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Department of Biology, York University, Toronto, Canada;
* Integrative Physiology, Karolinska Institute, Stockholm, Sweden; and
Department of Medicine, Division of Cardiology, Helsinki University Central Hospital, Helsinki, Finland
1Correspondence: Department of Biology, York University, Toronto, M3J 1P3 Ontario, Canada. E-mail: gsweeney{at}yorku.ca
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONEFFECT OF LEPTIN AT...DIRECT PERIPHERAL EFFECTS OF...THE EFFECT OF LEPTIN...LEPTIN AND INSULIN SIGNALING...CONCLUSIONS AND PERSPECTIVESREFERENCES |
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Key Words: obesity • lipoatrophy • lipodystrophy • diabetes mellitus • glucose metabolism
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONEFFECT OF LEPTIN AT...DIRECT PERIPHERAL EFFECTS OF...THE EFFECT OF LEPTIN...LEPTIN AND INSULIN SIGNALING...CONCLUSIONS AND PERSPECTIVESREFERENCES |
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2
3
4)
, a wealth of information has accumulated regarding the role of leptin on body weight regulation (5
, 6)
. Leptin’s ability to decrease food intake and increase energy expenditure identified it as the circulating factor postulated by Hervey to decrease food intake in lean rats during parabiosis studies with ventromedial hypothalamus lesioned obese rats (7)
. Mice homozygous for a mutation in the ob gene, which prevents production of leptin, exhibit early-onset obesity and weigh three to four times more than normal mice (8)
. Leptin has a broad range of effects on physiological processes in reproductive, immune, and neuroendocrine systems (9
10
11
12
13)
. The ob/ob mouse is insulin resistant and diabetic, suggesting leptin plays a role in glucose homeostasis and possibly in the pathogenesis of common obesity related metabolic diseases, including insulin resistance and type 2 diabetes (14)
. However, investigation of whether leptin is a diabetogenic or an antidiabetogenic hormone has produced many conflicting conclusions. For example, several studies have reported that leptin treatment increases insulin sensitivity in normal and diabetic rats (15
, 16)
and can correct the diabetic phenotype of ob/ob mice (17)
. However, others present evidence that leptin impairs insulin action in human hepatic cell lines (18)
, isolated rat adipocytes (19)
, and skeletal muscle (20
, 21)
. In human cross-sectional studies, circadian leptin cycles correlate negatively with 24 h cycles in insulin sensitivity (22)
, and leptin concentrations are higher in insulin-resistant than -sensitive men independent of adiposity (23)
. A substantial amount of literature reports that leptin has no effect on insulin sensitivity (24
25
26
27)
.
Making analysis of these observations more complicated is the fact that, unlike commonly studied obese rodent models, the majority of obese humans exhibit high plasma concentrations of leptin (28)
. Indeed, in humans weight loss is invariably followed by a reduction in plasma leptin levels and a coincidental increase in insulin sensitivity. In contrast, individuals or animals with a paucity of fat, and consequently low plasma leptin levels, also exhibit insulin resistance and diabetes (29)
. The paradoxical observations reported to date raise the question of whether alterations in leptin action contribute to diabetes caused by obesity or lipodystrophy merely as a correlate with these phenomena or if they occur as a consequence of insulin resistance. For example, when insulin resistance is induced by enhanced glucosamine availability, the increase in plasma leptin and adipose leptin mRNA and protein concentration is accompanied by an increase in leptin mRNA and protein concentration in skeletal muscle (30)
. Here we provide a summary of the many apparently paradoxical observations regarding the effects of leptin on glucose metabolism, insulin secretion, and insulin sensitivity.
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EFFECT OF LEPTIN AT THE WHOLE BODY LEVEL |
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TOPABSTRACTINTRODUCTIONEFFECT OF LEPTIN AT...DIRECT PERIPHERAL EFFECTS OF...THE EFFECT OF LEPTIN...LEPTIN AND INSULIN SIGNALING...CONCLUSIONS AND PERSPECTIVESREFERENCES |
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). Compared with vehicle-treated controls, treatment of normal Sprague Dawley rats with subcutaneous (s.c.) infusion of leptin (1 or 10 µg/h) for 48 h reduced plasma levels of glucose and insulin without any effect on body weight (15)
. During the 48 h of leptin treatment, these animals and matched controls were fasted. Additional studies demonstrated that acute intravenous (i.v.) injection of leptin increased insulin sensitivity in normal Sprague Dawley rats, as determined by increased glucose utilization during hyperinsulinemic glucose clamps (15)
. Leptin infusion to normal rats (0.5 mg/kg for 8 days) increased insulin-stimulated glucose uptake and enhanced inhibition of hepatic glucose production by insulin during a hyperinsulinemic clamp (31)
. Consistent with this, a 5 h i.v. leptin infusion (without concomitant insulin infusion) in mice increased glucose turnover and glucose uptake but decreased hepatic glycogen content (32)
. Plasma insulin and glucose levels were unchanged. Changing the route of leptin administration to intracerebroventricular (ICV) produced similar results, suggesting the in vivo effects of leptin on glucose metabolism were centrally mediated (32)
. The observation that ICV infusion of leptin (1 µg·kg-1·h-1 for 6 h) to rats caused a redistribution of hepatic glucose flux further supports a role for central effects of leptin in regulating metabolism in peripheral tissues (24)
. Moreover, microinjection of leptin into the ventromedial hypothalamus (VMH), but not lateral hypothalamus, produced effects on peripheral glucose metabolism suggesting this region of the brain regulated such effects of leptin (33)
.
