Human Leptin: An Adipocyte Hormone with Weight-Regulatory and Endocrine Functions

Inhaltsübersicht

 

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ABSTRACT

Leptin is synthesized and secreted primarily by adipocytes, and is present in serum in direct proportion to the amount of adipose tissue. The primary role of leptin is to provide to the central nervous system a signal of energy intake and energy stores in the body so that the hypothalamus can efficiently maintain a stable body weight. The receptor for leptin in the hypothalamus signals by activation of an associated janus kinase which phosphorylates signal transducer and activator of transcription (STAT) proteins that regulate neuronal gene expression. Genetic mutations in leptin and its receptor can result in obesity in both rodents and humans, supporting a central role for leptin in the regulation of body weight. Leptin has also been implicated in a variety of physiological processes other than body weight homeostasis. Many of these functions are mediated through the central nervous system; however, the presence of leptin receptors in tissues throughout the body suggests that leptin can also have direct effects on cells and tissues. Serum leptin levels have been associated with cardiovascular risk factors after correction for adiposity. Leptin can promote platelet aggregation, which requires expression of functional leptin receptors on the platelet. Leptin-induced increases in sympathetic nerve activity have been suggested to contribute to hypertension, and leptin has been observed to increase oxidative stress in cultured endothelial cells. Many of these pathophysiologic effects of leptin on the vasculature are most likely of importance when leptin levels are elevated in obese subjects due to resistance to the weight-reducing effects of the hormone. An improved understanding of the effects of leptin on the vasculature will provide valuable insight into the relationship between obesity and cardiovascular disease.

 

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KEYWORDS

Obesity - hyperleptinemia - hypertension - angiogenesis - thrombosis - oxidative stress

As discussed in detail in the preceding chapter, obesity is a major risk factor for cardiovascular disease.[1] [2] [3] The importance of this association is underscored by the fact that the prevalence of overweight and obesity continue to increase in both adults and children, and therefore an epidemic of cardiovascular disease is also underway. Adipose tissue is now recognized as a major endocrine organ synthesizing and secreting many biologically active molecules such as leptin, adiponectin, tumor necrosis factor α (TNF-α), plasminogen activator inhibitor 1 (PAI-1), and interleukin 6 (IL-6),[4] which can have both physiological and pathophysiological effects on the cardiovascular system. The primary role of leptin is to provide a signal to the central nervous system of energy intake and energy stores in the body so that the hypothalamus can efficiently maintain a stable body weight. However, it is now recognized that leptin also participates in several other physiological processes, both through effects mediated by the central nervous system and by direct actions on nonneural tissues. This chapter summarizes the role of leptin in regulation of body weight homeostasis. Effects of leptin on various aspects of cardiovascular function will also be reviewed.

 

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LEPTIN AND THE LEPTIN RECEPTOR

The gene for leptin in both humans (LEP) and rodents (Lep) encodes a 167-amino acid protein with an amino-terminal secretory signal sequence of 21 amino acids.[5] The signal sequence is cleaved during protein processing, and leptin circulates in the blood as a 16-kDa protein.[6] Leptin is not stored within the adipocyte but is constitutively secreted. Therefore, leptin synthesis and release from adipocytes is primarily regulated by transcriptional mechanisms, and most studies in vivo and in vitro find that changes in leptin secretion result from concomitant changes in Lep gene expression.[7]

The leptin receptor is a member of the class I cytokine receptor family.[8] These cytokine receptors do not possess endogenous kinase activity within the intracellular domain but, instead, associate with a janus kinase (JAK). Binding of leptin to its receptor activates JAK, which phosphorylates tyrosines within the leptin receptor itself. JAK also phosphorylates signal transducer and activator of transcription (STAT) proteins associated with the leptin receptor. The STAT proteins then dimerize and translocate to the nucleus to initiate gene transcription. STAT-3 is the major STAT protein activated by the hypothalamic leptin receptor in mice.[9] Leptin binding to its receptor in the hypothalamus has also been demonstrated to result in an increase in phosphatidylinositol 3-kinase[10] [11] and phosphodiesterase 3B,[11] with one study suggesting that activation of PDE3 is a prerequisite for JAK-STAT signaling to take place.[11]

