Leptin as an immunomodulator

Leptin is an adipocyte-derived hormone/cytokine that links nutritional status with neuroendocrine and immune functions. In humans, leptin influences energy homeostasis and regulates neuroendocrine function primarily in states of energy deficiency. Initially described as an antiobesity hormone, leptin has subsequently been shown also to influence basal metabolism, hematopoiesis, thermogenesis, reproduction, and angiogenesis. As a cytokine, leptin can affect thymic homeostasis and the secretion of acute-phase reactants such as interleukin-1 (IL-1) and tumor-necrosis factor-alpha (TNF-α). Leptin links nutritional status and proinflammatory T helper 1 (Th1) immune responses and the decrease in leptin plasma concentration during food deprivation leads to impaired immune function. Similar to other pro-inflammatory cytokines, leptin promotes Th1-cell differentiation and can modulate the onset and progression of autoimmune responses in several animal models of disease. Here, we review the advances and controversy for a role of leptin in the pathophysiology of immune responses and discuss novel possible therapeutic implications for leptin modulators.     

Enhanced leptin sensitivity and improved glucose homeostasis in mice lacking suppressor of cytokine signaling-3 in POMC-expressing cells

Suppressor of cytokine signaling-3 (Socs-3) negatively regulates the action of various cytokines, as well as the metabolic hormones leptin and insulin. Mice with haploinsufficiency of Socs-3, or those with neuronal deletion of Socs-3, are lean and more leptin and insulin sensitive. To examine the role of Socs-3 within specific neurons critical to energy balance, we created mice with selective deletion of Socs-3 within pro-opiomelanocortin (POMC)-expressing cells. These mice had enhanced leptin sensitivity, measured by weight loss and food intake after leptin infusion. On chow diet, glucose homeostasis was improved despite normal weight gain. On a high-fat diet, the rate of weight gain was reduced, due to increased energy expenditure rather than decreased food intake; glucose homeostasis and insulin sensitivity were substantially improved. These studies demonstrate that Socs-3 within POMC neurons regulates leptin sensitivity and glucose homeostasis, and plays a key role in linking high-fat diet to disordered metabolism.     

Leptin: linking adipocyte metabolism with cardiovascular and autoimmune diseases

Leptin was originally discovered as an adipocyte-derived hormone involved in the central control of body weight and energy homeostasis. It is now clear that leptin is a pleiotropic cytokine, with activities on many peripheral cell types. These findings may help explain the surprising role of leptin in pathophysiological processes. Recent evidence suggests that leptin contributes to atherosclerosis and to the increased risk of cardiovascular disease in obese people. Leptin also appears to be involved in T-cell-dependent immunity and possibly in the development and maintenance of certain autoimmune diseases. Here, we review the role of leptin in cardiovascular and autoimmune diseases, and also briefly address the potential therapeutic use of leptin antagonists.     

The weight of leptin in immunity

Leptin is an adipocyte-derived hormone/cytokine that links nutritional status with neuroendocrine and immune functions. As a hormone, leptin regulates food intake and basal metabolism, and is sexually dimorphic - that is, its serum concentration is higher in females than in males with a similar body fat mass. As a cytokine, leptin can affect thymic homeostasis and the secretion of acute-phase reactants such as interleukin-1 and tumour-necrosis factor. Similar to other pro-inflammatory cytokines, leptin promotes T helper 1 (TH1)-cell differentiation and can modulate the onset and progression of autoimmune responses in several animal models of disease. Here, we review the advances and controversy for a role of leptin in the pathophysiology of immune responses.     

The adipocyte: a model for integration of endocrine and metabolic signaling in energy metabolism regulation

The ability to ensure continuous availability of energy despite highly variable supplies in the environment is a major determinant of the survival of all species. In higher organisms, including mammals, the capacity to efficiently store excess energy as triglycerides in adipocytes, from which stored energy could be rapidly released for use at other sites, was developed. To orchestrate the processes of energy storage and release, highly integrated systems operating on several physiological levels have evolved. The adipocyte is no longer considered a passive bystander, because fat cells actively secrete many members of the cytokine family, such as leptin, tumor necrosis factor-alpha, and interleukin-6, among other cytokine signals, which influence peripheral fuel storage, mobilization, and combustion, as well as energy homeostasis. The existence of a network of adipose tissue signaling pathways, arranged in a hierarchical fashion, constitutes a metabolic repertoire that enables the organism to adapt to a wide range of different metabolic challenges, such as starvation, stress, infection, and short periods of gross energy excess.     