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Whereas an insulin-sensitizing effect of leptin at the whole body level may be apparent in some cases, effects on individual tissues are likely to vary (34)
. Treatment of normal male rats with leptin (4 mg·kg-1·day-1 for 7 days) was associated with decreases in food intake, body weight, and plasma triglyceride (TG), insulin, and glucose levels (34)
. Under similar conditions, an i.v. bolus injection of labeled 2-deoxyglucose after 90 min hyperinsulinemic euglycemic clamp demonstrated leptin treatment was associated with an increase in glucose uptake in brown adipose tissue and skeletal muscle but with a decrease in white adipose tissue (34)
. Similarly, microinjection of leptin into the VMH increased glucose uptake in brown adipose tissue, skeletal muscle, and heart but not in white adipose tissue (33)
.
In another study, the effect of i.v. administration of 1 µg/min leptin to male Wistar rats for 90 min on whole body glucose uptake and hepatic glucose production rate was assessed using a euglycemic hyperinsulinemic clamp (25)
. These parameters were unchanged between control and leptin-treated animals, suggesting leptin had no acute effect on insulin sensitivity under these conditions (25)
. The inability of leptin to mediate insulin action was supported by another study where ICV infusion of leptin (1 µg·kg-1·h-1 for 6 h) to rats did not alter peripheral glucose uptake, glycolysis, or glycogen synthesis (24)
.
Effect of leptin on glucose homeostasis in animal models of diabetes
Lean insulin-deficient (streptozotocin diabetic) animals
Effects of leptin administration have been determined on glucose homeostasis in a lean, insulin-deficient animal model of diabetes mellitus. Streptozotocin-induced (STZ) diabetes occurs subsequent to destruction of pancreatic ß cells and is associated with decreases in adipose leptin mRNA expression and circulating leptin levels (35
, 36)
. Treatment of STZ insulin-deficient rats with s.c. infusion of recombinant murine leptin (4 mg·kg-1·day-1 for 12–14 days) restored euglycemia and normalized peripheral insulin sensitivity during a hyperinsulinemic euglycemic clamp (16)
. These results suggest that leptin mediates an anti-diabetic effect in this diabetic animal model. These effects of leptin were achieved through an insulin-independent and an insulin-sensitizing mechanism (16)
.
Monogenetic obese animal models of diabetes mellitus
The first demonstration of the role of leptin as a regulator of glycemia and insulinemia was shown in ob/ob mice treated with intraperitoneal injections (0.1–10 mg/kg) of this hormone (2
3
4)
. The diabetic phenotype was reversed in leptin-treated mice; this effect was achieved in animals treated with low-dose leptin, which did not cause a significant weight loss (2
3
4)
. These findings suggest that the effects of leptin on blood glucose and insulin levels are not due to a reduction in food intake. Subsequently, adenoviral gene therapy of ob/ob mice with mouse leptin cDNA resulted in normalization of plasma glucose and insulin levels; in this case, the positive effect on glucose homeostasis was accompanied by reduced food intake and body weight (17)
.
Mice with a mutation in the leptin receptor (db/db), resulting in expression of a truncated protein, have a phenotype similar to ob/ob mice (37)
. Several obese rat models such as fa/fa Zucker (which have a missense mutation in the extracellular domain of the leptin receptor) and Koletsky (which have a null mutation in leptin receptor) exhibit insulin resistance, hyperglycemia, and impaired glucose tolerance (20
, 37
38
39
40)
. In such models, a reduction in body weight and correction of metabolic abnormalities do not occur in response to treatment with leptin (41)
. Whereas ICV administration of leptin to normal rats improved glucose tolerance, this effect is not observed in obese Zucker rats (42)
.
In the Otsuka Long-Evans Tokushima fatty rat, a genetic model for spontaneous development of non-insulin-dependent diabetes mellitus with obesity, i.v. leptin administration (50 nmol·kg-1·h-1 for 16 h) does not alter plasma insulin or glucose levels or insulin-stimulated glucose uptake in hind limb muscle (43)
. In contrast, a similar leptin treatment increased insulin-stimulated glucose uptake in hind limb muscles and decreased plasma insulin levels in lean control rats. The authors conclude that these observations suggest the existence of leptin resistance in the obese rats (43)
.