In addition to the hypothalamic leptin receptor (Ob-Rb, or long receptor isoform) described above, five other leptin receptor isoforms have been identified (Ob-Ra, Ob-Rc, Ob-Rd, Ob-Re, Ob-Rf), all of which are encoded by alternative splicing of the same gene.[12] [13] The extracellular domain of each of these receptors is identical to Ob-Rb; however, the intracellular domains terminate at different lengths. Because of the truncated intracellular domain, these short leptin receptors lack the Box 2 motif at which STAT proteins bind, and these leptin receptors do not activate STAT signaling. The short receptor isoform Ob-Ra, present in most cells and tissues examined, activates JAK2 and MAPK in transient transfection models, but the physiologic significance of this observation is not yet known.[14] Ob-Ra is highly expressed in the choroid plexus, where it functions to transport leptin across the blood/cerebrospinal fluid barrier.[15] [16] [17]

The Ob-Re receptor isoform lacks both the intracellular and transmembrane domain and circulates in the blood as a leptin binding protein.[18] [19] This leptin binding protein functions as other binding proteins to prolong the half-life of the hormone.[20]

 

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Genetic Mutations in Leptin and the Leptin Receptor in Rodents Result in Obesity

Two separate mutations in the Lep gene that block the synthesis of leptin have been identified in ob/ob mice.[5] In C57BL/6J ob/ob mice, a T to C substitution in codon 105 changes an arginine to a premature stop. In ob^2j/ob^2j mice, the insertion of a transposon in the first intron of the Lep gene completely disrupts mRNA synthesis.[21] Both strains of mice lack circulating leptin. Ob/ob mice are hyperphagic, cold intolerant, and morbidly obese.

A single point mutation in the hypothalamic leptin receptor results in morbid obesity in C57BL/KsJ db/db mice.[12] [22] As discussed above, differential splicing of the leptin receptor message yields long and short forms of the leptin receptor. In db/db mice, a G-to-T substitution generates a new splice donor within an exon of the short receptor, resulting in alternative splicing of the receptor coding region and the addition of a premature termination signal in the long form of the receptor. This defect in the message for the leptin receptor results in synthesis of a truncated long receptor that is unable to activate STAT proteins.[23] Two other mutations have been identified in db^Pas/db^Pas and db^3J/db^3J mice that result in receptors lacking transmembrane and cytoplasmic domains.[24]

In the Zucker fatty (fa/fa) rat, an A-to-C substitution at nucleotide 880 in the leptin receptor changes glutamine 269 to a proline.[25] [26] This mutation reduces the amount of leptin receptor on the cell surface and the capacity of the receptor to signal.[26] [27] In obese Koletsky rats, no leptin receptor mRNA is detectable in the brain because of a point mutation (T2349A) in codon 763, which creates a premature stop codon just before the transmembrane domain.[28] [29] The lack of functional leptin receptors results in obesity in both Zucker and Koletsky rats.

 

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Exogenous Leptin Stimulates Weight Loss in Rodents

Shortly following the discovery of the Lep gene, the effect of leptin to promote weight loss was demonstrated.[30] Daily intraperitoneal injection of leptin in C57BL/6J ob/ob mice resulted in a dose- and time-dependent decrease in body weight. Leptin also reduced body weight in C57BL/6J heterozygotes (+/?) and wild-type mice, although at much higher doses. Leptin administration had no effect in C57BL/6J db/db mice at any concentration tested. Leptin-induced weight loss in ob/ob mice resulted from an increase in oxygen consumption, body temperature, and locomotor activity, as well as a reduction in food intake. In lean mice, leptin had no effect on body temperature or locomoter activity but did reduce food intake. Leptin treatment also lowered insulin and glucose in ob/ob mice-a finding discussed in greater detail later. Early experiments also demonstrated that the hypothalamus was the major site through which leptin acted to regulate body weight, as administration of leptin directly into the lateral or third ventricle was sufficient to inhibit food intake in both obese and lean mice.

