. Cota D, Proulx K, Smith KA, Kozma SC, Thomas G, et al. 2006. Hypothalamic mTOR
signaling regulates food intake. Science 312:927–30
78. Minokoshi Y, Alquier T, Furukawa N, Kim YB, Lee A, et al. 2004. AMP-kinase regulates
food intake by responding to hormonal and nutrient signals in the hypothalamus. Nature
428:569–74
79. Bates SH, Dundon TA, Seifert M, Carlson M, Maratos-Flier E, Myers MG Jr. 2004.
LRb-STAT3 signaling is required for the neuroendocrine regulation of energy expen-
diture by leptin. Diabetes 53:3067–73
www.annualreviews.org
Mechanisms of Leptin Action and Leptin Resistance 553
Annu. Rev. Physiol. 2008.70:537-556. Downloaded from www.annualreviews.org
by Universita degli Studi di Roma Tor Vergata on 10/14/10. For personal use only.
ANRV336-PH70-23 ARI 28 December 2007 17:52
80. Bates SH, Kulkarni RN, Seifert M, Myers MG Jr. 2005. Roles for leptin
receptor/STAT3-dependent and -independent signals in the regulation of glucose
homeostasis. Cell Metab. 1:169–78
81. Buettner C, Pocai A, Muse ED, Etgen AM, Myers MG Jr, Rossetti L. 2006. Critical
role of STAT3 in leptin’s metabolic actions. Cell Metab. 4:49–60
82. Bodary PF, Shen Y, Ohman M, Bahrou KL, Vargas FB, et al. 2007. Leptin regulates
neointima formation after arterial injury through mechanisms independent of blood
pressure and the leptin receptor/STAT3 signaling pathways involved in energy balance.
Arterioscler. Thromb. Vasc. Biol. 27:70–76
83. Dunn SL, Bjornholm M, Bates SH, Chen Z, Seifert M, Myers MG Jr. 2005. Feed-
back inhibition of leptin receptor/Jak2 signaling via Tyr1138 of the leptin receptor and
suppressor of cytokine signaling 3. Mol. Endocrinol. 19:925–38
84. M
¨
unzberg H, Jobst EE, Bates SH, Jones J, Villanueva E, et al. 2007. Appropriate in-
hibition of orexigenic hypothalamic arcuate nucleus neurons independently of leptin
receptor/STAT3 signaling. J. Neurosci. 27:69–74
85. Bjornholm M, M
¨
unzberg H, Leshan RL, Villanueva E, Bates SH, et al. 2007. J. Clin.
Invest. 117:1354–60
86. Vaisse C, Halaas JL, Horvath CM, Darnell JE Jr, Stoffel M, Friedman JM. 1996. Leptin
activation of Stat3 in the hypothalamus of wild-type and ob/ob mice but not db/db mice.
Nat. Genet. 14:95–97
87. Carpenter LR, Farruggella TJ, Symes A, Karow ML, Yancopoulos G. 1998. Enhanc-
ing leptin response by preventing SH2-containing phosphatase 2 interaction with Ob
receptor. Proc. Natl. Acad. Sci. USA 95:6061–66
88. Li C, Friedman JM. 1999. Leptin receptor activation of SH2 domain containing protein
tyrosine phosphatase 2 modulates Ob receptor signal transduction. Proc. Natl. Acad. Sci.
USA 96:9677–82
89. Mori H, Hanada R, Hanada T, Aki D, Mashima R, et al. 2004. Socs3 deficiency in the
brain elevates leptin sensitivity and confers resistance to diet-induced obesity. Nat. Med.
10:739–43
90. Howard JK, Cave BJ, Oksanen LJ, Tzameli I, Bjørbæk C, Flier JS. 2004. Enhanced
leptin sensitivity and attenuation of diet-induced obesity in mice with haploinsufficiency
of Socs3. Nat. Med. 10; 734–38
91. Zhang EE, Chapeau E, Hagihara K, Feng GS. 2004. Neuronal Shp2 tyrosine phos-
phatase controls energy balance and metabolism. Proc. Natl. Acad. Sci. USA 101:16064–
69
92. Feng GS. 1999. Shp-2 tyrosine phosphatase: signaling one cell or many. Exp. Cell Res.
253:47–54
93. Keilhack H, David FS, McGregor M, Cantley LC, Neel BG. 2005. Diverse biochem-
ical properties of Shp2 mutants. Implications for disease phenotypes. J. Biol. Chem.