Mice homozygous for mutation in the tubby gene develop late-onset obesity without diabetes (44)
. The role of leptin in this obese model demands further investigation. Thus far, no alteration in the hypothalamic expression of the long form leptin receptor (ob-Rb) has been reported to occur in tubby mice (45)
.
Dietary-induced obese animal models
Further evidence that leptin can modulate insulin action comes from studies using animals with high fat diet-induced obesity, which is commonly associated with elevated plasma leptin levels (46)
. In some animals, leptin levels in response to a high-fat diet remain low and rise only gradually (46)
. The type of dietary fat in such experiments is likely to determine the ultimate effect on plasma leptin levels (47)
. Nevertheless, rats with high fat diet-induced obesity typically exhibit impaired glucose tolerance and insulin resistance, with impairment of glucose uptake in skeletal muscle (48
, 49)
. Increasing plasma leptin levels in these animals by adenoviral gene therapy reduces adipose mass and intramuscular TG content 40% and 60%, respectively, and this is associated with a reversal of skeletal muscle insulin resistance and correction of hyperglycemia and hyperinsulinemia (48)
. Similarly, s.c. infusion of leptin (10 mg·kg-1·day-1) improves the reduced glucose tolerance and skeletal muscle glucose uptake in rats with high fat diet-induced obesity (49)
. These data provide evidence to suggest that administration of leptin may be useful to treat obesity and insulin resistance in high fat diet-induced obesity. However, leptin supplementation to obesity-prone C57BL/6J mice, which develop reduced plasma leptin levels in response to fat feeding, does not prevent the development of diet-induced obesity (50)
. Plasma glucose or insulin levels are not different in obesity-prone C57BL/6J mice treated with leptin and control mice (50)
.
Effect in obese humans
Obesity due to leptin or leptin receptor mutations in humans is rare (51)
. Nevertheless, a homozygous frameshift mutation in the gene for leptin resulting in generation of a truncated protein was found in two severely obese children (52)
. These children had undetectable serum leptin levels despite an elevated fat mass (52)
. A missense mutation in the leptin gene, which led to human obesity, was subsequently identified (53)
. A mutation of the leptin receptor that results in loss of the transmembrane and cytoplasmic domains was recently characterized (54)
. Individuals homozygous for the mutation develop obesity and hyperleptinemia (54)
.
Administration of leptin to leptin-deficient obese children induced many behavioral and metabolic responses, promoting a return toward steady-state conditions (55)
. For example, these children have normal fasting glucose levels but elevated fasting insulin levels, which can be corrected by leptin administration (55)
. The low prevalence of human mutations pertaining to leptin action should not undermine the fact that the existence of such mutations provides direct genetic evidence that leptin is an important regulator of energy balance in humans. Humans with only one functional leptin gene have markedly lower serum leptin concentrations than controls and an increased prevalence of obesity, possibly as a consequence of their hypoleptinemia (56)
. In a Pima Indian population prone to obesity, the subjects who gained weight during a 3 year follow-up period had relatively lower circulating leptin concentrations at baseline compared with subjects whose weight was stable (57)
. Thus, leptin therapy might be effective when targeted to ‘hypoleptinemic’ obesity. The prevalence of ‘low leptin secretors’, humans with low serum leptin concentrations relative to their adiposity, is estimated to be 
5–10% of obese subjects (28
, 58
, 59)
. The vast majority of obese humans, however, have high circulating leptin concentrations (28)
, indicating the possible existence of a leptin-resistant state. In a recent study (60)
, varying amounts of leptin (0.01, 0.03, 0.10, and 0.30 mg·kg-1·day-1) were administered to a group of obese humans. Subjects receiving the highest dose of leptin (0.30 mg·kg-1·day-1) presented a significant and progressive reduction of body weight (-7.1 kg) without any changes on glycemic control or insulin action during the 24 wk period of study (60)
. The overall effect of leptin was modest, however, as administration of placebo was associated with a weight loss of 1.3 kg. The average serum leptin concentration in this group reached values as high as 667 ng/mL, which was 
30- to 40-fold higher than the placebo and baseline values. Thus, to overcome a leptin-resistant state in humans, it is likely that very high blood levels of this hormone must be achieved. Part of the leptin resistance may be due to limited entry of leptin into the central nervous system, as leptin transport to brain appears to be a saturable carrier-mediated process (61)
. A leptin analog that enters central nervous system more readily might be a preferred preparation for clinical therapy.
