International Journal of Obesity (2005) 29, 11751183

& 2005 Nature Publishing Group All rights reserved 0307-0565/05 $30.00
www.nature.com/ijo

REVIEW
Direct metabolic regulation in skeletal muscle and fat
tissue by leptin: implications for glucose and fatty
acids homeostasis
RB Ceddia1*
1

Department of Kinesiology and Health Science, York University, Toronto, Ontario, Canada

In recent years, the adipose tissue has emerged as an important endocrine organ. It is now recognized that besides storing
energy the adipocytes also secrete several bioactive peptides, collectively called adipocytokines. Among these adipocytokines,
leptin, the product of the ob gene, has been extensively investigated over the last decade. Skeletal muscle and adipose tissue,
two major tissues involved in the regulation of glucose and fatty acids metabolism, have been consistently demonstrated to be
directly affected by leptin. By binding to its receptors located in skeletal muscle and fat cells, leptin promotes energy dissipation
and prevents fatty acid accumulation and lipotoxicity in these tissues. On the other hand, under conditions of peripheral leptin
resistance, such as observed in obese humans, the activation of pathways involved in fatty acid oxidation may be impaired. This
leads to intracellular accumulation of lipid intermediates and causes insulin resistance. This review examines the metabolic
pathways that are directly activated by leptin and how it regulates glucose and fatty acids metabolism in skeletal muscle and fat
tissue. Furthermore, the impact of peripheral leptin resistance in these tissues leading to dysfunctional metabolic adaptations is
also discussed.
International Journal of Obesity (2005) 29, 11751183. doi:10.1038/sj.ijo.0803025; published online 19 July 2005
Keywords: leptin; insulin; adipocyte; fatty acids; leptin resistance

Leptin and its receptors (Ob-Rs)

Leptin arises predominantly (495%) from adipose tissue
(especially subcutaneous depots) and its secretion is proportional to the size of whole-body adipose tissue mass and
nutritional status.1,2 In humans, leptin is encoded by a gene
located in chromosome 7q31.3, and is similar to that in
rodents.3 Leptin is translated as a 167 amino-acid protein
with an amino-terminal secretory signal sequence of 21
amino acids. The signal sequence is functional and results in
the translocation of leptin into microsomes with subsequent
cleavage of the signal peptide. Therefore, leptin circulates in
the blood as a 16 kDa protein with 146 amino acids.4
It has been postulated that leptin serves as a regulator of
energy balance. In fact, treatment of rodents with leptin
injections significantly reduced food intake and fat mass and
increased energy expenditure.57 Additionally, exogenous

*Correspondence: Dr RB Ceddia, Department of Kinesiology and Health

Science, York University, 4700 Keele St, Toronto, Ontario, Canada M3J
1P3.
E-mail: roceddia@yorku.ca
Received 18 September 2004; revised 10 March 2005; accepted 4 April
2005; published online 19 July 2005

administration of recombinant leptin reversed the typical

diabetic phenotype of ob/ob mice and improved the metabolic defects inherent of these animals.57 Interestingly, the
normalization of glycemia and insulinemia in ob/ob mice
was observed even before any alteration in body weight took
place, indicating that leptin plays an important role in the
regulation of glucose homeostasis independently of its
weight reducing effects.58
Leptin exerts its effects by binding to its receptors located
in several tissues throughout the body. The receptor for
leptin (Ob-R) was first cloned from a mouse choroid plexus
cDNA expression library9 following identification of [125I]
leptin binding sites in this tissue. The receptor presents high
homology with the gp130 subunit of the IL-6 receptor and is
a member of the extended class I cytokine-receptor family9
including interleukin-6 (IL-6), the granulocyte-colony stimulating factor (G-CSF) and the leukemia-inhibitory factor
(LIF).9,10 However, the leptin receptor oligomerizes with
itself but not with its closely related cytokine signal
transducer gp130.11
At the cellular level, Ob-R is known to signal through
cytoplasmic tyrosine kinases of the Janus kinase family
(JAKs) and signal transducers and activators of transcription