The leptin receptor is detectable in several areas of the CNS but is highly expressed in the arcuate, paraventricular, ventromedial, and dorsomedial nuclei of the hypothalamus.[31] Leptin accesses the arcuate nucleus directly from the blood within the median eminence, which lacks a blood-brain barrier. Leptin binding to its receptor in the arcuate nucleus reduces the expression of neuropeptide Y (NPY) and agouti-related peptide (AgRP) neurotransmitters, which stimulate food intake. Leptin binding in the arcuate also increases the expression of neurotransmitters that inhibit food intake, α melanocyte stimulating hormone (α-MSH), and cocaine- and amphetamine-regulated transcript (CART), in a second set of neurons. Leptin-responsive neurons in the arcuate communicate with other areas of the brain and also mediate the effects of leptin on the sympathetic nervous system and hypothalamic pituitary axes.

 

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LEPTIN IN HUMANS

 

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Regulation of Serum Leptin Levels

The primary determinant of serum leptin under conditions of consistent food intake is the amount of body fat (reviewed in detail in ref. 30). Leptin is highly correlated with fat mass in adults, children, and newborns. The elevation in serum leptin in obesity results from both increased fat mass and increased leptin release from larger adipocytes in obese subjects. LEP gene expression is greater in larger adipocytes than smaller adipocytes isolated from the same piece of adipose tissue, and leptin secretion is strongly correlated with fat cell volume.

Serum leptin is significantly greater in women than in men with equivalent body fat mass.[32] One explanation for this finding is that women have a significantly greater subcutaneous adipose tissue mass relative to omental adipose mass than men.[33] In studies of adipose tissue obtained from females, LEP gene expression/leptin production is greater in subcutaneous than omental adipocytes from the same individual.[34] [35] [36] In morbidly obese subjects, the subcutaneous adipocytes of females are significantly larger than omental adipocytes in the same subject.[37] [38] Cell size therefore explains in part the greater leptin production in subcutaneous versus omental adipose tissue and the gender effect on serum leptin.

Reproductive hormones also influence leptin production. Testosterone therapy reduces serum leptin in hypogonadal men, and leptin levels decrease as serum testosterone increases during pubertal development in boys.[39] [40] [41] Estrogen, in combination with antiandrogens, increases leptin in male-to-female transsexuals, and testosterone decreases leptin in female-to-male transsexuals, independent of changes in adipose tissue mass.[42] In vitro, estradiol stimulates-and dihydrotestosterone inhibits-leptin production in human omental adipose tissue pieces cultured for 48 h.[43] [44] Although these in vitro experiments indicate that the reproductive hormones exert direct effects on leptin synthesis, the mechanism is not yet elucidated.

Changes in the amount of adipose tissue alter leptin mRNA levels in the adipocyte and the circulating concentration of the hormone. A decrease in adipose tissue with weight loss results in a decrease in leptin. An increase in the adipose tissue with weight gain significantly increases circulating leptin.[45] The mechanism for changes in leptin with weight change involve changes in adipose tissue mass, adipocyte size, and effects of other hormones and cytokines on leptin synthesis in the adipocyte.

Caloric intake regulates serum leptin independent of changes in adipose tissue mass. With regular daily food intake (three meals per day in humans) leptin levels are fairly constant, exhibiting a maximal daily variation of about 30%.[46] However, with short-term fasting (24 h), serum leptin falls and will increase within 4-5 h of refeeding. Maintenance of euglycemia prevents the fasting-induced drop in leptin, implicating insulin or glucose as the nutritional signal that is recognized by the adipocyte for leptin synthesis.[47] [48] In a prolonged study of energy restriction (moderate and severe), changes in serum leptin were best correlated with changes in glycemia.[49]

Leptin exhibits a diurnal profile that is entrained to food intake. The peak in serum leptin occurs at about 0200 h, in both lean and obese subjects under normal living conditions. Day/night reversal shifts the peak in serum leptin by 12 h. A meal shift of 6.5 h without changing light or sleep cycles shifts the leptin peak 5-7 h, indicating that the nocturnal rise in leptin may represent a delayed postprandial response induced by after-meal excusions in glucose and insulin.[50]

