增食欲素调节下丘脑-垂体-肾上腺轴的研究进展

增食欲素A和增食欲素B是下丘脑神经肽,通过激活两种G蛋白耦联受体发挥作用.增食欲素及其受体表达于下丘脑室旁核和正中隆起,增食欲素受体还表达于脑垂体促皮质激素细胞、肾上腺皮质和髓质.增食欲素能调节摄食、能量代谢平衡、睡醒周期、血压等,还能调节下丘脑-垂体-肾上腺(HPA)轴.现就增食欲素及其受体在HPA轴中枢支和周围支(peripheral branches)的表达及作用机制作一综述.     

增食欲素调节下丘脑-垂体-肾上腺轴的研究进展

增食欲素A和增食欲素B是下丘脑神经肽,通过激活两种G蛋白耦联受体发挥作用.增食欲素及其受体表达于下丘脑室旁核和正中隆起,增食欲素受体还表达于脑垂体促皮质激素细胞、肾上腺皮质和髓质.增食欲素能调节摄食、能量代谢平衡、睡醒周期、血压等,还能调节下丘脑-垂体-肾上腺(HPA)轴.现就增食欲素及其受体在HPA轴中枢支和周围支(peripheral branches)的表达及作用机制作一综述.     

增食欲素调节下丘脑-垂体-肾上腺轴的研究进展

增食欲素A和增食欲素B是下丘脑神经肽,通过激活两种G蛋白耦联受体发挥作用.增食欲素及其受体表达于下丘脑室旁核和正中隆起,增食欲素受体还表达于脑垂体促皮质激素细胞、肾上腺皮质和髓质.增食欲素能调节摄食、能量代谢平衡、睡醒周期、血压等,还能调节下丘脑-垂体-肾上腺(HPA)轴.现就增食欲素及其受体在HPA轴中枢支和周围支(peripheral branches)的表达及作用机制作一综述.     

增食欲素的研究进展

增食欲素是新近发现的神经肽 ,研究显示它在增加摄食、饮水、调节睡眠觉醒周期、生殖、体温、血压和感觉等方面有广泛作用。文中综述了增食欲素的基因及蛋白质结构、组织分布和作用 ,介绍了增食欲素受体。     

增食欲素的研究进展

增食欲素是新近发现的神经肽，研究显示它在增加摄食、饮水、调节睡眠觉醒周期、生殖、体温、血压和感觉等方面有广泛作用。文中综述了增食欲素的基因及蛋白质结构、组织分布和作用，介绍了增食欲素受体。     

高果糖膳食对大鼠下丘脑增食欲素系统的影响

增食欲素是涉及摄食及内分泌代谢调控的神经肽。本研究以高果糖饲料诱导胰岛素抵抗(IR)大鼠模型。高胰岛素正葡萄糖钳夹技术证实的胰岛素抵抗 (IR)大鼠模型中增食欲素、瘦素的变化。结果显示 ,高果糖饲料可诱导IR ;破坏增食欲素与瘦素的平衡。血糖、胰岛素、脂代谢及瘦素均可参与增食欲素调控。     

中枢神经系统参与肥胖调节的分子生物学进展

下丘脑是调节摄食行为和能量平衡的关键部位。脂肪组织分泌的leptin(瘦素 )通过下丘脑内侧基底部的受体 ,正调神经肽YmRNA、负调阿黑皮素原 (POMC)mRNA的表达 ,抑制食欲和进食 ;而下丘脑外侧部的黑素细胞凝聚素、增食欲素 (orexin)则刺激进食。两者共同调控能量自稳态 ,参与肥胖的调节。进食促进因子和抑制因子亦相互作用构成下丘脑能量调节网络 ,探讨网络构成及作用的分子机制是未来研究肥胖发生的方向。     

增食欲素系统及其功能的研究进展

两组科学家在1998年分别报道了增食欲素(Orexin)。增食欲素A(OXA)和增食欲素B(OXB)是由外侧下丘脑神经元产生的神经肽,通过与两种7次跨膜G蛋白偶联受体——增食欲素受体结合来发挥作用。Orexin主要参与摄食和能量代谢、睡眠-觉醒周期调节,同时也在呼吸、情绪行为、心血管、胃肠道、细胞增殖和凋亡等方面发挥作用。随着近年来研究的进展,Orexin对胰岛β细胞的调节也越来越受到重视,包括Orexin参与的胰腺内分泌和IR两个过程。本文对Orexin系统及其功能的研究进展作一综述。     

中枢神经系统参与肥胖调节的分子生物学进展

下丘脑是调节摄食行为和能量平衡的关键部位。脂肪组织分泌的ｌｅｐｔｉｎ（瘦素）通过下丘脑内侧基底部的受体,正调神经肽Ｙ ｍＲＮＡ、负调阿黑皮素原（ＰＯＭＣ）ｍＲＮＡ的表达,抑制食欲和进食;而下丘脑外侧部的黑素细胞凝聚素、增食欲素（ｏｒｅｘｉｎ）则刺激进食。两者共同调控能量自稳态,参与肥胖的调节。进食促进因子和抑制因子亦相互作用构成下丘脑能量调节网络,探讨风险结构及作用的分子机制是未来研究肥胖发生的方     