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Leptin

Ob-Rb
PM

Y Jak2
P

Y-985

Y-1077

P Y
ST
AT
3

Y-1138

ER

SOCS3

Nucle
us

STA T
3 ind
u
gene ced
s

PI3-k

AMPK
AKT

AMP
P AMPK

ACC
P

Y-705
STAT3

PT

Y-7
STA 05
T3

P IRSs

Y-705

3
CS
SO

B
P- 1

Jak2 Y P

STAT3

Glucose uptake
and metabolism

P ACC

Fatty acid
oxidation

CPT-1 / PGC-1 / ACO

Figure 1 Intracellular signaling by the leptin receptor (Ob-Rb) and metabolic and gene expression regulation. Leptin binding to the extracellular domain of Ob-Rb
dimer activates the JAk2 tyrosine kinase, which associates membrane-proximally with the receptor. Activated Jak2 phosphorylates itself and a number of substrates
including Y985 and Y1138 of Ob-Rb, and also insulin receptor substrates (IRSs). IRS1 and 2 interact and activate PI3-k and engage downstream pathways involved in
glucose uptake and metabolism. After phosphorylation of membrane-distal Y1138 of Ob-Rb by Jak2, STAT3 is recruited via its SH2 (Src homology) domain and
becomes itself a substrate for Jak2. Subsequently, phosphorylated STAT3 dimerizes, translocates to the nucleus, and induces the expression of several genes,
including those involved in fatty acid oxidation (CPT1, PGC1, ACO, etc), and also the suppressor of cytokine signaling (SOCS3). SOCS3 takes part in a feedback loop
inhibiting leptin signaling by binding to Y985 and Y1077; however, binding affinity for Y1007 is much weaker (dashed line). PTP-1B is localized on the surface of the
endoplasmic reticulum (ER), and is also involved in negative regulation of leptin signaling by dephosphorylation of Jak2 apparently after internalization of the leptinOb-Rb complex. Leptin signaling also increases intracellular AMP content, which may be responsible for directly activating AMPK. This, in turn, phosphorylates and
inactivates ACC leading to reduction of malonyl-CoA formation and deinhibition of CPT1 activity, a rate limiting step for long-chain fatty acids transport into the
mitochondria and for fatty acid oxidation. PM plasma membrane.

(STAT) pathway.912 Leptin binds to its receptor and initiates

a phosphoryation cascade via the Jak/STAT pathway and
increases phosphorylation of signal transducers and activators of transcription (STAT3).912 STAT3 dimerizes, translocates to the nucleus and regulates transcriptional activity of
its target genes (Figure 1).
The human and murine leptin receptors are highly similar
in amino-acid sequences for both the extracellular (78%
identity) and intracellular domains (71% identity).10 There
are at least six isoforms of the Ob-R(a-f), which are products
of a single lepr gene and result from alternative mRNA
splicing and/or proteolytic processing.10,1214
Ob-Rs can be classified as secreted (Ob-Re), short (Ob-Ra, c,
d, and f), and long (Ob-Rb) forms (Figure 2). All murine Ob-R
isoforms share identical extracellular, ligand binding domain
of 816 amino acids, while the intracellular domain of the Cterminus is different9,15 (Figure 2). Ob-Rb (also referred to as
Ob-RL; L long) has a long cytoplasmic domain of approximately 320 amino acids containing the motifs (Box 1, Box 2,
and three tyrosine residues to positions Y985, Y1077, and
Y1138) required for full activation of the JAK/STAT intracellular signaling pathway.1016 Owing to the truncation of the
intracellular domain, all short isoforms of Ob-R are considered not capable of intracellular signaling; however, it has
been demonstrated that Ob-Ra elicits signal transduction
(expression of immediate early genes, c-fos, c-jun, and jun-B)
in CHO cells added with leptin.17 Ob-Re is truncated before
the membrane-spanning domain and is likely to be a
secreted isoform of the receptor, which is believed to be
International Journal of Obesity