280:30984–93
94. Considine RV, Sinha MK, Heiman ML, Kriauciunas A, Stephens TW, et al. 1996.
Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N.
Engl. J. Med. 334:292–95
95. Farooqi IS, O’Rahilly S. 2005. Monogenic obesity in humans. Annu. Rev. Med. 56:443–
58
96. Maffei M, Stoffel M, Barone M, Moon B, Dammerman M, et al. 1996. Absence of
mutations in the human Ob gene in obese/diabetic subjects. Diabetes 45:679–82
97. Banks WA. 2004. The many lives of leptin. Peptides 25:331–38
554 Myers
·
Cowley
·
unzberg
Annu. Rev. Physiol. 2008.70:537-556. Downloaded from www.annualreviews.org
by Universita degli Studi di Roma Tor Vergata on 10/14/10. For personal use only.
ANRV336-PH70-23 ARI 28 December 2007 17:52
98. M
¨
unzberg H, Bjornholm M, Bates SH, Myers MG Jr. 2005. Leptin receptor action and
mechanisms of leptin resistance. Cell Mol. Life Sci. 62:642–52
99. Bouret SG, Simerly RB. 2006. Developmental programming of hypothalamic feeding
circuits. Clin. Genet. 70:295–301
100. Considine RV, Considine EL, Williams CJ, Hyde TM, Caro JF. 1996. The hypotha-
lamic leptin receptor in humans: identification of incidental sequence polymorphisms
and absence of the db/db mouse and fa/fa rat mutations. Diabetes 45:992–94
101. El Haschimi K, Pierroz DD, Hileman SM, Bjørbæk C, Flier JS. 2000. Two defects
contribute to hypothalamic leptin resistance in mice with diet-induced obesity. J. Clin.
Invest. 105:1827–32
102. M
¨
unzberg H, Flier JS, Bjørbæk C. 2004. Region-specific leptin resistance within the
hypothalamus of diet-induced-obese mice. Endocrinology 145:4880–89
103. White MF. 2006. Regulating insulin signaling and beta-cell function through IRS pro-
teins. Can. J. Physiol. Pharmacol. 84:725–37
104. Kershaw EE, Flier JS. 2004. Adipose tissue as an endocrine organ. J. Clin. Endocrinol.
Metab. 89:2548–56
105. Bence KK, Delibegovic M, Xue B, Gorgun CZ, Hotamisligil GS, et al. 2006. Neuronal
PTP1B regulates body weight, adiposity and leptin action. Nat. Med. 12:917–24
106. Zabolotny JM, Bence-Hanulec KK, Stricker-Krongrad A, Haj F, Wang Y, et al. 2002.
PTP1B regulates leptin signal transduction in vivo. Dev. Cell 2:489–95
107. Cheng A, Uetani N, Simoncic PD, Chaubey VP, Lee-Loy A, et al. 2002. Attenuation
of leptin action and regulation of obesity by protein tyrosine phosphatase 1B. Dev. Cell
2:497–503
108. Tups A, Ellis C, Moar KM, Logie TJ, Adam CL, et al. 2004. Photoperiodic regulation of
leptin sensitivity in the Siberian hamster, Phodopus sungorus, is reflected in arcuate nucleus
SOCS-3 (suppressor of cytokine signaling) gene expression. Endocrinology 145:1185–93
109. Krol E, Tups A, Archer ZA, Ross AW, Moar KM, et al. 2007. Altered expression of
SOCS3 in the hypothalamic arcuate nucleus during seasonal body mass changes in the
field vole, Microtus agrestis. J. Neuroendocrinol. 19:83–94
109a. Faouzi M, Leshan R, Bjornholm M, Hennessey T, Jones J, M
¨
unzberg H. 2007. Differ-
ential accessibility of circulating leptin to individual hypothalamic sites. Endocrinology
148:5414–23
109b. Ellison PT. 2001. On Fertile Ground: A Natural History of Reproduction. Cambridge, MA:
Harvard Univ. Press
110. Figlewicz DP. 2003. Adiposity signals and food reward: expanding the CNS roles of
insulin and leptin. Am. J. Physiol. Regul. Integr. Comp. Physiol. 284:R882–92
111. Kelley AE, Berridge KC. 2002. The neuroscience of natural rewards: relevance to ad-
dictive drugs. J. Neurosci. 22:3306–11
112. Figlewicz DP, Bennett J, Evans SB, Kaiyala K, Sipols AJ, Benoit SC. 2004. Intraventric-
ular insulin and leptin reverse place preference conditioned with high-fat diet in rats.