The macronutrient content of the diet can also influence serum leptin. Consumption of high-fat/low-carbohydrate meals (60%/20%) over the course of 1 day reduces leptin levels.[51] High-fat/low-carbohydrate meals induce smaller insulin and glucose excursions than meals of standard fat/carbohydrate content, again implicating insulin and glucose in the nutritional regulation of leptin production. Dietary fructose, which does not stimulate insulin secretion, also results in lower leptin levels when consumed as 30% of the total carbohydrate in the diet.[52]

Direct evidence for glucose and insulin regulation of leptin synthesis in humans has been obtained with the euglycemic-hyperinsulinemic clamp. Serum leptin is elevated by prolonged (9 h) euglycemic-hyperinsulinemic clamps at physiologic insulin,[53] or within 4-8 h with supraphysiologic insulin concentrations.[54] In cultured rat adipocytes, leptin release is highly dependent on the extent of glucose metabolism.[55]

Hexosamine biosynthesis is one link between glucose metabolism and leptin production.[56] In rodents, activation of hexosamine biosynthesis by infusion of glucosamine, uridine, or free fatty acids increased serum leptin. In transgenic mice overexpressing the rate-limiting enzyme in hexosamine biosynthesis, glutamine:fructose-6-phosphate amidotransferase (GFAT), serum leptin, and adipose tissue Lep gene expression are significantly increased.[57] UDP-GlcNAc in the subcutaneous adipose tissue of obese humans is increased 3.2-fold compared with lean subjects, and a significant positive relationship between adipose tissue UDP-GlcNAc and body mass index is present.[58] In cultured subcutaneous adipocytes, an increase in hexosamine biosynthesis increased leptin release, and inhibition of GFAT activity reduced glucose-stimulated leptin release. These observations indicate that hexosamine biosynthesis links glucose metabolism to leptin production. However, these findings do not rule out the possibility that other pathways for glucose metabolism may also regulate leptin release.

The sympathetic nervous system regulates adipose tissue metabolism through direct innervation of the tissue or by the release of catecholamines from the adrenal glanda. To mimic activation of the sympathetic nervous system, several groups have infused isoproterenol and observed a significant reduction in serum leptin.[59] [60] [61] These observations are in agreement with in vitro data indicating that catecholamines inhibit leptin production,[62] [63] [64] although the mechanism through which this occurs has not been elucidated.

 

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Leptin Resistance

Serum leptin levels are elevated in obese subjects. This observation has led to the hypothesis that obese individuals are resistant to the weight-reducing actions of leptin.[45] Leptin resistance is dependent on the premise, defined by the lipostasis theory, that the major function of leptin is to oppose body weight gain. However, from an evolutionary perspective, it is difficult to conceive of a mechanism that would limit food intake in times of excess. Flier and colleagues have hypothesized that the major function of leptin is not to signal the excess storage of energy in times of food abundance but, rather, to signal the reduction in energy intake associated with food deprivation.[65] The reduction in leptin with fasting is associated with metabolic, hormonal, and behavioral changes designed to conserve energy and increase energy intake. Administration of leptin to prevent the fasting-induced fall in endogenous hormone levels prevents adaptations to food restriction, thus implicating leptin as the signal of food deprivation.[66] [67] The concept of leptin resistance is compatible with the role of leptin as a signal of energy deprivation. It may be that the central nervous system in obese individuals does not properly receive or process the leptin signal, despite the elevated serum leptin levels, and that this results in metabolic adaptations to increase energy intake.

Two molecular possibilities have been put forth to explain leptin resistance. High-fat diets have been shown to decrease the effectiveness of peripherally injected leptin to induce weight loss in rodents, and the defect appears to involve access of leptin to the brain.[68] [69] The implication of these experiments is that diet-induced defective leptin transport into the brain contributes to the development of obesity. Suppressors of cytokine signaling (SOCS) are a group of early genes activated by the JAK/STAT signal transduction pathway that act in a negative feedback loop to limit cytokine signaling. SOCS-3 is a potent inhibitor of leptin receptor-initiated JAK/STAT signaling in cultured cell lines, and leptin induces SOCS-3 mRNA in the hypothalamus.[70] Interestingly, SOCS-3 mRNA is increased in leptin-responsive hypothalamic neurons in Agouti mice. Agouti mice are resistant to central leptin administration, indicating that the increased SOCS-3 expression is the cause of leptin resistance in these animals.[70] Further work will be needed to understand the importance of this observation and its relevance to obesity in humans.