involved in modulating the activity of circulating leptin18

(Figure 2).
Most tissues, including the adipose tissue, skeletal muscle,
pancreas, and liver express short and long forms of Ob-R.1921
Peripheral tissues in general express 10 times more mRNA
encoding the short forms than the long form of Ob-R.20,21 In
normal mouse tissues, the relative abundance of the long form
expressed as a percentage of total Ob-R mRNA is: stomach
(11%), small intestine (7%), pancreas (11%), skeletal muscle
(8%), fat tissue (6%), liver (5%), heart (10%), and hypothalamus (36%).20,21 The presence of the long and short forms of
the Ob-R in peripheral tissues gives support to the observations
that leptin exerts direct physiological effects, independently of
signaling to the central nervous system (CNS).2224

Direct effects of leptin on glucose and lipid

metabolism in skeletal muscle
Skeletal muscle is quantitatively the most important site for
insulin-stimulated glucose disposal and for fatty acid oxidation.25,26 Also, it represents approximately 40% of total body
mass in nonobese subjects, and can account for up to 30% of
resting metabolic rate.27 A direct effect of leptin in skeletal
muscle may play a major role in the development of insulin
resistance and obesity. Indeed, it has been demonstrated that
leptin per se acutely raised basal glucose uptake in isolated
soleus muscles from rats28 and mice,29 and in C2C1230 and L6
skeletal muscle cells.31 Furthermore, leptin increased basal
and insulin-stimulated glucose oxidation in rat muscles.28

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Ob-Ra

Ob-Rb

Ob-Rc

Ob-Rd

Ob-Re

Ob-Rf

Ig

CRD

Fn3

Extracellular

805

Transmembrane
Box 1 motif
Box 2 motif

Intracellular

COO-

894

892
Y985
Y1077

901

896

Y1138
1162

Figure 2 Leptin receptor isoforms. There are at least six different isoforms of the leptin receptor Ob-R(a-f) in mouse. All share identical extracellular ligand-bind
domains but they differ at the C-terminus. Five of the six have transmembrane domains but only Ob-Rb encodes all protein motifs capable of activating the Jak-Stat
signal transduction pathway. JAKs associate constitutively with a conserved box 1 motif (intracellular amino acids 617), which is critical for JAK2 activation. A
putative Box 2 motif (intracellular amino acids 4960), apparently required for maximal activation of JAK2, has also been identified. Additionally, Ob-Rb has three
conserved tyrosines in its cytoplasmic domain, corresponding to positions Y985, Y1077, and Y1138. The latter functions as a docking site for STAT3. Ob-Re is
truncated before the membrane-spanning domain and is secreted. Ig immunoglobulin domain; CRD cytokine receptor domain; Fn3 fibronectin III domain.

Utilizing [1-14C]- and [2-14C]-pyruvate, it was demonstrated that leptin stimulates the activity of both the
pyruvate dehydrogenase (PDH) complex and Krebs cycle in
soleus muscles.28 This could be due to a direct stimulation of
PDH and Krebs cycle by leptin, or a consequence of an
indirect effect of this hormone activating mitochondrial
uncoupling and increasing oxygen consumption. Mitochondria uncoupling reduces the intracellular ATP/ADP ratio,
which activates PDH and the enzymes of the Krebs cycle.32
In fact, it has been demonstrated that leptin directly
increases oxygen consumption in soleus muscles isolated
from lean mice but not in db/db mice, which have a
dysfunctional long form of the leptin receptor.33
Besides glucose metabolism, evidence has also been
provided that leptin directly increases the production of
14
CO2 from [14C]-oleate and [14C]-palmitic acid and opposes
the lipogenic effects of insulin in skeletal muscles isolated
from mice,3436 humans,37 and rats.38 A similar response has
also been reported in C2C12 myotubes.39
In intact soleus and EDL muscles, leptin and insulin had
opposite effects on lipid metabolism, with leptin favoring
lipid oxidation and insulin favoring lipid storage in TG.
Hormone-induced alterations in muscle lipid metabolism
were more pronounced in soleus than in EDL. The
differences in response of soleus compared with that of
EDL were probably due to differences in fiber type composition and metabolic characteristics.35 Compared with EDL,
soleus is highly oxidative and has higher activities of
oxidative enzymes, more mitochondria, and a greater
capacity to store and use lipid fuels.40