Sexually different actions of leptin in proopiomelanocortin neurons to regulate glucose homeostasis

Leptin regulates energy balance and glucose homeostasis, at least in part, via activation of receptors in the arcuate nucleus of the hypothalamus located in proopiomelanocortin (POMC) neurons. Females have greater sensitivity to central leptin than males, suggested by a greater anorectic effect of central leptin administration in females. We hypothesized that the regulation of energy balance and peripheral glucose homeostasis of female rodents would be affected to a greater extent than in males if the action of leptin in POMC neurons were disturbed. Male and female mice lacking leptin receptors only in POMC neurons gained significantly more body weight and accumulated more body fat. However, female mice gained disproportionately more visceral adiposity than males, and this appeared to be largely the result of differences in energy expenditure. When maintained on a high-fat diet (HFD), both male and female mutants had higher levels of insulin following exogenous glucose challenges. Chow- and HFD-fed males but not females had abnormal glucose disappearance curves following insulin administrations. Collectively, these data indicate that the action of leptin in POMC neurons is sexually different to influence the regulation of energy balance, fat distribution, and glucose homeostasis.     

Leptin beyond body weight regulation--current concepts concerning its role in immune function and inflammation

Leptin, a 16 kDa non-glycosylated polypeptide produced primarily by adipocytes and released into the systemic circulation, exerts a multitude of regulatory functions including energy utilization and storage, regulation of various endocrine axes, bone metabolism, and thermoregulation. In addition to leptin's best known role as regulator of energy homeostasis, several studies indicate that leptin plays a pivotal role in immune and inflammatory response. Because of its dual nature as a hormone and cytokine, leptin can be nowadays considered the link between neuroendocrine and immune system. The increase in leptin production that occurs during infections and inflammatory processes strongly suggests that this adipokine is a part of the cytokines network which governs inflammatory/immune response and host defence mechanisms. Indeed, leptin plays a relevant role in inflammatory processes involving either innate or adaptive immune responses. Several studies have implicated leptin in the pathogenesis of autoimmune inflammatory conditions such as encephalomyelitis, type I diabetes, bowel inflammation and also articular degenerative diseases such as rheumatoid arthritis and osteoarthritis. Although the mechanisms by which leptin exerts its action as modulator of inflammatory/immune response are likely to be more complex than predicted and far to be completely depicted, there is a general consensus about its pivotal role as pro-inflammatory and immune-modulating agent. Here, we review the most recent advances on leptin biology with a particular attention to its adipokine facet, even though its role as metabolic hormone will be also addressed.     

Leptin grows up and gets a neural network

Studies seeking a dominant site of action for the hormone leptin have focused on leptin receptor-expressing neuropeptidergic neurons. In this issue, Vong et?al. show that leptin regulates energy homeostasis predominantly via a distributed network of GABAergic neurons.     

Wired on hormones: endocrine regulation of hypothalamic development

The hormones that regulate the hypothalamic circuits that control essential functions, such as reproduction and energy homeostasis, also specify brain architecture by regulating key developmental events. The cellular mechanisms underlying the developmental actions of testosterone and estrogen to determine patterns of neuronal cell death, synaptogenesis and axon guidance are being identified. Recent neuroanatomical evidence indicates that the adipocyte-derived hormone leptin may direct the development of hypothalamic pathways involved in energy homeostasis by promoting axonal projections from the arcuate nucleus of the hypothalamus to other hypothalamic sites that mediate the effects of leptin on food intake and body weight. Understanding how sex steroids and leptin regulate hypothalamic development will enable us to identify hormonally directed signaling events essential to the specification of neural circuitry that is optimized for sustained homeostasis.     