Behav. Neurosci. 118:479–87
113. Figlewicz DP, Woods SC. 2000. Adiposity signals and brain reward mechanisms. Trends
Pharmacol. Sci. 21:235–36
114. Carr KD. 2007. Chronic food restriction: enhancing effects on drug reward and striatal
cell signaling. Physiol. Behav. 91:459–72
115. Shizgal P, Fulton S, Woodside B. 2001. Brain reward circuitry and the regulation of
energy balance. Int. J. Obes. Relat. Metab. Disord. 25(Suppl. 5):S17–21
116. Fulton S, Woodside B, Shizgal P. 2000. Modulation of brain reward circuitry by leptin.
Science 287:125–28
www.annualreviews.org
Mechanisms of Leptin Action and Leptin Resistance 555
Annu. Rev. Physiol. 2008.70:537-556. Downloaded from www.annualreviews.org
by Universita degli Studi di Roma Tor Vergata on 10/14/10. For personal use only.
ANRV336-PH70-23 ARI 28 December 2007 17:52
117. Figlewicz DP, Naleid AM, Sipols AJ. 2007. Modulation of food reward by adiposity
signals. Physiol. Behav. 91:473–78
118. Fulton S, Woodside B, Shizgal P. 2006. Potentiation of brain stimulation reward by
weight loss: evidence for functional heterogeneity in brain reward circuitry. Behav. Brain
Res. 174:56–63
119. Cota D, Tschop MH, Horvath TL, Levine AS. 2006. Cannabinoids, opioids and eating
behavior: the molecular face of hedonism? Brain Res. Brain Res. Rev. 51:85–107
556 Myers
·
Cowley
·
unzberg
Annu. Rev. Physiol. 2008.70:537-556. Downloaded from www.annualreviews.org
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Annual Review of
Physiology
Volume 70, 2008
Contents
Frontispiece
Joseph F. Hoffman pppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppxvi
PERSPECTIVES, David Julius, Editor
My Passion and Passages with Red Blood Cells
Joseph F. Hoffman ppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp1
CARDIOVASCULAR PHYSIOLOGY, Jeffrey Robbins, Section Editor
Calcium Cycling and Signaling in Cardiac Myocytes
Donald M. Bers pppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp23
Hypoxia-Induced Signaling in the Cardiovascular System
M. Celeste Simon, Liping Liu, Bryan C. Barnhart, and Regina M. Young ppppppppppp51
CELL PHYSIOLOGY, David E. Clapham, Associate and Section Editor
Bcl-2 Protein Family Members: Versatile Regulators of Calcium
Signaling in Cell Survival and Apoptosis
Yiping Rong and Clark W. Distelhorst ppppppppppppppppppppppppppppppppppppppppppppppppppp73
Mechanisms of Sperm Chemotaxis
U. Benjamin Kaupp, Nachiket D. Kashikar, and Ingo Weyand pppppppppppppppppppppppp 93
ECOLOGICAL, EVOLUTIONARY, AND COMPARATIVE
PHYSIOLOGY, Martin E. Feder, Section Editor
Advances in Biological Structure, Function, and Physiology Using
Synchrotron X-Ray Imaging
Mark W. Westneat, John J. Socha, and Wah-Keat Lee pppppppppppppppppppppppppppppppp119
Advances in Comparative Physiology from High-Speed Imaging
of Animal and Fluid Motion
George V. Lauder and Peter G.A. Madden ppppppppppppppppppppppppppppppppppppppppppppp143
vii
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ENDOCRINOLOGY, Holly A. Ingraham, Section Editor
Estrogen Signaling through the Transmembrane G Protein–Coupled
Receptor GPR30
Eric R. Prossnitz, Jeffrey B. Arterburn, Harriet O. Smith, Tudor I. Oprea,
Larry A. Sklar, and Helen J. Hathaway ppppppppppppppppppppppppppppppppppppppppppppp165
Insulin-Like Signaling, Nutrient Homeostasis, and Life Span
Akiko Taguchi and Morris F. White ppppppppppppppppppppppppppppppppppppppppppppppppppppp191
The Role of Kisspeptins and GPR54 in the Neuroendocrine
Regulation of Reproduction
Simina M. Popa, Donald K. Clifton, and Robert A. Steiner ppppppppppppppppppppppppppp213
GASTROINTESTINAL PHYSIOLOGY, James M. Anderson, Section Editor
Gastrointestinal Satiety Signals
Owais B. Chaudhri, Victoria Salem, Kevin G. Murphy, and Stephen R. Bloom ppppp239
Mechanisms and Regulation of Epithelial Ca
2+
Absorption in Health
and Disease
