The thymoprotective function of leptin is indirectly mediated via suppression of obesity

Leptin is an adipokine that regulates metabolism and plays an important role as a neuroendocrine hormone. Leptin mediates these functions via the leptin receptor, and deficiency in either leptin or its receptor leads to obesity in humans and mice. Leptin has far reaching effects on the immune system, as observed in obese mice, which display decreased thymic function and increased inflammatory responses. With expression of the leptin receptor on T cells and supporting thymic epithelium, aberrant signalling through the leptin receptor has been thought to be the direct cause of thymic involution in obese mice. Here, we demonstrate that the absence of leptin receptor on either thymic epithelial cells or T cells does not lead to the loss of thymic function, demonstrating that the thymoprotective effect of leptin is mediated by obesity suppression rather than direct signalling to the cellular components of the thymus.     

Maternal obesity and the developmental programming of hypertension: a role for leptin

Mother–child cohort studies have established that both pre‐pregnancy body mass index (BMI) and gestational weight gain are independently associated with cardio‐metabolic risk factors in young adult offspring, including systolic and diastolic blood pressure. Animal models in sheep and non‐human primates provide further evidence for the influence of maternal obesity on offspring cardiovascular function, whilst recent studies in rodents suggest that perinatal exposure to the metabolic milieu of maternal obesity may permanently change the central regulatory pathways involved in blood pressure regulation. Leptin plays an important role in the central control of appetite, is also involved in activation of efferent sympathetic pathways to both thermogenic and non‐thermogenic tissues, such as the kidney, and is therefore implicated in obesity‐related hypertension. Leptin is also thought to have a neurotrophic role in the development of the hypothalamus, and altered neonatal leptin profiles secondary to maternal obesity are associated with permanently altered hypothalamic structure and function. In rodent studies, maternal obesity confers persistent sympathoexcitatory hyper‐responsiveness and hypertension acquired in the early stages of development. Experimental neonatal hyperleptinaemia in naive rat pups provides further evidence of heightened sympathetic tone and proof of principle that hyperleptinaemia during a critical window of hypothalamic development may directly lead to adulthood hypertension. Insight from these animal models raises the possibility that early‐life exposure to leptin in humans may lead to early onset essential hypertension. Ongoing mother–child cohort and intervention studies in obese pregnant women provide a unique opportunity to address associations between maternal obesity and offspring cardiovascular function. The goal of the review is to highlight the potential importance of leptin in the developmental programming of hypertension in obese pregnancy.     

肥胖儿童瘦素受体基因外显子3057位 G→A突变及其临床意义

目的　探讨瘦素受体 ( leptin receptor,L EPR)基因第 2 0外显子变异对脂质代谢的影响。方法用聚合酶链反应 -限制性片段长度多态性分析方法及聚丙烯酰胺凝胶电泳方法分析瘦素受体基因的第 2 0外显子基因变异频率 ,并测定单纯型肥胖儿童及健康儿童的血清中甘油三酯、总胆固醇、高密度脂蛋白、低密度脂蛋白。两组分别测身高、体重 ,按公式计算体重指数 ,脂肪百分比。结果　有 3种第 2 0外显子的基因型 ,其酶切片段分别为 A/A型 :2 0 1bp、75 bp;G/A型 :2 0 1bp、173bp、75 bp;G/G型 :173bp、75 bp。肥胖儿童与健康儿童比较 ,前者瘦素受体基因的第 2 0外显子 30 5 7位 G→ A突变频率增高 ,差异有显著性 ( P<0 .0 5 )。A/A基因型的肥胖儿童其血清甘油三酯浓度、体重指数、脂肪百分比均明显高于 G/G基因型者 ( P<0 .0 1) ,而血清高密度脂蛋白水平则低于后者 ( P<0 .0 1) ,对于 G/A型肥胖儿童来说 ,除其血清甘油三酯浓度高于G/G基因型者外 ( P<0 .0 5 ) ,余各项指标均与另外两种基因型无明显差别。结论　本组单纯型肥胖儿童瘦素受体基因第 2 0外显子存在基因多态性 ,且这种变化明显影响肥胖儿童的脂质代谢及体脂分布     

The role of leptin in leptin resistance and obesity

Although the presence of hyperleptinemia with leptin resistance and obesity has long been recognized, a causal role of elevated leptin in these biological states remains unclear. This article summarizes some recent work from our laboratory supporting the concept that leptin, in and of itself, promotes leptin resistance and such resistance compounds the metabolic impact of diet-induced obesity. Results from multiple studies demonstrate that (1) chronically elevated central leptin decreases hypothalamic leptin receptor expression and protein levels and impairs leptin signaling; (2) leptin resistance and obesity are associated with reduced leptin receptors and diminished maximal leptin signaling capacity; and (3) leptin resistance confers increased susceptibility to diet-induced obesity. In essence, the augmented leptin accompanying obesity contributes to leptin resistance, and this leptin resistance promotes further obesity, leading to a vicious cycle of escalating metabolic devastation.     