Effect in lipoatrophic humans
Various classes of lipoatrophy have been described in humans (29
, 62)
, For example, humans with congenital generalized lipodystrophy (CGL) (63)
are born with extreme paucity of white fat. These subjects exhibit profound insulin resistance, hyperinsulinemia, hyperglycemia, enlarged fatty liver, varying degrees of triglyceridemia, and very low levels of serum leptin (29)
Analysis of lipoatrophic humans on treatment with recombinant leptin is currently ongoing. Preliminary results are interesting and suggest leptin therapy is effective in ameliorating the metabolic abnormalities of these patients. The recent advent of gene therapy, whereby leptin replacement can potentially be achieved through genetically engineered human keratinocyte grafts, promises a viable therapeutic approach for permanent treatment of metabolic abnormalities arising from leptin deficiency in lipoatrophic individuals (64)
.
Effect in lipoatrophic animal models
The recent development of transgenic mouse models of lipodystrophy (65
, 66)
has facilitated a greater understanding of the role of leptin in glucose homeostasis and the development of insulin resistance and diabetes. These models of lipodystrophy present marked insulin resistance (up to a 400-fold elevation in plasma insulin), hyperglycemia (>300 mg/dl), fatty liver, and hypertriglyceridemia (67
, 68)
. In concordance with humans with CGL, lipodystrophic mice have very low levels of serum leptin (67
, 68)
.
Lipoatrophic mice generated by transgenic overexpression of the nuclear form of sterol regulatory element binding protein 1c (nSREBP-1c), under the control of the adipocyte-specific aP2 enhancer/promoter, developed severe insulin resistance and diabetes (68)
. When these mice were treated with leptin by continuous infusion (5 µg/day), hyperinsulinemia and hyperglycemia are almost normalized after 12 days of leptin treatment (69)
. Hepatic TG concentration is completely normalized. There were no changes in plasma insulin and glucose concentrations after food restriction and subsequent weight loss in transgenic mice studied as controls, suggesting that the beneficial metabolic effects of leptin are not merely secondary to a leptin-induced reduction in food intake and body weight (69)
.
Fatless mice generated via adipose-specific expression of a dominant-negative protein (A-Zip/F), which prevents DNA binding of B-ZIP transcription factors of the C/EBP and Jun families, develop severe insulin resistance and diabetes (67
, 70)
. This phenotype can be corrected by fat transplantation; unlike aP2-nSREBP-1c mice, however, leptin administration is ineffective (71
, 72)
. Since fat transplantation is associated with increased plasma leptin levels, these observations suggest that another adipose-derived factor is responsible for improved metabolic control in these animals. A candidate for this factor is adiponectin, an adipocyte-derived hormone (73)
. Depletion of visible white adipose tissue was accomplished by treating PPAR
+/- mice with an inhibitor of PPAR/retinoid X receptor (74)
. A combination of physiological doses of adiponectin and leptin almost completely corrected insulin resistance in these animals, whereas either adiponectin or leptin alone were only partially effective (74)
.
A-Zip/F-1 mice have been bred with a strain of skinny mice having transgenic hepatic overexpression of leptin (75)
. The resultant mice have virtually no adipose tissue, yet plasma leptin levels are elevated. Defects associated with lipoatrophy, including insulin resistance, diabetes, and hepatic steatosis, are effectively ameliorated in these mice (75)
. In contrast to previous studies (72)
, administration of leptin to A-Zip/F-1 mice improved insulin sensitivity (75)
.
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DIRECT PERIPHERAL EFFECTS OF LEPTIN ON SKELETAL MUSCLE, ADIPOSE TISSUE AND LIVER |
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TOPABSTRACTINTRODUCTIONEFFECT OF LEPTIN AT...DIRECT PERIPHERAL EFFECTS OF...THE EFFECT OF LEPTIN...LEPTIN AND INSULIN SIGNALING...CONCLUSIONS AND PERSPECTIVESREFERENCES |
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, 77)
. The presence of leptin receptor isoforms in these tissues (78
79
80)
indicates there is potential for direct peripheral effects of leptin on these tissues. Thus, an understanding of these effects of leptin may help clarify the apparent paradoxical role of this hormone in whole body glucose homeostasis. As outlined below, many studies clearly suggest that under appropriate circumstances, leptin can exert direct effects on basal or insulin-stimulated glucose uptake and metabolism in peripheral tissues.