Yoshiro Suzuki, Christopher P. Landowski, and Matthias A. Hediger pppppppppppppppp257
Polarized Calcium Signaling in Exocrine Gland Cells
Ole H. Petersen and Alexei V. Tepikin pppppppppppppppppppppppppppppppppppppppppppppppppp273
RENAL AND ELECTROLYTE PHYSIOLOGY, Gerhard H. Giebisch,
Section Editor
A Current View of the Mammalian Aquaglyceroporins
Aleksandra Rojek, Jeppe Praetorius, Jørgen Frøkiaer, Søren Nielsen,
and Robert A. Fenton pppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp301
Molecular Physiology of the WNK Kinases
Kristopher T. Kahle, Aaron M. Ring, and Richard P. Lifton pppppppppppppppppppppppppp329
Physiological Regulation of Prostaglandins in the Kidney
Chuan-Ming Hao and Matthew D. Breyer ppppppppppppppppppppppppppppppppppppppppppppp357
Regulation of Renal Function by the Gastrointestinal Tract: Potential
Role of Gut-Derived Peptides and Hormones
A.R. Michell, E.S. Debnam, and R.J. Unwin pppppppppppppppppppppppppppppppppppppppppp379
RESPIRATORY PHYSIOLOGY, Richard C. Boucher, Jr., Section Editor
Regulation of Airway Mucin Gene Expression
Philip Thai, Artem Loukoianov, Shinichiro Wachi, and Reen Wu pppppppppppppppppppp405
Structure and Function of the Cell Surface (Tethered) Mucins
Christine L. Hattrup and Sandra J. Gendler ppppppppppppppppppppppppppppppppppppppppppp431
viii Contents
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Structure and Function of the Polymeric Mucins in Airways Mucus
David J. Thornton, Karine Rousseau, and Michael A. McGuckin pppppppppppppppppppp459
Regulated Airway Goblet Cell Mucin Secretion
C. William Davis and Burton F. Dickey pppppppppppppppppppppppppppppppppppppppppppppppp487
SPECIAL TOPIC, OBESITY, Joel Elmquist and Jeffrey Flier, Special Topic Editors
The Integrative Role of CNS Fuel-Sensing Mechanisms in Energy
Balance and Glucose Regulation
Darleen Sandoval, Daniela Cota, and Randy J. Seeley pppppppppppppppppppppppppppppppp513
Mechanisms of Leptin Action and Leptin Resistance
Martin G. Myers, Michael A. Cowley, and Heike Münzberg ppppppppppppppppppppppppp537
Indexes
Cumulative Index of Contributing Authors, Volumes 66–70 pppppppppppppppppppppppp557
Cumulative Index of Chapter Titles, Volumes 66–70 ppppppppppppppppppppppppppppppppp560
Errata
An online log of corrections to Annual Review of Physiology articles may be found at
http://physiol.annualreviews.org/errata.shtml
Contents ix
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... The LEP gene on chromosome 7 produces leptin, a signaling peptide associated with immunological and gastrointestinal system function (11). Adipose tissue mass produces leptin, a protein hormone whose levels are linked to changes in nutritional status and energy storage in a variety of nutritional situations. ...
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Humans and animals are affected by hydatid cyst disease as a worldwide zoonotic disease, which is caused by the metacestode stage of Echinococcus spp. This study was performed to evaluate the histological change of liver and blood concentrations of biomarkers, such as ghrelin, p-selectin, and leptin, in humans infected with hydatid cyst. A total of 30 surgical specimens of liver and blood of infected humans and 30 healthy individuals as a control group were evaluated. Liver tissue sections in cases infected with hydatid cyst and control group, histological abnormalities in the liver, including fibrosis, increased inflammatory cells, dystrophic areas, and necrosis were compared in this study. In addition, serum leptin levels were significantly lower in patients with hydatid cyst disease than in the control group (P-value<0.05), whereas p-selectin and ghrelin levels significantly decreased in patients (P-value<0.05). The results of this research can be effective in improving and promoting the treatment programs of hydatidosis.