Contribution of leptin to the formation of neuroleptic obesity in patients with schizophrenia during antipsychotic therapy

We studied the dynamics of serum leptin level and some anthropometric values in patients with schizophrenia treated with risperidone, olanzapine, and clozapine showed gender-dependent specific correlations between the studied parameters. Translated from Byulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 146, No. 9, pp. 324–326, September, 2008     

肥胖儿童血清高敏C反应蛋白、瘦素、可溶性瘦素受体和胰岛素的水平及意义

目的探讨肥胖儿童血清高敏C反应蛋白、瘦素、可溶性瘦素受体及胰岛素的水平变化及临床意义。方法对64例12岁肥胖儿童进行血清高敏C反应蛋白（high-sensitivity C-reactive pro-tein,hs-CRP）、瘦素（leptin,Lp）、可溶性瘦素受体（soluble leptin receptor,sLR）及胰岛素（Insulin,INS）的水平测定,与48例健康体检儿童进行对照比较。其中,血清Lp、INS采用放射免疫分析法（RIA）测定,sLR采用酶联免疫吸附试验法检测,hs-CRP采用电化学发光免疫法测定。结果肥胖儿童组血清hs-CRP、Lp、INS水平及BMI均显著高于对照组（均P〈0.01）,sLR水平低于对照组（P〈0.05）;相关性分析显示肥胖儿童血清hs-CRP水平与Lp、INS、BMI之间均呈显著性正相关性（r=0.575,P〈0.01;r=0.504,P〈0.01;r=0.685,P〈0.01）,与sLR呈显著性负相关性（r=-0.339,P〈0.01）;Lp与INS、BMI之间呈显著性正相关性（r=0.352,P〈0.01;r=0.503,P〈0.01）,与sLR呈显著性负相关性（r=-0.467,P〈0.01）,sLR与BMI呈显著性负相关性（r=-0.398,P〈0.01）。结论肥胖儿童已存在炎症状态的改变及瘦素、胰岛素抵抗,且三方面密切相关。对这些血清学指标的检测,有助于儿童肥胖状态的监控和治疗。     

Influence of hypo- and hyperglycaemia on plasma leptin concentrations in healthy women and in women with polycystic ovary syndrome

BACKGROUND: Insulin resistance and obesity play an important role in the pathogenesis of polycystic ovary syndrome (PCOS). It is known that experimentally induced insulin resistance diminishes the stimulatory effect of insulin on leptin secretion. It is not yet known whether the long-term insulin resistance as found in PCOS patients alters the leptin response to hypo- and hyperglycaemia. METHODS: We induced hyper- and hypoglycaemia by glucose clamp technique in 7 patients with PCOS and 20 healthy controls. After a plasma glucose level of 8.8 mmol/l was reached, the plasma glucose level was reduced stepwise to 6.8, 4.8 and 2.8 mmol/l. RESULTS: The PCOS patients required lower glucose infusion rates to reach the glycaemic targets (P < 0.05). Serum insulin and C-peptide concentrations increased significantly during the clamp compared with the baseline in both groups (P < 0.001 for insulin, and P < 0.001, P < 0.005 for C-peptide control and PCOS, respectively) and increased significantly more in PCOS patients compared with the control group (both P < 0.05). Basal leptin levels were significantly higher in the PCOS group than in the control group (P = 0.005). In the controls, the leptin concentration increased significantly during the clamp (P < 0.001 for each glycaemic target), whereas in the PCOS group, leptin secretion increased only during hypoglycaemia (P = 0.04). CONCLUSIONS: Compared with the healthy controls, the response of leptin secretion to hyper- and hypoglycaemia was diminished in PCOS patients. Changes in leptin secretion seem not to be caused by hyper- and hypoglycaemia, but rather by hyperinsulinaemia. Reduced insulin sensitivity seems to be responsible for the diminished leptin response, which might contribute to the obesity found in PCOS patients.     

瘦素抵抗的免疫调节作用及其与肿瘤发生的关系

瘦素是一种内分泌激素,与受体结合后发挥调节食欲、能量代谢、生殖和造血等多种生物学作用.瘦素抵抗与肿瘤发生发展密切相关,除对肿瘤细胞的增殖及凋亡等发挥作用外,还参与调节肿瘤局部微环境中多种免疫细胞的数目与功能,通过调控抗肿瘤免疫活性参与肿瘤发生发展.目前已发现瘦素抵抗的免疫调节作用在多种类型肿瘤中发挥功能,对肿瘤的诊断与防治具有重要意义.     

Inflammatory processes in obesity: focus on endothelial dysfunction and the role of adipokines as inflammatory mediators

Obesity predisposes the affected individuals to several metabolic, inflammatory, cardiovascular and malignant pathologies and is a top risk factor for premature mortality. It is now well known that inflammation has a major causative role in obesity-associated disease development and that obesity favors the establishment of a pro-inflammatory milieu at the level of adipose microenvironment. These inflammatory signals result in a disruption of normal cellular-crosstalk between adipose and non-adipose components leading to an altered metabolic and immunological status and a dysfunctional phenotype. Abnormal secretion of adipokines – small adipose-derived signaling molecules – can further assist in the inflammatory processes to offset the adipose tissue towards a dysfunctional state. Although adipokines have been recognized as the link between obesity and pathogenesis, studies are needed to fully understand their mechanism of action and underscore their therapeutic value. Here, we have reviewed obesity-induced metabolic and immunological changes at the level of vasculature and emphasize on the importance of adipokines, particularly leptin, vaspin and visfatin, for their therapeutic relevance.