International Journal of Obesity (2004) 28, S75–S80
& 2004 Nature Publishing Group All rights reserved 0307-0565/04 $30.00
www.nature.com/ijo
PAPER
Hormones regulating lipid metabolism and plasma
lipids in childhood obesity
M Gil-Campos1, R Cañete1 and A Gil2*
1
Unit of Pediatric Endocrinology, University Hospital Reina Sofia, Avda. Menendez Pidal, Cordoba, Spain; and 2Department
of Biochemistry and Molecular Biology, School of Pharmacy, University of Granada, Campus de Cartuja, Granada, Spain
OBJECTIVE: To review the mechanisms by which leptin, insulin and adiponectin influence lipid metabolism and plasma lipids in
obesity, as well as to describe the associations between these hormones in prepubertal children.
METHOD: Revision of relevant papers published in the last 5 y related to the interactions of leptin, insulin and adiponectin, with
special emphasis on those reporting potential mechanisms by which these hormones regulate lipid metabolism and plasma
lipids. We also provide original results concerning the relationships found between plasma lipids and leptin, and insulin and
adiponectin in prepubertal obese children.
RESULTS: Recent data in the literature shed new light to explain the effects of both leptin and adiponectin in the regulation of
lipid metabolism in peripheral tissues. Activation of the AMP-dependent kinase pathway and subsequent increased fatty acid
oxidation seems to be the main mechanism of action of these hormones in the regulation of lipid metabolism. In addition, we
have found that insulin plasma levels are positively associated to leptin but negatively correlated with adiponectin in obese
children. Adiponectin is negatively associated to plasma lipid markers of metabolic syndrome but positively related to HDLcholesterol, whereas insulin and leptin show opposite patterns. These results support the effect of adiponectin in increasing
insulin sensitivity and decreasing plasma triglycerides.
CONCLUSION: Leptin, insulin and adiponectin are associated hormones that regulate lipid metabolism in childhood.
Adiponectin appears to be the missing link to explain the alterations in lipid metabolism and plasma lipids seen in obesity.
International Journal of Obesity (2004) 28, S75–S80. doi:10.1038/sj.ijo.0802806
Keywords: adiponectin; AMP kinase; insulin resistance; metabolic syndrome; plasma lipids
Introduction
Obesity is characterized by an altered balance between
energy intake and energy expenditure. Energy homeostasis
is accomplished through a highly integrated and redundant
neurohumoral system that minimizes the impact of
short-term fluctuations in energy balance on fat mass.1
Critical elements of this control system are hormones
secreted in proportion to body adiposity, including
leptin, insulin and adiponectin, and the central nervous
system (CNS) and other peripheral targets upon which they
act. Some of these CNS targets stimulate food intake and
anabolic pathways, promoting weight gain, whereas others
reduce food intake and catabolic pathways, promoting
weight loss.2,3 Moreover, a number of hormones, including
leptin, insulin, adiponectin and catecholamines, regulate the
*Correspondence: Professor A Gil, Departamento de Bioquı́mica y
Biologı́a Molecular, Universidad de Granada, Facultad de Farmacia,
18071 Granada, España, Spain.
E-mail: [email protected]
fuel metabolism, that is, lipid metabolism, in a number of
peripheral tissues, independently of the regulation of food
intake.4–8
Obesity is associated to the metabolic syndrome characterized by hyperinsulinemia, glucose intolerance or diabetes
type 2 and two or more of the following factors: hypertension, hypertriglyceridemia, decreased plasma levels of
HDL-cholesterol (HDL-c), small and dense LDL particles,
increased apoprotein B (apo-B), decreased apoprotein
A-I (apo-A-I) and alterations of hemostasia.9 Typical alterations of the metabolic syndrome may begin early in
childhood, as they have been reported in prepubertal
children10,11 and adolescence.12 However, the etiology
of insulin resistance and its associated biochemical alterations, particularly those affecting lipid metabolism, continue
to be a matter of debate. Changes in leptin, insulin
and adiponectin, associated to obesity and their effects
on lipid metabolism, may explain the alterations in plasma
lipids and other characteristic features of the metabolic
syndrome.
Hormones and plasma lipids
M Gil-Campos et al
S76
In this study, we briefly review the relationships of leptin,
insulin and adiponectin with obesity and particularly in the
regulation of lipid metabolism and plasma lipids. We also
provide results about the relationships of those hormones
with plasma lipids in prepubertal children.