Skeletal muscle
In skeletal muscle, insulin-stimulated glucose uptake is mediated mainly by GLUT4 translocation from intracellular pools to the plasma membrane and PI3-kinase activation plays an important role in this process (81
, 82)
. In isolated mouse soleus and rat epitrochlearis muscles, leptin exposure (3–1000 ng/mL) for 2 h did not alter basal or insulin-stimulated glucose uptake (27)
. Similar results have been reported using rat epitrochlearis and soleus muscles exposed to leptin (0, 16, 160, and 1600 ng/mL) for 1 h (83)
and in human skeletal muscle cells treated with leptin (16000 ng/mL) for 18 and 24–48 h, respectively (84)
. However in vivo administration of leptin (4 mg·kg-1·day-1) by s.c. infusion for 7 days increased 2-deoxyglucose uptake in EDL and soleus muscles (34)
. Similarly, a 5 h i.v. infusion (1 mg/h) or ICV administration (5 ng/h) of leptin into wild-type mice increased glucose uptake (32)
. These in vivo observations correlate well with some in vitro studies showing leptin increases glucose uptake in isolated rodent skeletal muscle (85
86
87)
. The magnitude of the increased glucose uptake elicited by leptin is generally much lower than that achieved by insulin (85)
. Leptin has been shown to not alter basal yet reduce insulin-stimulated glucose uptake in L6 rat skeletal muscle cells, the latter being achieved without altering translocation of GLUT4 to the cell surface (21)
. In C2C12 myotubes, leptin does not alter insulin-stimulated glucose transport or glycogen synthesis, but directly mimicked 80–90% of the insulin effect on these variables (88)
. Differences in the experimental procedures (i.e., species, age, and strain of animals, sources of leptin, and time exposure to this hormone) adopted to study the effects of leptin on glucose metabolism in skeletal muscle could explain these contrary findings.
Glucose (85)
and fatty acid oxidation (89
, 90)
are regulated by leptin in muscle. Leptin opposes the lipogenic (89
, 90)
and glycogenic (78
, 90)
effects of insulin and increases substrate oxidation (85
, 89
, 90)
in isolated mouse soleus muscle. Leptin administration selectively activates 5'-AMP-activated protein kinase (AMPK) in skeletal muscle, leading to the inhibition of acetyl coenzyme A carboxylase and subsequent stimulation of fatty acid oxidation (91)
. Remarkably, the early activation of AMPK by leptin appears to be a direct effect of leptin on skeletal muscle whereas the later activation is dependent on the activation of hypothalamic/sympathetic nervous system axis by leptin (91)
. Thus, in animal models of chronic hyperleptinemia, a prolonged action of the hormone may lead to depletion of TG content of tissues and therefore cause an improvement of skeletal muscle and whole body insulin sensitivity. A recent clinical study emphasizes the importance of intramyocellular fat to insulin action (92)
. A group of morbidly obese patients underwent a biliopancreatic diversion, which leads to a profound lipid malabsorption. After 6 months follow-up, the patients had lost weight (33±10 kg) but their BMI was still in the obese range (39±8 kg/m2). Nevertheless, in parallel with a decrease in intramyocellular lipid content and circulating leptin concentrations, insulin resistance was completely reversed. Direct or indirect skeletal muscle AMPK activation by leptin may also be a mechanism whereby leptin enhances glucose uptake, but this remains to be determined. A number of studies have shown that AMPK activation leads to increased muscle glucose transport independent of insulin (reviewed in ref 93
).
Adipose tissue
Leptin decreases insulin sensitivity and reduces insulin-stimulated glucose uptake in rat adipocytes (19)
. However, several subsequent studies have suggested that leptin has no effect on basal or insulin-stimulated glucose transport or metabolism in adipocytes isolated from rat (27
, 84
, 94)
or ob/ob mouse (84)
. Further evidence to suggest that leptin can inhibit insulin action in fat cells includes the observation that leptin inhibits insulin-stimulated incorporation of glucose (95)
and acetate (96)
into total lipids. However, an additive effect on glucose oxidation was observed when fat cells were exposed to leptin and insulin (95)
. Chronic exposure to leptin has been hypothesized to promote glucose and fatty acid degradation, preventing accumulation of triglycerides and subsequent development of insulin resistance and lipotoxic diabetes (97)
. Leptin administration specifically reduces visceral adiposity and enhances insulin action both in regard to inhibition of hepatic glucose production and stimulation of peripheral glucose uptake (31)
.
Data from in vivo studies suggest that leptin exerts differential effects in white and brown adipose tissue. Administration of a single leptin injection to the ventromedial hypothalamus of rats increases glucose uptake in brown but not white adipose tissue (33)
. Similar results were observed on acute i.v. or ICV administration of leptin to mice (32)
. The ability of leptin to alter glucose uptake was suppressed after surgical sympathetic denervation of interscapular brown adipose tissue, suggesting this effect of leptin was centrally mediated via sympathetic nerves (33
, 98)
; s.c. administration of leptin suppressed 2-DG uptake 50% in white adipose tissue, an effect that correlated with a marked reduction in the amount of GLUT4 expression in this tissue (34)
.
Liver
Studies designed to examine the response of whole liver, liver cells, and liver cell lines to leptin yield confounding and paradoxical interpretations. Cohen et al. (18)
exposed human hepatocellular carcinoma HepG2 and rat hepatoma H4-II-E cell lines to very high leptin concentrations (960 ng/mL) and observed leptin attenuated several insulin-induced activities, including tyrosine phosphorylation of the insulin receptor substrate-1 (IRS-1), association of the adapter molecular growth factor receptor bound protein 2 with IRS-1, and down-regulation of gluconeogenesis (18)
(Table 2
). Attenuation of these insulin-induced intracellular signaling responses raises the possibility that leptin could increase hepatic glucose output, cause insulin resistance (18
, 99)
, and lead to hyperglycemia. However, other in vitro studies (100
101
102)
have not confirmed this hypothesis.