 

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Human Leptin and Leptin Receptor Mutations

Mutations in the LEP gene have been found in several families. The first two cases were identified in an 8-year-old Pakistani girl, weighing 86 kg, and her 2-year-old male cousin, weighing 29 kg.[71] In these subjects, a guanine nucleotide in codon 133 is deleted, resulting in a frameshift and the synthesis of a truncated protein. The incomplete leptin molecule is degraded and not released into the circulation.[72] The identical point mutation has also been found in three more Pakistani children from two other unrelated families.[73] The lack of leptin in these children results in extreme hyperphagia and early-onset morbid obesity; however, leptin therapy has been very successful in these patients. A different LEP gene mutation was identified in three adults of a Turkish family.[74] In these three subjects, a C-to-T substitution in the first base of codon 105 changes arginine to tryptophan, which appears to impair leptin processing through the secretory pathway. Serum leptin was very low but detectable in all three subjects homozygous for this mutation. The lack of leptin in these subjects results in hyperphagia, morbid obesity, and hypogonadism. One subject also exhibited low sympathetic tone.

As with mutations in the LEP gene, mutations in the leptin receptor in humans are rare. A point mutation resulting in a truncated leptin receptor lacking the transmembrane and intracellular domains has been identified in three sisters of a Kabilian family.[75] The mutant extracellular domain circulates in the blood at high concentrations and acts as a leptin binding protein, greatly elevating serum leptin concentrations but also preventing leptin action.[76] As observed with leptin gene mutations, this leptin receptor mutation results in early-onset morbid obesity, hyperphagia, and hypothalamic hypogonadism.

 

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Leptin Therapy in Humans

Exogenous leptin administration as therapy for obesity has been ongoing in the first two children identified with a leptin gene defect[77] and has been initiated in the other three children with the same leptin defect, but from a separate family.[73] The major effect of leptin was to reduce appetite. Other beneficial effects included reductions in fat mass, hyperinsulinemia, hyperlipidemia, and an increase in immune cell number. Leptin therapy also facilitated appropriately timed pubertal development in the one child of appropriate age but did not cause early onset of puberty in the younger children.[77]

Leptin therapy for weight loss has also been tested in subjects without leptin gene mutations. As discussed above, obese subjects have been suggested to be leptin resistant. One might thus predict that this apparent “resistance” to the weight-reducing effects of endogenously produced leptin might mean that exogenous leptin administration would be ineffective in decreasing body weight. However, it has been demonstrated in a randomized, double-blind, placebo-controlled, escalating-dose trial in adult subjects that exogenously administered recombinant human leptin can induce modest weight loss.[78] The weight loss in this study was highly variable among the different participants, indicating that leptin therapy may be better suited to a specific phenotype of obesity that needs to more fully defined.

 

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METABOLIC EFFECTS OF LEPTIN OTHER THAN SATIETY CONTROL

Leptin has been implicated as a regulatory signal in a variety of physiological processes in addition to body weight homeostasis.[30] Many of these functions of leptin are mediated through the central nervous system; however, the presence of leptin receptors on numerous nonneural cells indicated that leptin can have direct effects on cells and tissues.

Leptin improves insulin sensitivity directly and independent of its effects on food intake and body weight. In rodents, insulin and glucose are reduced with leptin treatment before significant reductions in body fat content occur.[79] With long-term leptin treatment, insulin and glucose are reduced to a greater extent than in pair-fed controls.[79] [80] In acute infusion studies, supraphysiologic leptin increased whole-body glucose uptake 30% during the last 135 min of a 180-min hyperinsulinemic clamp in normal weight rats.[81] In mice, a 5-h intracerebroventricular administration of leptin (5 ng/h) enhanced whole-body glucose uptake, indicating that leptin influences insulin sensitivity through central mechanisms.[82] Leptin treatment ameliorates insulin resistance and diabetes in transgenic models of lipodystrophy through mechanisms not related to food intake.[83] [84]

Leptin may influence insulin action directly on target tissues. Leptin increases basal glucose uptake in C₂C₁₂ myotubes.[85] Leptin has also been shown to rapidly activate STAT3 and MAPK signaling in insulin target tissues.[86] Future work will be necessary to determine the interaction between the insulin and leptin signaling pathways in insulin target tissues.