The mechanism by which leptin directly affects glucose

and fatty acid metabolism in skeletal muscle still remains to
be fully determined. However, there seems to be a crosstalk
between the leptin and the insulin signaling pathways at the
levels of the insulin receptor substrate (IRS) and phosphatidylinositol-3 kinase (PI3-kinase)19,41 (Figure 1). According to
data obtained from C2C12 myotubes leptin activates JAK-2,
which induces tyrosine phosphorylation of IRS-2 leading to
activation of PI3-kinase and this is accompanied by an
increase in glucose uptake.30,41 Also, a direct thermogenic
effect of leptin on soleus muscle, which could influence
glucose and fatty acid metabolism, has been demonstrated to
be mediated by PI3-kinase signaling.33
More recently, it was reported that leptin directly activates
50 -AMP-activated protein kinase (AMPK) in skeletal muscle.36,42 AMPK is a heterotrimeric enzyme that functions as a
regulator of cellular metabolism in response to changes in
the energy status of the cells.43 When activated, AMPK shuts
down anabolic pathways and promotes catabolism in
response to a fall in the ATP/AMP ratio by phosphorylating
key enzymes of intermediary metabolism.43 AMPK also plays
an important role in the contraction- and hypoxia-induced
glucose uptake in muscle.43,44 Therefore, the observations
that leptin increases in vitro28,29,30,31and in vivo28,45 glucose
uptake and metabolism can be at least partially explained by
the direct activation of AMPK in skeletal muscle by this
hormone.
AMPK activation also leads to an increase in fatty acid
oxidation preventing it from accumulating in the muscle cell
as TG or in other lipid fractions4648 (Figure 3). Importantly,
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Glucose

Insu
lin

IR
P
P
P
P
P

12
Glucose- 6P

Lactate

PP

Glycogen

Oxidation

GLUT4

1
AMPK

ACC

IIRRSS
--11

P-AMPK

DA
G

7
P
S

FA-CoA

+
-1
CP T

Acetyl-CoA

PKC

Y IRS-1

Malonyl-CoA
3

P-ACC

-1

10
PI3-K

AMPKK

IRS

9
Y

NEFA

Rb
bO

Le

11

tin

CPT-1
ation
Oxid
a
ndri
cho
Mito

PM
Figure 3 Schematic model of the direct effects of leptin on glucose and fatty acids metabolism in skeletal muscle. When leptin binds to its receptor (Ob-Rb), AMPK
is phosphorylated and activated (1), which in turn phosphorylates and inactivates ACC (2). This leads to a reduction in malonyl-CoA formation (3), deinhibition of
carnitine palmitoyltransferase (CPT1) (4), and increase in fatty acid oxidation (5). The increase in fatty acid oxidation reduces the formation of a diacylglycerol (DAG)
pool from long-chain fatty acyl-CoA (FA-CoA) (6) and prevents the toxic effects of lipid intermediates. In the absence of leptin or under conditions of leptin
resistance, nonesterified fatty acids (NEFA) accumulate in the cell, DAG is formed (6) and the insulin signaling cascade follows an abnormal pathway (dashed lines).
DAG serves to activate a serine kinase, possibly protein kinase C (PKC)-y (7). PKCy phosphorylates the insulin receptor substrate (IRS)-1 on a serine residue (8) and
interferes with the ability of insulin (through its receptor, IR) to phosphorylate IRS-1 on a tyrosine residue (9) and recruit and activate phosphatidylinositol 3-kinase
(PI3-K) (10). The net effect, therefore, is loss of the stimulus for GLUT4 translocation to the cell surface promoted by PI3-K (11) and impairment of insulin-stimulated
glucose uptake (12) and metabolism. PM plasma membrane.