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In the presence of leptin, the release of glucose from several gluconeogenic precursors (glycerol, L-lactate, L-alanine, and L-glutamine) by isolated rat hepatocytes is significantly reduced ( 27%) (100)
. In perfused rat livers, glucagon- (100)
and epinephrine-stimulated (101)
glycogenolysis is reduced by 60% and 48% in response to leptin administration, respectively (Table 2)
. These latter effects seem to be mediated through a PI3-kinase-dependent activation of the cAMP-hydrolyzing phosphodiesterase 3B (PDE3B) and a subsequent reduction of cAMP levels caused by leptin (102)
.
In a more systemic approach using nondestructive [13C] NMR methodology to follow the kinetics of intermediary metabolism, Cohen et al. (103)
demonstrated that the rate of glycogen synthesis by ob/ob mice liver was threefold greater after chronic s.c. administration of leptin (0.5 mg/kg for 5 days). This was associated with significantly increased hepatic glycogen synthase activity. When leptin was administered directly in vitro to perfused liver of ob/ob mice, glycogen synthesis was 1.6-fold greater compared with untreated liver from ob/ob mice (103)
. A twofold increase in glycogen synthesis was noted in response to direct administration of leptin to perfused liver from lean mice (103)
. In another study, however, moderate hyperleptinemia induced by adenoviral leptin therapy failed to affect glycogen synthase, glycogen phosphorylase, and phosphodiesterase 3B activities, although liver glycogen levels were higher following administration of a glucose bolus in hyperleptinemic Wistar rats compared with controls (103)
. The authors concluded that moderate hyperleptinemia decreased liver glycogen degradation during the fed-to-fasted transition (103)
.
Short-term (6 h) i.v. administration of leptin in rats results in enhanced insulin-induced suppression of hepatic glucose production due to a marked suppression in hepatic glycogenolysis. The percentage contribution of gluconeogenesis to hepatic glucose production during physiological hyperinsulinemia increased markedly in parallel with an increase in hepatic PEPCK mRNA levels (24
, 104)
. These results were reproduced by ICV administration of leptin (24
, 104)
, suggesting that leptin induces a redistribution of intrahepatic glucose fluxes via its central receptors.
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THE EFFECT OF LEPTIN ON INSULIN SECRETION |
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TOPABSTRACTINTRODUCTIONEFFECT OF LEPTIN AT...DIRECT PERIPHERAL EFFECTS OF...THE EFFECT OF LEPTIN...LEPTIN AND INSULIN SIGNALING...CONCLUSIONS AND PERSPECTIVESREFERENCES |
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3
4
, 15
, 31
, 69
, 86)
. Of course, the reduction observed in plasma insulin levels could be secondary to an increase in insulin sensitivity and glucose disposal in peripheral tissues caused by leptin treatment. However, leptin directly inhibits insulin secretion from pancreatic ß cells (105)
. Nevertheless, the ability of leptin to regulate insulin secretion remains a contentious issue due to conflicting results in the literature (106
107
108)
.
Many in vitro studies performed with isolated mouse (106
, 109)
rat (110
, 111)
, and human (112)
pancreatic islets and insulin-secreting cell lines (106
, 109
, 113)
provide evidence of the existence of an ‘adipo-insular axis’, in which leptin represents a negative feedback signal from the adipose tissue to the endocrine pancreas (105
, 114)
. There is now compelling evidence that leptin inhibits the glucose stimulated insulin secretion (GSIS) in isolated pancreatic islets (106
, 109
110
111
112)
, insulin-secreting cell lines (106
, 109
, 113)
, isolated perfused rat pancreas (114
, 115)
, and at the whole body level in vivo (26)
(Table 3
). Leptin receptors are expressed in ß cells (116
, 117)
, and the mechanism whereby leptin exerts an inhibitory effect on GSIS involves activation of ATP-sensitive potassium (KATP) channels in pancreatic ß cells (109
, 111
, 113)
. Closure of KATP channels, which alters the membrane potential to cause Ca2+ influx and increases in cytoplasmic Ca2+ concentration (118
, 119)
, plays a key role in secretion of insulin granules. Activation of KATP channels by leptin results in a hyperpolarization of ß cells, which prevents the Ca2+ influx and thus inhibits insulin secretion. Besides the activation of KATP channels, evidence has been provided that leptin acutely reduces insulin secretion by suppressing proinsulin mRNA expression (112)
. Other possible mechanisms whereby leptin may regulate insulin secretion include stimulation of the sympathetic nervous system (115)
, inhibition of secretion stimulated by glucagon-like peptide I, or other agents that increase intracellular cAMP levels (114
, 120)
or phospholipase C activity (121)
, and reducing the activity of the Ca2+-dependent protein kinase C (PKC) isoform (110)
. These observations led to the proposition that the failure of leptin to inhibit insulin secretion from ß cells of ob/ob and db/db mice may partly explain the development of hyperinsulinemia, insulin resistance, and the progression to NIDDM (106)
. A failure of leptin to inhibit GSIS due to leptin resistance in ß cells of human obese subjects may result in chronic hyperinsulinemia and contribute to the pathogenesis of NIDDM (112)
.