Socs3 deficiency in the brain elevates leptin sensitivity and confers resistance to diet-induced obesity

Leptin is an adipocyte-derived hormone that plays a key role in energy homeostasis, yet resistance to leptin is a feature of most cases of obesity in humans and rodents. In vitro analysis suggested that the suppressor of cytokine signaling-3 (Socs3) is a negative-feedback regulator of leptin signaling involved in leptin resistance. To determine the functional significance of Socs3 in vivo, we generated neural cell-specific SOCS3 conditional knockout mice using the Cre-loxP system. Compared to their wild-type littermates, Socs3-deficient mice showed enhanced leptin-induced hypothalamic Stat3 tyrosine phosphorylation as well as pro-opiomelanocortin (POMC) induction, and this resulted in a greater body weight loss and suppression of food intake. Moreover, the Socs3-deficient mice were resistant to high fat diet-induced weight gain and hyperleptinemia, and insulin-sensitivity was retained. These data indicate that Socs3 is a key regulator of diet-induced leptin as well as insulin resistance. Our study demonstrates the negative regulatory role of Socs3 in leptin signaling in vivo, and thus suppression of Socs3 in the brain is a potential therapy for leptin-resistance in obesity.     

Nutritional modulation of leptin expression and leptin action in obesity and obesity-associated complications

In obesity, an elevated accumulation and dysregulation of adipose tissue, due to an imbalance between energy intake and energy expenditure, usually coexists with the loss of responsiveness to leptin in central nervous system, and subsequently with hyperleptinemia. Leptin, a peptide hormone mainly produced by white adipose tissue, regulates energy homeostasis by stimulating energy expenditure and inhibiting food intake. Human obesity is characterized by increased plasma leptin levels, which have been related with different obesity-associated complications, such as chronic inflammatory state (risk factor for diabetes, cardiovascular and autoimmune diseases), as well as infertility and different types of cancer. Besides, leptin is also produced by placenta, and high leptin levels during pregnancy may be related with some pathological conditions such as gestational diabetes. This review focuses on the current insights and emerging concepts on potentially valuable nutrients and food components that may modulate leptin metabolism. Notably, several dietary food components, such as phenols, peptides, and vitamins, are able to decrease inflammation and improve leptin sensitivity by up- or down-regulation of leptin signaling molecules. On the other hand, some food components, such as saturated fatty acids may worsen chronic inflammation increasing the risk for pathological complications. Future research into nutritional mechanisms that restore leptin metabolism and signals of energy homeostasis may inspire new treatment options for obesity-related disorders.     

Leptin augments alveolar macrophage leukotriene synthesis by increasing phospholipase activity and enhancing group IVC iPLA2 (cPLA2gamma) protein expression

Leptin is a hormone secreted by adipocytes in correlation with total body fat mass. In addition to regulating energy homeostasis, leptin modulates immune functions such as macrophage phagocytosis and cytokine synthesis. Previously, we reported defective leukotriene synthesis in macrophages from leptin-deficient mice that could be restored with exogenous leptin. In the present study, we utilized macrophages from normal rodents to explore the mechanism by which leptin could enhance cellular leukotriene synthesis. Leptin pretreatment of either rat alveolar or murine peritoneal macrophages for 16 h dose dependently increased the synthesis of leukotriene B4 and cysteinyl leukotrienes in response to calcium ionophore or the particulate zymosan. Leptin also enhanced calcium ionophore-stimulated release of free arachidonic acid. Calcium-dependent and -independent arachidonoyl-selective phospholipase activities in macrophage lysates were likewise increased following leptin treatment. Immunoblot analysis of leptin-treated cells revealed that group IVC iPLA2 (cPLA2gamma) protein expression increased approximately 80%. These data demonstrate for the first time that phospholipase A2 activity and cPLA2gamma protein levels in alveolar macrophages represent targets for upregulation by leptin and provide previously unrecognized mechanisms by which this hormone can promote inflammatory responses.     

Lipoprotein receptor LRP1 regulates leptin signaling and energy homeostasis in the adult central nervous system

Obesity is a growing epidemic characterized by excess fat storage in adipocytes. Although lipoprotein receptors play important roles in lipid uptake, their role in controlling food intake and obesity is not known. Here we show that the lipoprotein receptor LRP1 regulates leptin signaling and energy homeostasis. Conditional deletion of the Lrp1 gene in the brain resulted in an obese phenotype characterized by increased food intake, decreased energy consumption, and decreased leptin signaling. LRP1 directly binds to leptin and the leptin receptor complex and is required for leptin receptor phosphorylation and Stat3 activation. We further showed that deletion of the Lrp1 gene specifically in the hypothalamus by Cre lentivirus injection is sufficient to trigger accelerated weight gain. Together, our results demonstrate that the lipoprotein receptor LRP1, which is critical in lipid metabolism, also regulates food intake and energy homeostasis in the adult central nervous system.     