Regulation of lipid metabolism by leptin, insulin
and adiponectin
Insulin and leptin are secreted in direct proportion, and
adiponectin in negative proportion, to the size of the adipose
mass. These three hormones are key molecules in the
regulation of lipid metabolism. During states of positive
energy balance, as it occurs in obesity, the adipose mass
expands and more leptin and insulin1,4 but less adiponectin
are secreted.13,14 Leptin and insulin reach the brain and, as a
consequence, anabolic pathways are inhibited and catabolic
pathways are activated. These two hormones, as well as
adiponectin, also interact with peripheral tissue receptors
modulating energy metabolism.8,15–17
Leptin: a regulator of excessive energy intake and lipid
metabolism
Leptin is produced by adipose tissue and considered to be
one of the main peripheral signals that regulate food intake,
energy expenditure and body weight, by reporting
nutritional information to key regulatory centers in the
hypothalamus.15 Leptin exerts complex effects on the
storage and metabolism of fats and carbohydrates. These
are mediated both directly, through actions on specific
tissues, and indirectly, through CNS endocrine and neural
mechanisms.4
Leptin stimulates fatty acid oxidation and glucose uptake
and prevents lipid accumulation in non-adipose tissues,
which can lead to lipotoxicity and functional impairments.6
The increase in the expression of uncoupling proteins (UCP)
in adipose tissue and muscle, which occurs during leptin
treatment may also account for leptin’s ability to prevent the
decrease in energy expenditure that takes place during the
reduction of food intake.4
Studies involving, intrahypothalamically or intravenously,
leptin injection, as well as incubation of soleus muscle or
cultured muscle cells with leptin, have demonstrated that
leptin stimulates fatty acid oxidation in skeletal muscle by
activating (phosphorylating) AMPK. This enzyme potently
stimulates fatty acid oxidation in muscle by inhibiting
(phosphorylating) acetyl-CoA carboxilase (ACC) activity,
which inhibits malonyl-CoA synthesis, activating carnitine
palmitoyl transferase 1 (CPT1) activity.6 Early activation of
AMPK occurs by leptin action on muscle, whereas later
activation depends on leptin action through the hypothalamic–sympathetic nervous system axis.18,19 According to
this, leptin inactivates (dephosphorylates) AMPK in the
hypothalamus, as well as other anorexigenic compounds,
that is, insulin, and C-75. These findings demonstrate that
International Journal of Obesity
AMPK plays a role not only in the alteration of metabolic
pathways in muscle and liver but also in the regulation of
feeding, and identify AMPK as a novel target for anti-obesity
drugs.19
Although AMPK inactivation in the hypothalamus is
puzzling, this finding could be pointing out to the actual
role of diet-induced obesity hyperleptinemia. Weight gain
begins when the caloric balance becomes positive, but,
ultimately, weight reaches a plateau, indicating that caloric
balance has been restored; this equilibrium of caloric intake
and expenditure may reflect the action of endogenous
hyperleptinemia on the hypothalamus.20 Figure 1 shows
the effects of hyperleptinemia on AMPK in both the
hypothalamus and skeletal muscle.
There is a controversy about the direct interaction between
leptin and insulin. Apparently, hyperinsulinemia promotes
fat deposition, which subsequently increases leptin expression.5,17 Leptin has also been suggested to be related to
insulin resistance.21 Moreover, in healthy children and
adults, obese individuals or those who have insulin-dependent or non-insulin-dependent diabetes, there is a positive
correlation between leptin and insulin concentrations during fasting, independent of body fat content. These results
led to the suggestion that leptin might be the signal from
adipocytes to islets to hypersecrete insulin when fat content
is increased and insulin sensitivity is lowered.22 However, a
great deal of additional information is needed to clarify the
relationship between leptin and insulin sensitivity, in both
physiological and pathological conditions.
It is well known that insulin actions are mainly mediated
by phosphatidyl inositol-3-kinase (PI-3K), which influences
mitogenesis, glucose uptake by GLUT4 transporter and
protein phosphatase, which mainly affects glucogen synthesis and lipogenesis.23 Since leptin contributes to enhance
fatty acid oxidation in muscle, and probably in other tissues,
this hormone would counteract the action of insulin,
preventing an excess of triglyceride (TG) accumulation in
obesity and other related metabolic disorders.