|
Though most studies support the observation that leptin exerts an acute inhibitory effect on insulin secretion, some studies have reported that depending on factors such as leptin concentration, leptin exposure time, and glucose concentration, insulin secretion by ß cells is unaffected (49
, 122
, 123)
or may even be increased by leptin exposure (49
, 106
107
108
, 121)
(Table 3)
. Thus, the functional role played by leptin receptors in the endocrine pancreas is unresolved.
Leptin appears to play an important role in the maintenance of normal GSIS through the prevention TG accumulation in ß cells (97
, 124)
. Defective leptin receptors in ß cells of Zucker diabetic fatty (ZDF) rats is associated with excess accumulation of TG in these cells (97
, 124)
. The chronic overloading of islets with fat causes lipotoxicity, which may result in a >50% loss of ß cells late in the course of ZDF diabetes and reduced GSIS response (124)
. One potential mode of action may involve overabundance of long-chain fatty acids, which favors ceramide formation and stimulation of inducible NO synthase expression, which leads to lipoapoptosis in pancreatic ß cells (97
, 125)
. Overexpressing the wild-type full-length long form leptin receptor (obRb) in ZDF rat pancreatic islets effectively reduces TG content of ß cells and reverses the diabetogenic phenotype (126)
. TG content in ZDF islets overexpressing obRb is reduced 87% after chronic exposure to leptin (126)
, and this is associated with restoration of the GSIS response (127)
.
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LEPTIN AND INSULIN SIGNALING PATHWAYS: POTENTIAL FOR INTRACELLULAR CROSS-TALK |
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TOPABSTRACTINTRODUCTIONEFFECT OF LEPTIN AT...DIRECT PERIPHERAL EFFECTS OF...THE EFFECT OF LEPTIN...LEPTIN AND INSULIN SIGNALING...CONCLUSIONS AND PERSPECTIVESREFERENCES |
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, including regulation of glycogen synthase kinase (129)
, Akt (129)
, mTOR (130)
, PKC (130)
, and IRS proteins (129
, 131)
. Thus, there is clearly potential for ‘cross-talk’ between intracellular signaling in response to these hormones (Table 4
). The first demonstration of cross-talk between leptin and insulin signaling was the observation that leptin attenuated insulin-induced tyrosine phosphorylation of IRS-1 and association of the adapter molecular growth factor receptor-bound protein 2 with IRS-1 in the human hepatocellular carcinoma (HepG2) cells (18)
. In rat-1 fibroblasts and NIH3T3 cells, leptin impaired insulin-stimulated autophosphorylation of the insulin receptor and tyrosine phosphorylation of IRS-1 (132)
. Leptin inhibited insulin binding in isolated rat adipocytes (133)
. In a subsequent study, however, leptin did not inhibit insulin action in hepatoma cells (80)
. These studies highlight a potential mechanism whereby cross-talk between leptin and insulin signaling pathways could induce obesity-associated insulin resistance (18
, 99)
.
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PI3-kinase activation mediates many metabolic effects of insulin including stimulation of glucose transport, lipogenesis, glycogen synthesis, inhibition of gluconeogenesis by attenuation of PEPCK gene expression, promotion of protein synthesis, and protection against apoptosis (134
, 135)
. Many effects of leptin are mediated via PI 3-kinase, including regulation of glucose uptake (88
, 136)
, Na,K-pump (137)
, hormone-sensitive lipase (138)
, epithelial cell invasiveness (130)
, and KATP channels (139)
. Therefore, some degree of cross-talk may exist between leptin and insulin signaling at the level of PI3-kinase. In Fao cells, insulin-induced association of the regulatory p85 subunit of PI 3-kinase with IRS-1 was increased whereas p85 association with IRS-2 was significantly diminished after leptin preincubation (129)
. This indicates that leptin can differentially modify insulin signaling through these two substrates. These results suggest complex interactions between the leptin and insulin signaling pathways that can potentially lead to differential modification of the metabolic and mitotic effects of insulin exerted through IRS-1 and IRS-2 and the downstream kinase cascades activated by each (129)
.