... Ambas, se han observado alteradas en pacientes con OB. [53][54][55][56] La evidencia muestra que los pacientes que presentan OB con OA presentan hiperlipidemia a nivel local en el líquido sinovial y una alta expresión de leptina en el cartílago en comparación con pacientes con normopeso. 58 En uno de los primeros estudios prospectivos sobre el tema, encontraron que las personas con un índice de peso relativo superior al 120 % de su peso ideal, al inicio del estudio tenían un riesgo relativo de 3.12 (IC del 95 % 1.65-5.88) para desarrollar OA en las manos, en comparación con el grupo de referencia cuyo peso inicial era entre 95 y 109 % de su peso corporal ideal. ...
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RESUMEN Actualmente, los problemas de salud referentes a las enfermedades crónicas no transmisibles han tenido un auge importante debido al incremento en las cifras de morbilidad y mortalidad en el país, es por ello que los sistemas de salud destinan gran parte de su presupuesto en acciones para combatirlas a nivel global y nacional. Una de las enfermedades crónicas más importantes es la obesidad, ya que se estima como uno de los principales factores de riesgo para otras enfermedades. Si bien se considera a las enfermedades metabólicas como las principales complicaciones relacionadas con la obesidad, no debería restárseles importancia a las alteraciones osteomusculares provocadas por el exceso de peso, como lo es la osteoartritis. La evolución de los pacientes que sufren esta enfermedad, en fases tempranas o más avanzadas, conlleva una discapacidad considerable que les priva de llevar a cabo su vida diaria; donde la obesidad se puede contemplar como el principal factor de riesgo tanto para su etiología como para acelerar el proceso degenerativo de la misma. Los mecanismos identificados que han asociado a la obesidad con el desarrollo de la osteoartritis son complicaciones metabólicas y músculo articulares. Una hipótesis que ha sido abordada continuamente sobre el exceso de peso desde el punto de vista de la física, implica que diversas articulaciones soportan un mayor peso del cual pueden resistir, por lo tanto puede provocar y acelerar el desgaste articular con su consecuente inmovilidad. Sin embargo, el proceso parece ser más complejo, ya que recientes investigaciones han considerado que el estado inflamatorio de bajo grado generado por la obesidad, con la secreción de adipoquinas proinflamatorias como el factor de necrosis tumoral, interleucina 1 y 6, así como la leptina, pueden favorecer la expresión de enzimas degradadoras de la matriz extracelular, generando atrofia de los condrocitos y con ello la disfunción articular. Cualquiera de estos dos caminos puede ocasionar pérdida de movilidad, dolor y, por ende, disminuir la calidad de vida. Por consiguiente, el objetivo de este artículo es describir la relación que existe entre la obesidad y la osteoartritis, desde el punto de vista biomecánico y sistémico. ABSTRACT Currently, health problems related to chronic non-communicable diseases have had a significant boom due to the increase in morbidity and mortality rates in the country, which is why health systems dedicate a large part of their budget to actions to combat them globally and nationally. One of the most important chronic diseases is obesity, since it is considered one of the main catalysts that predisposes the development of other diseases. Although, there are other conditions and complications that lead to obesity that are not considered with the same severity, as is the case of those who suffer disabilities due to excess weight, as is the case of people diagnosed with osteoarthritis. The evolution of patients suffering from this disease, in early or more advanced stages, entails a considerable disability that deprives them of carrying out their daily lives; where obesity can be considered as the main risk factor both for its etiology and to accelerating its degenerative process. The identified mechanisms that have associated obesity as the protagonist of the development of osteoarthritis are metabolic and musculo-articular complications. A hypothesis that has been continuously addressed about excess weight from the point of view of physics, implies to various joints supporting a greater weight than they can resist, therefore it can generate and accelerate joint wear with its consequent immobility. However, the attrition process seems to be more complex since it has now been concluded that the low-grade inflammatory state that is generated in obesity, with the secretion of pro-inflammatory adipokines such as tumor necrosis factor, interleukin 1 and 6, as well like leptin, they can favor the expression of enzymes that degrade the extracellular matrix, generating atrophy of the chondrocytes and joint dysfunction. Either way can lead to loss of mobility, pain, and decreased quality of life. For this reason, the objective of this article is to describe the relationship between obesity and osteoarthritis, from the biomechanical and systemic point of view.
... These receptors, like the leptin receptor, bind to Janus kinase (JAK) and phosphorylate tyrosine on the cytoplasmic portion of the receptor, to which STAT 3 (signal transducer and activator of transcription 3) is recruited (Heinrich et al., 2002). The concentration of leptin in serum is directly proportional to the amount of white adipose tissue (WAT) or food intake [11,12]. ...