Leptin stimulates lipolysis in white adipose tissue both in vivo and vitro.[87] This effect of leptin results from both centrally mediated activation of the sympathetic nervous system as well as a direct effect of leptin on adipocytes. Lipolysis induced by hyperleptinemia in rats in vivo does not result in the release of free fatty acids into the circulation, and evidence indicates that leptin stimulates the oxidation of fatty acids within adipocytes.[88]

Observations from many different studies suggest that leptin has many functions related to reproduction.[89] Leptin is a coordinating signal to the central nervous system that energy stores are sufficient to support the higher energy needs associated with reproduction. Leptin is also involved in fetal growth and development, ovarian steroidogenesis, and placental function.

Leptin is also involved in hematopoiesis and immune function.[30] [90] Leptin receptors are present on blast cells, promyelocytes, promonocytes, macrophages, and other bone marrow cells. Leptin stimulates proliferation of hematopoietic cell lines transfected to express leptin receptor. Leptin also stimulates proliferation of primitive hematopoietic progenitors from murine bone marrow and induces granulocyte-macrophage colony formation in vitro. Leptin prevents the starvation-induced reduction in immune function in mice and stimulates the proliferation of naive and memory T cells. Leptin also increases CD4+ T cell number and proliferation in humans with leptin gene defects.[73]

 

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LEPTIN AND THE VASCULATURE

An association between serum leptin and various cardiovascular risk factors has been observed in both longitudinal and cross-sectional studies in which corrections have been made for differences in body adiposity.[91] Elevated serum leptin is associated with increased risk of stroke, chronic heart failure, coronary heart disease, acute myocardial infarction, and left cardiac hypertrophy. The mechanisms through which leptin contributes to cardiovascular complications are not well understood, but many of these effects of leptin are based on the presumption of a “selective leptin resistance.” As discussed above, obese subjects have been suggested to be leptin resistant with respect to body weight regulation, as serum leptin is elevated, but food intake is not reduced. Resistance to the appetite-suppressing actions of leptin action is likely localized to the central nervous system. As many of the cardiovascular effects of leptin are postulated to occur through a direct effect of the hormone on tissues outside the CNS, it is possible that peripheral effects of the hormone remain intact in obese individuals. It has also been suggested that central leptin resistance may be selective and that some centrally mediated effects of the hormone, such as sympathetic responses, remain intact.[92]

 

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Prothrombotic Effects of Leptin

The long form of the leptin receptor is present on many hematopoietic cell lines including platelets.[93] In vitro exposure to high concentrations of leptin enhances ADP-induced aggregation of platelet-enriched human plasma. A leptin-mediated enhancement of ADP-induced platelet aggregation has also been observed in mouse plasma. In contrast, leptin has no effect on aggregation of platelets from db/db mice, supporting the hypothesis that leptin effects on platelet aggregation require the functional long form of the leptin receptor.[94] In ob/ob mice, which completely lack leptin, there is also an attenuated thrombotic response to vascular injury,[94] thus indicating that leptin may contribute to the increased risk of thrombosis in obese subjects. One study in humans found that leptin levels were associated with low tPA activity and high PAI-1 levels after adjustment for age, body mass index, and insulin levels.[95]

 