when the intracellular TG pool exceeds a certain amount, it

becomes toxic (lipotoxicity)47,49 and alters function within
muscle cells leading to insulin resistance in animals and
humans.47,4951 Interestingly, hyperleptinemic rats, induced
by adenovirus gene transfer, presented a profound reduction
in muscle TG content.52 The TG content of skeletal muscle
extracted from hyperleptinemic rats was 8% of the free
feeding control rats and 25% of pair fed controls.52 When
tissue TG content is severely depleted by hyperleptinemia in
normal rats, there is a dramatic increase in insulin sensitivity.5254 Whether this is a direct effect of leptin or mediated
by the CNS still remains to be determined. However,
treatment of high-fat-fed rats (60% fat for 8 days) with
adenovirus coding for leptin raises plasma leptin levels up to
60 ng/ml without changing cocaine- and amphetamineregulated transcript (CART) mRNA or food intake, indicating
that leptin action on the hypothalamus had not been
increased. Nevertheless, their body fat declined 36%,
suggesting that an extra-hypothalamic mechanism was
responsible for this effect of leptin.55
Support for a direct antilipotoxic effect of leptin on
skeletal muscle also comes from the observations that
activation of AMPK by 50 aminoimidazole-4-carboxamide-1b-D-ribonucleoside (AICAR) ameliorated fatty acid inducedinduced insulin resistance in isolated rat extensor digitorum
longus muscle and this effect was abolished by an AMPKspecific inhibitor.56 Also, blocking AMPK activation, by using
a dominant negative strategy,35,42 inhibited basal and leptinstimulated acetyl CoA carboxylase (ACC) phosphorylation in
International Journal of Obesity

muscle cells.35 ACC phosphorylation is a crucial step towards

releasing the inhibitory effect of malonyl-CoA on CPT1 and
to promote fatty acid oxidation.4346 Therefore, the direct
activation of AMPK35,42 may be the mechanism by which
leptin induces fatty acids oxidation in peripheral tissues
independently of the CNS and prevents the deleterious
effects of intramyocellular lipid accumulation42,45,47(Figure 3).
The glucose-fatty acid cycle initially proposed by Randle
et al57 to explain how nonesterified fatty acids (NEFA) caused
insulin resistance was that NEFA compete with glucose for
oxidation in isolated rat heart and diaphragm muscles. More
specifically, fatty acids caused an increase in the intramitochondrial acetyl CoA/CoA and NADH/NAD ratios, with
subsequent inactivation of pyruvate dehydrogenase.57 This
in turn would cause intracellular citrate concentrations to
increase, leading to inhibition of phosphofrutokinase, a key
rate-controlling enzyme in glycolysis. This would lead to
accumulation of glucose-6-phosphate and inhibition of
hexokinase II activity, causing an increase in intracellular
glucose concentration and impairment in glucose uptake.57
Although the glucose-fatty acid cycle concept prevailed for
almost four decades,50 new experiments have provided
evidence that NEFA may cause insulin resistance by also
directly affecting the GLUT4 transporter (alterations in the
trafficking, budding, fusion or activity of GLUT4) or by
altering upstream insulin signaling events such as IRS-1associated PI3-kinase25,51 in skeletal muscle. These alterations were associated with the activation of protein kinase Cy