Adiponectin: a link between adiposity, insulin
resistance and lipid metabolism
Adiponectin is an adipose tissue-derived hormone that has
an important role as a modulator of insulin action and
exhibits anti-inflammatory and antiatherogenic properties.24,25 In humans, adiponectin levels are inversely related
to the degree of adiposity and positively associated with
insulin sensitivity both in healthy subjects and in diabetic
patients.26 Plasma adiponectin concentrations have been
reported to be decreased in some insulin-resistance states,
such as obesity and type 2 diabetes mellitus, and also in
patients with coronary artery disease.13 Moreover, plasma
levels of adiponectin have been shown to correlate negatively with body mass index, insulin and TG levels, and
positively with HDL-c in adult obese subjects.16
Hormones and plasma lipids
M Gil-Campos et al
S77
-
Increased food intake
Pancreas
ACC P
MalonylMalonyl-CoA
Insulin
Hypothalamus
P
AMPK
Adipose
tissue
Leptin
Blood Brain Barrier
Leptin receptor
P
+
P
+
AMPK
PPARPPAR-alfa
Gene Expression
P
ACC
Skeletal muscle
ACC
+
AcetylAcetyl-CoA
AcylAcyl-CoA
MalonylMalonyl-CoA
+
CPT1
Oxidation
Fatty Acid Oxidation
Enzymes
+
TG
Figure 1 Model for the mechanism of action of insulin on fatty acid oxidation in muscle and on hypothalamus in the control of energy intake. ACC: acetyl CoA
carboxylase; AMPK: AMP-dependent kinase; CPT1: carnitine palmitoyl transferase 1; PPAR: peroxisome proliferator-activated receptor; TGs: triglycerides.
Adiponectin increases insulin sensitivity by enhancing
tissue fat oxidation, which results in reduced circulating
fatty acid levels and TG contents in liver and muscle.26
Adiponectin increases the tyrosine kinase activity of insulin
receptor by enhancing the activity of the oxidative phosphorylation UCPs.7 Adiponectin knockout mice fed a
carbohydrate-rich diet develop insulin resistance and have
a reduced PI-3K activity.27 In addition, adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMPK.7,8,28 Thus, the administration of either globular
adiponectin or the complete adipokine to mice increases the
AMPK-dependent phosphorylation in skeletal muscle; in the
liver, this activation only occurs when the complete form of
the hormone is injected.7 As stated above, activation of
AMPK results in increased oxidation of acyl-CoA. Adipo R1
and adipo R2 adiponectin receptors have been identified and
cloned recently in myocytes and the liver, respectively, and
expression of adipo R1 is associated with an increase in the
activity of AMPK, ACC and p38 mitogen-activated protein
kinase (MAPK), whereas in hepatocytes there is an increase
in the phosphorylation of AMPK and ACC; adiponectin also
increases the activity of PPAR-a, a transcription factor
playing a key role in the regulation of fatty acid oxidation.8
Figure 2 shows a model for the mechanism of action of
adiponectin in the regulation of fatty acid oxidation and
insulin sensitivity.
Relationships between insulin, leptin and adiponectin and plasma lipids in prepubertal obese
children
We have recently carried out a study in obese (n ¼ 34) and
control (n ¼ 20) prepubertal children to determine the
potential relationships between insulin, leptin and adiponectin and plasma lipids.
Plasma TGs as well as apo-B levels were significantly higher
in obese than in controls (Po0.001). However, cholesterol
was slightly lower in the obese group. Moreover, HDL-c
levels were significantly reduced in obese children compared
with the control group. However, no major differences were
observed for apo-A-I. Insulin and leptin were markedly
higher in the obese group who developed an insulin
resistance pattern, whereas adiponectin was significantly
reduced compared with the control children.
A high positive and significant correlation was observed
between insulin and TGs and apo-B plasma levels, whereas
the correlation was negative for HDL-c. The same pattern
was observed for the relationships between leptin and
plasma lipids, except that no correlation was found for
leptin and apo-B. By contrast, adiponectin plasma concentrations correlated negatively with TGs and apo-B and
positively with HDL-c. Absolute values for the correlations
between adiponectin and plasma lipids were higher than
those obtained for insulin and leptin (Table 1).
International Journal of Obesity
Hormones and plasma lipids
M Gil-Campos et al
S78
SKELETAL MUSCLE
MONOMERS AND TRIMERIC AND HEXAMERIC
AGGREGATES OF ADIPONECTIN
INSULIN
Insulin Receptor
Adiponectin R1 Receptor
P
P
P
Glucose
uptake
GLUT4
P
P
+
?