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Breast milk is the optimal food for infants and toddlers, providing basic nutrients. It is also a source of many biologically active substances. Among them are hormones responsible for metabolic balance. One of the hormones taken in with breast milk by a breastfed baby is leptin. This hormone is involved in the regulation of appetite, informing the brain about the body’s energy resources. Having the correct mechanisms related to the action of leptin is a factor reducing the risk of obesity. The natural presence of leptin in the composition of breast milk suggests that it has a specific role in shaping the health of a breastfed child. Obesity as a disease of civilization affects more and more people, including children. The development of this disease is multifaceted and determined by many factors, including genetic and environmental factors such as eating habits and low physical activity. Behind obesity, there are complex mechanisms in which many elements of the human body are involved. Understanding the effects of breastfeeding as a natural source of leptin can help prevent childhood obesity and development of this disease in future life.
... Leptin is a hormone produced by the adipose tissue and communicates the state of body energy repletion to the central nervous system (CNS) in order to suppress food intake and permit energy expenditure [22][23][24]. Most obese individuals exhibit elevated circulating leptin levels commensurate with their adipose mass, a condition defined as leptin resistance [25]. In our study we observed that leptin levels were higher in the HFD group when compared to the BEE group. ...
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... Moreover, resistance to hormones that are involved in energy metabolism has been reported in obese individuals; leptin is a polypeptide hormone secreted by adipocytes. Increment in triglyceride content of adipocytes is accompanied with increment of leptin secretion by these cells; leptin plays a central role in energy balance (Farhangi et al., 2013;Martin et al., 2008;Myers et al., 2008). MIC-1/GDF15 acts similar to leptin in energy metabolism. ...
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... Studies show that people respond to weight loss program is not the same. Serums leptin and insulin and resistance to them are two physiological factors that can affect weight loss programs (Boutcher & Dunn, 2009;King et al., 2007;Myers, Cowley, & Munzberg, 2008;Roth, Kratz, Ralston, & Reinehr, 2011). It seems in pubertal phase the changes in insulin resistance and leptin is more evident. ...
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Leptin, secreted by white adipocytes, has profound feeding, metabolic, and neuroendocrine effects. Leptin acts on the brain, but the specific anatomic sites and pathways responsible for mediating these effects are still unclear. We have systematically examined distributions of mRNA of leptin receptor isoforms in the rat brain by using a probe specific for the long form and a probe recognizing all known forms of the leptin receptor. The mRNA for the long form of the receptor (OB-Rb) localized to selected nuclear groups in the rat brain. Within the hypothalamus, dense hybridization was observed in the arcuate, dorsomedial, ventromedial, and ventral premamillary nuclei. Within the dorsomedial nucleus, particularly intense hybridization was observed in the caudal regions of the nucleus ventral to the compact formation. Receptors were preferentially localized to the dorsomedial division of the ventromedial nucleus. Hybridization accumulated throughout the arcuate nucleus, extending from the retrochiasmatic region to the posterior periventricular region. Moderate hybridization was observed in the periventricular hypothalamic nucleus, lateral hypothalamic area, medial mammillary nucleus, posterior hypothalamic nucleus, nucleus of the lateral olfactory tract, and within substantia nigra pars compacta. Several thalamic nuclei were also found to contain dense hybridization. These groups included the mediodorsal, ventral anterior, ventral medial, submedial, ventral posterior, and lateral dorsal thalamic nuclei. Hybridization was also observed in the medial and lateral geniculate nuclei. Intense hybridization was observed in the Purkinje and granular cell layers of the cerebellum. A probe recognizing all known forms of the leptin receptor hybridized to all of these sites within the brain. In addition, intense hybridization was observed in the choroid plexus, meninges, and also surrounding blood vessels. These findings indicate that circulating leptin may act through hypothalamic nuclear groups involved in regulating feeding, body weight, and neuroendocrine function. The localization of leptin receptor mRNA in extrahypothalamic sites in the thalamus and cerebellum suggests that leptin may act on specific sensory and motor systems. Leptin receptors localized in nonneuronal cells in the meninges, choroid plexus, and blood vessels may be involved in transport of leptin into the brain and in the clearance of leptin from the cerebrospinal fluid. J. Comp. Neurol. 395:535–547, 1998. © 1998 Wiley-Liss, Inc.