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(PKCy),58 a known serine kinase that has been shown to be
activated by diacylglycerol. Based on this information, a new
mechanism has been proposed: increasing intracellular fatty
acid metabolites, such as diaylglycerol or fatty acyl CoAs,
activates a serine/threonine kinase cascade or protein kinase
C, leading to phosphorylation of serine/threonine sites on
insulin receptor substrates.58,59 Serine-phosphorylated forms
of these proteins fail to associate with an active PI3-kinase
resulting in decreased activation of glucose transport and
other associated downstream events25,51 leading to insulin
resistance (Figure 3).
Either from the glucose-fatty acid cycle57 or from the PKC
activation perspectives,58,59 prevention of intramyocellular
lipid accumulation seems to be an important mechanism by
which leptin may protect from the development of NEFAinduced insulin resistance in skeletal muscle. Through its
intracellular signaling pathways, leptin directly phosphorylates and activates AMPK, which in turn phosphorylates
and inactivates ACC and releases the inhibition on carnitine
palmitoyltransferase-1 (CPT1)60,61 by reducing intracellular
malonyl-CoA levels. This results in upregulation of fatty
acids oxidation and downregulation of lipid synthesis.43,44,4648 The direct activation of AMPK in skeletal
muscle by leptin36 may represent an important pathway
that prevents lipotoxicity in this tissue (Figure 3).

Direct effects of leptin on glucose and lipid

metabolism in adipose tissue
The administration of leptin in vivo causes dramatic reduction of fat depots in rodents.58 For instance, epididymal
white adipose tissue practically disappeared in lean C57BL/6
mice treated with human recombinant leptin.62 Molecular
analysis of adipose tissue revealed a rapid, selective increase
in the mRNA expression of thermogenic proteins and
lipolytic enzymes, including uncoupling proteins 1 and 2,
lipoprotein lipase, and hormone-sensitive lipase, with decreases in the lipogenic enzyme fatty acid synthase,
endogenous leptin, and cytochrome c oxidase.62 These
peripheral effects of leptin were followed by increased
thermogenesis and lipid oxidation in brown fat coupled
with increased lipolysis and decreased fat synthesis in white
and brown fat, which led to a rapid reduction in the body
weight and adiposity of lean C57BL/6 mice.62 Also TG stores
were strongly depleted in normal Wistar and lean wild-type
diabetic fatty (ZDF) rats in which hyperleptinemia was
induced by the injection of recombinant adenovirus containing the rat leptin cDNA.53,63 These in vivo effects could be
explained by leptin acting via the hypothalamus but they do
not rule out concomitant autocrine/paracrine effect of this
hormone that could be mediated by the long form of the
leptin receptor which is present in adipocytes.20,21 In fact, it
has been demonstrated in isolated adipocytes that leptin
reduces the binding of insulin to its receptor,64 impairs
insulin signaling,65 reduces the metabolic actions of insulin

on glucose uptake, glycogen synthesis, lipogenesis,66,67 and

the incorporation of glucose68 and acetate into lipids.68,69
Additionally, the expression of fatty acid synthase (FAS) and
ACC,63,67,70 and the maximal activity of malic enzyme,68
which are involved in the fatty acids synthesis pathway, have
also been shown to be reduced by leptin. On the other hand,
in the same cell system, leptin has been reported to increase
the expression of acyl-CoA oxidase (ACO), CPT1, peroxisome
proliferator-activated receptor-a (PPAR-a),70 and uncoupling
protein-2 (UCP2),69 and to promote glucose68 and fatty acids
oxidation,6671 and lypolysis.66,70,71 More recently, it was
also demonstrated that hyperleptinemia increases the expression of PPAR gamma coactivator-1 (PGC-1, an upregulator of mitochondrial biogenesis), promotes the
phosphorylation of AMPK and ACC and rapidly (up to 14
days) transforms the adipocytes into fat-oxidizing machines in rats.72 All these observations from in vivo and in
vitro animal studies suggest that leptin should promote
energy dissipation and limit lipid deposition in fat cells.
Intriguingly, in human obesity and in some animal models
of obesity the interstitial concentration of leptin surrounding adipocytes are extremely high73 and yet excessive lipid
storage in these cells is obviously not prevented. Apparently,
there is a suppressive mechanism that impairs leptin action
in fat tissue. This could be achieved by blocking signal
transduction by the leptin receptor in adipocytes. In fact, it
has been demonstrated that Socs-1 and 3 proteins are
increased in adipocytes of diet-induced and ventromedial
hypothalamus lesion (VMH) animal models of obesity.73 As
previously described, Socs proteins have been shown to
block the action of leptin on STAT-3 phosphorylation,7477 a
major pathway of intracellular leptin signal transduction,
which is consistent with the generation of leptin resistance
in fat cells and prevention of the autocrine and paracrine
effects of this hormone.
The importance of the direct effect of leptin on adipose
tissue has been reinforced with the in vivo studies of
adipocyte-selective reduction of the leptin receptors induced
by antisense RNA. This study provides evidence that leptin
resistance (not necessarily restricted to the level of the
receptor) in adipocytes increases adiposity, dyslipidemia, and
insulin resistance,78 suggesting that this may be the
molecular link between obesity and type 2 diabetes. Indeed,
fat tissue represents a large proportion of body mass (1520%
and 2030% for healthy men and women, respectively,
and more than 40% in obese subjects).79 Therefore, dysfunctional responses to leptin in this tissue may be of great
impact to whole-body glucose and fatty acid homeostasis.