Electrophysiological Analysis of Circuits Controlling Energy Homeostasis

Since the discovery of leptin and the central melanocortin circuit, electrophysiological studies have played a major role in elucidating mechanisms underlying energy homeostasis. This review highlights the contribution of findings made by electrophysiological measurements to the current understanding of hypothalamic neuronal networks involved in energy homeostasis with a specific focus on the arcuate–paraventricular nucleus circuit.     

Neuron transplantation partially reverses an obesity disorder in mice

Mice lacking leptin receptors are grossly obese and diabetic, in part due to dysfunction in brain circuits important for energy homeostasis. Transplantation of leptin receptor-expressing hypothalamic progenitor neurons into the brains of leptin receptor deficient mice led to integration into neural circuits, reduced obesity, and normalized circulating glucose levels.     

高原鼠兔瘦素蛋白乳腺特异表达载体的构建及细胞表达

瘦素(Leptin)蛋白是调节机体能量代谢的关键因子之一。前期研究显示高原鼠兔Leptin蛋白发生了适应性进化。功能实验表明,在温暖或寒冷条件下高原鼠兔Leptin通过减少食物摄取和增加能量消耗调节能量平衡,显示了其调节适应性产热过程的潜力。本研究以高原鼠兔Leptin cDNA为模板扩增高原鼠兔obese (ob)基因编码区序列504 bp,改造并构建哺乳动物真核细胞乳腺特异表达载体pBC1-lep,同时通过组织块法原代培养建立奶山羊乳腺上皮细胞系,并通过pBC1-lep质粒脂质体法转染及转基因细胞的筛选,成功获得转染Leptin的阳性细胞。本研究为利用转基因动物实现奶山羊乳腺中特异表达高原鼠兔Leptin提供了一条可能的途径,完成了乳腺特异真核表达载体的构建。     

Leptin and insulin pathways in POMC and AgRP neurons that modulate energy balance and glucose homeostasis

With the steady rise in the prevalence of obesity and its associated diseases, research aimed at understanding the mechanisms that regulate and control whole body energy homeostasis has gained new interest. Leptin and insulin, two anorectic hormones, have key roles in the regulation of body weight and energy homeostasis, as highlighted by the fact that several obese patients develop resistance to these hormones. Within the brain, the hypothalamic proopiomelanocortin and agouti‐related protein neurons have been identified as major targets of leptin and insulin action. Many studies have attempted to discern the individual contributions of various components of the principal pathways that mediate the central effects of leptin and insulin. The aim of this review is to discuss the latest findings that might shed light on, and lead to a better understanding of, energy balance and glucose homeostasis. In addition, recently discovered targets and mechanisms that mediate hormonal action in the brain are highlighted.     

Melanocortin and leptin signaling systems: central regulation of catabolic energy balance

The recent cloning of the ob gene (leptin) has revolutionized our understanding of obesity and the underlying factors that govern weight homeostasis. There is growing evidence that long term food intake regulation is controlled by the central nervous system by a number of peptide hormones in response to changes in leptin levels. Studies of these hormones, using both genetic and pharmacological approaches, have provided a foundation for decoding the molecular logic of the neuronal circuits which regulate food intake control and energy balance. A review of the current progress in the melanocortin-4 receptor pathway, with particular emphasis on its relation to leptin, neuropeptide Y and other obesity hormones known to modulate weight homeostasis, is presented.     

Expanding neurotransmitters in the hypothalamic neurocircuitry for energy balance regulation

The current epidemic of obesity and its associated metabolic syndromes impose unprecedented challenges to our society. Despite intensive research on obesity pathogenesis, an effective therapeutic strategy to treat and cure obesity is still lacking. Exciting studies in last decades have established the importance of the leptin neural pathway in the hypothalamus in the regulation of body weight homeostasis. Important hypothalamic neuropeptides have been identified as critical neurotransmitters from leptin-sensitive neurons to mediate leptin action. Recent research advance has significantly expanded the list of neurotransmitters involved in body weight-regulating neural pathways, including fast-acting neurotransmitters, gamma-aminobutyric acid (GABA) and glutamate. Given the limited knowledge on the leptin neural pathway for body weight homeostasis, understanding the function of neurotransmitters released from key neurons for energy balance regulation is essential for delineating leptin neural pathway and eventually for designing effective therapeutic drugs against the obesity epidemic.