+
IRS-1
+
p38MAPK
+
P
+
Glucose
uptake
GLUT4
PI-3 KINASE
P
+
AMPK
Sensitivity to insulin
PPARPPAR-alfa
Gene Expression
P
ACC
ACC
+
AcetylAcetyl-CoA
AcylAcyl-CoA
+
MalonylMalonyl-CoA
CPT1
Fatty Acid Oxidation
Enzymes
+
Oxidation
TG
Figure 2 Model of the interactions of insulin and adiponectin in the control of energy expenditure and lipid metabolism in muscle. ACC: acetyl CoA carboxylase;
AMPK: AMP-dependent kinase; CPT1: carnitine palmitoyl transferase 1; GLUT4: glucose transporter 4; IRS-1: insulin receptor substrate; PI-3 kinase: phosphatidyl
inositol-3 kinase; p38MAPK: p38 mitogen-activated protein kinase; PPAR: peroxisome proliferator-activated receptor; TGs: triglycerides.
Insulin and leptin were positively correlated, whereas
insulin and adiponectin showed a negative association
(Figure 3). Adiponectin and leptin were also negatively
correlated, but the association was relatively weak
(r ¼ 0.368; P ¼ 0.014).
Although leptin is related to the control of body composition and energy expenditure in animals and humans, the
tissue resistance observed in obese subjects explains the
observed high plasma levels of leptin without a concomitant
inhibition of food intake.4,12 In our study, leptin plasma
concentrations were positively associated to anthropometric
markers of fat mass and also to basal energy expenditure,
which corroborates that, also in prepubertal children, leptin
resistance is markedly evident. Leptin has been shown to be
associated to insulin by other investigators in childhood and
adult life.5,29 However, in the present study, only a weak
correlation was found between leptin and adiponectin,
suggesting that the association between these two hormones
is more a consequence of adiposity than a cause–effect
relationship in the development of insulin resistance.
Insulin resistance and an altered plasma lipid pattern are
common pathophysiological features of the metabolic
syndrome not only in adults but also in childhood and
adolescence.10,11 However, the etiology of insulin resistance
and its associated biochemical alterations, particularly those
affecting lipid metabolism, continue to be a matter of
debate.
International Journal of Obesity
Table 1 Correlation between insulin, leptin, and adiponectin, and plasma
lipids in prepubertal obese and control children
Variables
Insulin-TG
Insulin-HDL-c
Insulin-apo-B
Leptin-cholesterol
Leptin-HDL-c
Log adiponectin-TG
Adiponectin-HDL-c
Log adiponectin-Apo-B
Log leptin-HOMA
Log adiponectin-HOMA
r
P
0.446
0.412
0.329
0.393
0.535
0.478
0.635
0.432
0.502
0.433
0.001
0.002
0.016
0.008
o0.001
o0.001
o0.001
0.001
o0.001
0.004
TG: triacylglycerides; HDL-c: high-density lipoprotein cholesterol; Apo-B:
apoprotein B; HOMA: homeostasis model assessment of insulin resistance; r:
Pearson’s correlation coefficient; P: significance of obese children (n ¼ 34) and
control children (n ¼ 20).
Adiponectin seems to be the missing link between insulin
resistance and the alterations observed in plasma lipids. In
the present study, obese children exhibited a marked
hyperinsulinemia, which was positively associated with
plasma lipid markers of cardiovascular disease and metabolic
syndrome, that is, high levels of TGs and apo-B, but
negatively associated with HDL-c and plasma adiponectin
concentrations. Those associations were similar to or higher
than those observed for insulin. Moreover, insulin and
Hormones and plasma lipids
M Gil-Campos et al
1.4
1.5
1.2
Log Adiponectin (ng/ml)
log Leptin (pg/ml)
S79
2.0
1.0
0.5
r = 0.533
P < 0.001
0.0
r = -0.502
P < 0.001
1.0
0.8
0.6
−0.5
0.4
0
10
20
−10
30
0
Insulin (mU/l)
10
20
30
40
50
Insulin (mU/l)
Figure 3 Correlation between insulin and leptin, and insulin and adiponectin in prepubertal children.
adiponectin were highly but negatively correlated. From
these results, we suggest that adiponectin may have a direct
impact in the regulation of insulinemia as well as in
lipoprotein metabolism, confirming that, not only in adults
but also in prepubertal children, insulin and adiponectin are
antagonist hormones reciprocally regulated. Low levels of
adiponectin would decrease the interaction with its hepatic
and skeletal muscle receptors and contribute to downregulate the insulin transduction signal cascade, resulting
in a reduced fatty acid oxidation, activation of hepatic
gluconeogenesis and reduced glucose uptake in both tissues.
8
9
10
11
Acknowledgements
This study was supported by Fondo de Investigaciones
Sanitarias (FIS, Project no. PI 020826), Ministerio de Salud
y Consumo and the Fundación Salud 2000, Spain.
12
13
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