Physiological and molecular mechanisms of leptin

resistance
Since administration of leptin decreased food intake and
increased energy expenditure, resulting in loss of fat mass,
and correction of the diabetic phenotype in ob/ob mice,59
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leptin initially was hailed as a potential cure for human
obesity. However, with the exception of rare human patients
with genetic leptin deficiency,80 circulating leptin levels
correlate well with body mass index (BMI) and total body fat
mass.8183 In fact, obese individuals have elevated circulating
leptin, suggesting that they are resistant to the effects of
leptin. Indeed, although therapy with exogenous leptin in
humans caused weight loss, the effects were modest (7.1 kg
after 6 months of subcutaneous leptin injection compared to
1.3 kg for the placebo group) in obese subjects.84 Nonetheless, it was reported that the dose of leptin necessary to
elicit significant alterations in body weight was very high
(0.30 mg/kg per day) and the patients reached serum leptin
concentrations as high as 667.0 ng/ml, while in the placebo
group it remained around 25 ng/ml.84 This reinforced the
notion that leptin resistance has to be overcome in order to
improve responsiveness to this hormone in obese humans.
Whether resistance to leptin resides mainly in the CNS (in
those areas involved with the control food intake and energy
homeostasis) or in peripheral tissues involved in energy
storage (adipocytes) and dissipation (skeletal muscle), still
remains under debate.
A number of potential mechanisms have been postulated
to underlie leptin resistance, including defects in leptin
access into the brain, the presence of negative regulators of
leptin signaling, or in pathways/neurons that mediate
downstream leptin action.85,86 All these postulated mechanisms are related to the action of leptin in the CNS87,88 and
very little has been published regarding leptin resistance in
peripheral tissues. It has been demonstrated that the
transport of leptin across the bloodbrain barrier is saturated
at plasma leptin levels between 4 and 15 ng/ml, nevertheless,
exogenously elevated plasma leptin levels (above 15 ng/ml)
elicit reduction in fat mass and improvements of glucose
uptake and insulin sensitivity in rats,55,70 suggesting that
direct peripheral effects of leptin may be responsible for
these metabolic alterations caused by leptin treatment.
It has been repeatedly demonstrated that leptin exerts
its effects by also acting directly in peripheral tissues
such as skeletal muscle,28,29,33,34,37,38 fat tissue,66,68,70,71
pancreas,8991 and liver,92 which play important roles in
the regulation of glucose and fatty acids metabolism and
whole-body energy homeostasis in mammals. Additionally,
it has been reported that isolated soleus muscles from highfat diet-induced obese (HFDIO) rats are not sensitive to the
leptin-induced increase in fatty acid oxidation,38 suggesting
that the development of leptin resistance in skeletal muscle
may contribute to the intramuscular accumulation of lipids.
This is in line with the observations that in isolated soleus
muscles from HFDIO mice, leptin failed to increase oxygen
consumption when compared to muscles isolated from the
lean mice.33 Similar results have also been reported in
isolated rectus abdominal muscles from humans, showing
that leptin increased the partitioning of fatty acids towards
oxidation in muscles from lean but not from obese
subjects.37
International Journal of Obesity