Further evidence for possible effects of leptin on intracellular insulin signaling leading to altered glucose metabolism has been provided by studies with A-ZIP/F1 fatless mice. Basal and insulin-stimulated IRS-1-associated PI3-kinase activity was reduced 55% and 47%, respectively, in skeletal muscle of fatless mice compared with wild-type mice (70)
. In liver, a 47% reduction in insulin-stimulated, IRS-2-associated PI3-kinase activity was observed (70)
. However, when fatless mice were submitted to fat transplantation (900 mg of parametrial fat from wild-type littermates), a 2.5-fold increase in insulin-stimulated whole body glucose uptake was observed, and this correlated with normalized insulin activation of IRS-1-associated PI3-kinase activity in muscle and enhanced IRS-2-associated PI3-kinase activity in liver.
SOCS proteins are induced by several cytokines and are involved in negative feedback loops by inhibiting cytokine mediated Jak-Stat activation. Leptin induces the expression of SOCS-3, which then inhibits proximal leptin signaling (140)
. Insulin induces SOCS-3 expression in 3T3-L1 adipocytes. Once expressed, SOCS-3 inhibits the insulin-induced activation of Stat5B by binding competition between Stat5B and SOCS-3 to the phosphorylated Tyr960 of the insulin receptor (141)
. In COS-7 cells, SOCS-3 decreases insulin-induced IRS-1 tyrosine phosphorylation and association with p85, a regulatory subunit of phosphatidylinositol-3 kinase (142)
. Thus, increased SOCS-3 expression due to high circulating leptin and insulin concentrations, characteristics of an insulin-resistant state, could be envisioned to lead to impaired proximal leptin and insulin signaling and therefore contribute to leptin and insulin resistance, respectively.
Association of intracellular signaling cross-talk with quantitative and qualitative metabolic effects of insulin on glucose metabolism has been difficult to assess since functional measurements were not performed in many of the above-mentioned studies. However, the effect of leptin on insulin signaling and glucose uptake has recently been examined in cultured rat skeletal muscle cells (21)
. Preincubation of cells with leptin for 30 min reduced insulin-stimulated glucose uptake (21)
. Translocation of GLUT4 to the cell surface and signals leading to this event (insulin receptor ß subunit, IRS-1, IRS-2, and Akt phosphorylation, and PI 3-kinase activity) were unaffected by leptin pretreatment. Instead, the ability of leptin to reduce insulin-stimulated glucose uptake was suggested to be due to inhibition of insulin-stimulated p38 MAP kinase activity and GLUT4 activity (21)
.
Most studies described so far focus on the possible interference of leptin with the intracellular signaling cascade of insulin and with the subsequent glucose uptake response and genesis of insulin resistance. Rarely has the effect of hyperinsulinemia on the intracellular signaling cascade of leptin and its contribution to the generation of ‘leptin resistance’ been studied. Chronic hyperinsulinemia, as frequently observed in obese subjects, could possibly exert a negative effect on the leptin signaling chain and lead to ‘leptin resistance.’ To address this question, Kellerer et al. (143)
have assessed effects of supraphysiological concentrations of insulin on the leptin-induced insulin secretion response of RINr1046–38 cell lines and the leptin signaling pathway of rat-1 and HEK293 cells. A 4 h preincubation of RINr1046–38 cells with 1 nmol/l of insulin completely canceled the leptin-induced insulin secretion response of these cells, supporting the negative cross-talk hypothesis between these two hormones. Leptin-stimulated JAK-2 autophosphorylation in HEK293 cells was inhibited after preincubation in the presence of high insulin levels. This inhibitory effect of insulin on JAK-2 phosphorylation was suggested to occur through activation of SHP-1-dependent pathways, causing dephosphorylation of JAK-2 and reduction of the intracellular leptin signaling (143)
. These results suggest that hyperinsulinemia may contribute to the pathogenesis of leptin resistance.
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CONCLUSIONS AND PERSPECTIVES |
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TOPABSTRACTINTRODUCTIONEFFECT OF LEPTIN AT...DIRECT PERIPHERAL EFFECTS OF...THE EFFECT OF LEPTIN...LEPTIN AND INSULIN SIGNALING...CONCLUSIONS AND PERSPECTIVESREFERENCES |
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). Selective leptin resistance may occur in obesity, such that centrally mediated effects of leptin (e.g., food intake, energy expenditure, and autonomic nerve control) are blunted and direct peripheral effects of leptin (e.g., on muscle, fat, and liver) become more prominent in the presence of high circulating levels of the hormone. This would support the bulk of in vitro observations that provide evidence to suggest leptin plays an inhibitory role on glucose metabolism, whereas in vivo leptin tends to play an insulin-sensitizing role due to central mechanisms. Resolving the precise role of leptin in the pathophysiology of insulin resistance and diabetes will be complex, but future studies are likely to prove fascinating.
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ACKNOWLEDGMENTS |
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REFERENCES |
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TOPABSTRACTINTRODUCTIONEFFECT OF LEPTIN AT...DIRECT PERIPHERAL EFFECTS OF...THE EFFECT OF LEPTIN...LEPTIN AND INSULIN SIGNALING...CONCLUSIONS AND PERSPECTIVESREFERENCES |
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