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Leptin and Hypertension

Leptin activates brown adipose tissue to induce weight loss via the sympathetic nervous system.[96] Leptin also increases sympathetic outflow in renal, lumbar, hind-limb, and adrenal gland sympathetic nerves.[97] [98] Intracerebroventricular and chronic intravenous leptin administration has been observed to increase mean arterial blood pressure and heart rate in some but not all studies in rodents.[91] Interestingly, leptin also stimulates nitric oxide release from endothelial cells,[99] a direct effect mediated through activation of Akt.[100] This leptin-induced increase in endothelial nitric oxide has been hypothesized to offset a sympathetically mediated increase in blood pressure in response to the hormone. Indeed, in the presence of the nitric oxide synthase inhibitor L-NAME, intravenous leptin increases blood pressure in rats.[101] As leptin has both pressor and depressor effects, these observations have been interpreted as suggesting that if the vasculature becomes resistant to the depressor actions of leptin, the pressor effects could take precedence, thus permitting the elevation in an obesity-associated increase in leptin to contribute to hypertension.[101] In contrast, several groups find no substantial vasodilator effects of leptin in vivo at concentrations sufficient to increase sympathetic outflow.[102] [103] In humans, several cross-sectional studies and one longitudinal study found significant positive correlations between mean blood pressure and serum leptin in normotensive and hypertensive subjects.[91]

In apparent contrast to the finding that leptin stimulates nitric oxide release from endothelial cells, one study has shown that leptin increases the synthesis and release of the vasoconstrictor endothelin 1 from human umbilical vein endothelial cells.[104] The authors suggest that leptin may have a role in the elevation in endothelin 1, which has been implicated in hypertension in obese subjects. Future studies will be needed to determine the hierarchy in leptin-induced nitric oxide and endothelin 1 release.

Finally, in one study of adolescents, increased leptin levels were significantly associated with a decrease in arterial distensibility measured by ultrasound.[105] This association between leptin and arterial distensibility was independent of fat mass, blood pressure, C-reactive protein, fasting insulin, and low-density lipoprotein cholesterol.

 

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Leptin Stimulates Angiogenesis

Leptin promotes the directional migration of human umbilical vein endothelial cells in vitro and a corneal response in vivo that was equivalent to that induced by vascular endothelial growth factor. The angiogenic effects of leptin are mediated by the long leptin receptor isoform, as determined by activation of STAT 3. The in vivo corneal response did not occur in fa/fa rats with defective leptin receptor, further demonstrating the specificity of the leptin effect.[106] The angiogenic effect of leptin was confirmed and extended to demonstrate that leptin could prevent apoptosis of umbilical vein endothelial cells and human adult vein endothelial cells.[107] Most recently, Schafer et al[108] have shown that leptin modulates neointima formation and lesion growth after arterial injury in mice.

 

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Leptin and Oxidative Stress in Endothelial Cells

Reactive oxygen species (ROS) play a central role in the development of atherosclerotic lesions.[109] Leptin increased accumulation of ROS in human umbilical vein endothelial cells and bovine aortic endothelial cells in a time- and dose-dependent manner.[110] [111] Leptin treatment also resulted in enhanced expression of monocyte chemoattractant protein 1, a chemotactic cytokine that elicits the direct migration of monocytes to inflammatory cites. The leptin-induced generation of ROS in endothelial cells results from increased mitochondrial fatty acid oxidation.[111]

 

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CONCLUSIONS

The discovery of leptin in 1994 provided extensive insight into the regulation of body weight homeostasis. However the existence of central leptin resistance has dampened initial enthusiasm that leptin would be a simple cure for obesity and the related complications of diabetes and cardiovascular disease. Further, it is now recognized that leptin can have effects on tissues and physiological processes not involved in body weight homeostasis, and that some of these effects are detrimental to health. Many of the pathophysiologic effects of leptin, such as those on the vasculature, are most likely of importance when leptin levels are elevated in obese subjects because of resistance to the weight-reducing effects of the hormone. As the obesity epidemic has resulted in an increased prevalence of diabetes and cardiovascular disease, a better understanding of the regulatory effects of leptin on both the central nervous system, and directly on peripheral tissues, will provide insight into the pathophysiology of obesity, diabetes, and cardiovascular disease.

 

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ACKNOWLEDGMENTS

Work of the author mentioned in this review has been supported by grants from the National Institutes of Health (R29 DK51140), the American Diabetes Association, and the Showalter Trust.

 

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