Potential mechanisms by which leptin resistance is

induced in peripheral tissues involves the suppressors of
cytokine signaling (Socs) family of molecules19,74 and
protein tyrosine phosphatase-1 (PTP-1B).19 Peripheral leptin
administration to mice rapidly induces Socs3 mRNA expression in the brain.75 Socs3 binds to the phosphorylated leptin
receptor through its Src homology-2 (SH2) domain and
inhibits Jak tyrosine kinase activity through its N-terminal
kinase inhibitory region, which functions as a pseudosubstrate.7477 Thus, Socs3 may be an important regulator
of leptin signaling and seems to play a major role in the
generation of peripheral leptin resistance.
PTP-1B has also been involved in leptin sensitivity. Mice
lacking PTP-1B are resistant to developing obesity, despite
having low serum leptin levels,93 indicating that this
phosphatase might function as a negative regulator of leptin
signaling. Further in vivo and in vitro experiments have
confirmed that PTP-1B deficiency increases leptin sensitivity.19 The mechanisms of this effect are not known. However,
it has been demonstrated that PTP-1B recognizes a specific
consensus substrate motif, (E/D)-pY-p-(R/K), which was
identified in Jak2,94,95 and this is supposed to impair
leptin-induced phosphorylation of Jak2.12 How PTP-1B
interacts with its substrates is not yet clear, although prior
internalization of the receptor complex has been suggested,
especially since PTP-1B is localized exclusively on the
endoplasmic reticulum (ER)96 and Jak2 has been detected
at the ER.97

Conclusions and future directions

There is now compelling evidence that leptin is capable of
directly regulating glucose and fatty acids metabolism in
skeletal muscle and fat tissue. These tissues play important
roles in whole-body glucose and lipid homeostasis, and are
implicated in the development of obesity, insulin resistance,
and type 2 diabetes. A number of molecular mechanisms and
metabolic pathways whereby leptin exerts its direct peripheral effects have been identified. Several connections have
been established between the leptin and intracellular signaling pathways in major insulin-sensitive tissues such as
skeletal muscle and fat tissue. Also, the recent discovery
that leptin directly activates AMPK revealed at least one
mechanistic explanation for the antiobesity and antidiabetic
roles that have been attributed to this hormone. Although
great progress has been made in the last few years towards
understanding the physiological roles of leptin, several
fundamental questions still need to be answered in order
to advance in the utilization of leptin or leptinomimetic
drugs to treat human obesity. What causes leptin resistance
and how can we prevent or reverse it? Are there specific
dietary components that impair leptin signaling and induce
resistance to this hormone in peripheral tissues? In rodents,
long-term exposure to high-fat diet induces peripheral leptin
resistance73,98 and this is also accompanied by high blood

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levels of NEFA and insulin resistance.73,98 NEFA also act as
signals involved in the regulation of gene expression. Several
genes are turned on by non-metabolized long-chain fatty
acids in a physiologically relevant manner.99,100 Therefore, it
can be hypothesized that chronically elevated fatty acids, as
observed in obese subjects,78,101,102 may induce the expression of genes involved in the generation of leptin resistance.
To date, no studies have investigated whether chronic
exposure of skeletal muscle to high levels of fatty acids
may affect the direct action of leptin in this tissue. If fatty
acids affect the expression and content of proteins such as
Socs3 and PTP-1B, involved in the generation of leptin
resistance, then this could impair the activation of the AMPK
pathway by leptin and facilitate intramyocellular accumulation of fatty acids, leading to lipotoxicity and insulin
resistance. Although no causeeffect relationship has been
established between fatty acids and hyperleptinemia. Future
experiments might help to clarify whether or not fatty acids
can directly affect the molecular pathways involved in leptin
signaling and the generation of leptin resistance in peripheral tissues. Answering these questions may lead to the
discovery of drugs to treat obesity and its related metabolic
disorders that are safer and more effective than the currently
available.

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