瘦素与其它调节食欲肽间的关系

瘦素是由肥胖基因编码、脂肪细胞分泌的一种蛋白质 ,主要作用于下丘脑 ,减少摄食 ,减轻体重。下丘脑中存在许多与调节食欲有关的肽 ,一些含有这些肽的神经元同时表达瘦素受体 ,瘦素通过其受体抑制增加食欲肽如神经肽Y、甘丙肽、增食欲素和 (或 )刺激减少食欲肽如前阿片黑素细胞皮质激素、可卡因与安非它明调节的转录物(CART)、胰升糖素样肽 1、神经降压素来共同调节能量代谢。     

Regulatory effect of orexin system on various diseases through mTOR signaling pathway

Orexin (OX)A and OXB are a pair of neuropeptides secreted by orexin-producing neurons in the lateral hypothalamus. The orexin system can regulate many physiological processes through these two receptor pathways, such as feeding behavior, sleep/wake state, energy homeostasis, reward, and the coordination of emotion. Mammalian target of rapamycin (mTOR) can coordinate upstream signals with downstream effectors, thereby regulating fundamental cellular processes and also plays an essential role in the signaling network downstream of the orexin system. In turn, the orexin system can activate mTOR. Here, we review the association of the orexin system with the mTOR signaling pathway mainly by discussing that drugs in various diseases exert their effects on the orexin system, indirectly affecting the mTOR signaling pathway.     

A treasure trove of hypothalamic neurocircuitries governing body weight homeostasis

Changes in physical activities and feeding habits have transformed the historically rare disease of obesity into a modern metabolic pandemic. Obesity occurs when energy intake exceeds energy expenditure over time. This energy imbalance significantly increases the risk for cardiovascular disease and type 2 diabetes mellitus and as such represents an enormous socioeconomic burden and health threat. To combat obesity, a better understanding of the molecular mechanisms and neurocircuitries underlying normal body weight homeostasis is required. In the 1940s, pioneering lesion experiments unveiled the importance of medial and lateral hypothalamic structures. In the 1980s and 1990s, several neuropeptides and peripheral hormones critical for appropriate feeding behavior, energy expenditure, and hence body weight homeostasis were identified. In the 2000s, results from metabolic analyses of genetically engineered mice bearing mutations only in selected neuronal groups greatly advanced our knowledge of the peripheral/brain feedback-loop modalities by which central neurons control energy balance. In this review, we will summarize these recent progresses with particular emphasis on the biochemical identities of hypothalamic neurons and molecular components underlying normal appetite, energy expenditure, and body weight homeostasis. We will also parse which of those neurons and molecules are critical components of homeostatic adaptive pathways against obesity induced by hypercaloric feeding.     

Sex-Biased Physiological Roles of NPFF1R,the Canonical Receptor of RFRP-3, in Food Intake and Metabolic Homeostasis Revealed by its Congenital Ablation in mice

BackgroundRF-amide-related peptide-3 (RFRP-3), the mammalian ortholog of gonadotropin-inhibiting hormone, operates as inhibitory signal for the reproductive axis. Recently, RFRP-3 has been also suggested to stimulate feeding, and therefore might contribute to the control of body weight and its alterations. Yet, characterization of the metabolic actions of RFRP-3 has been so far superficial and mostly pharmacological. Here, we aim to investigate the physiological roles of RFRP-3 signaling in the control of feeding and metabolic homeostasis using a novel mouse model of genetic ablation of its canonical receptor, NPFF1R.MethodsFood intake, body weight gain and composition, and key metabolic parameters, including glucose tolerance and insulin sensitivity, were monitored in mice with constitutive inactivation of NPFF1R.ResultsCongenital elimination of NPFF1R in male mice resulted in changes in feeding patterns, with a decrease in spontaneous food intake and altered responses to leptin and ghrelin: leptin-induced feeding suppression was exaggerated in NPFF1R null mice, whereas orexigenic responses to ghrelin were partially blunted. Concordant with this pro-anorectic phenotype, hypothalamic expression of Pomc was increased in NPFF1R null mice. In contrast, spontaneous feeding and neuropeptide expression remained unaltered in NPFF1R KO female mice. Despite propensity for reduced feeding, ablation of NPFF1R signaling in male mice did not cause overt alterations in body weight (BW) gain or composition, neither it affected BW responses to high fat diet (HFD), total energy expenditure or RQ ratios. Yet, NPFF1R KO males showed a decrease in locomotor activity. Conversely, NPFF1R null female mice tended to be heavier and displayed exaggerated BW increases in response to obesogenic insults, such as HFD or ovariectomy. These were associated to increased fat mass, decreased total energy expenditure in HFD, and unaltered RQ ratios or spontaneous locomotor activity. Finally, lack of NPFF1R signaling worsened the metabolic impact of HFD on glycemic homeostasis in males, as revealed by impaired glucose tolerance and insulin sensitivity, while female mice remained unaffected.ConclusionOur data support a discernible orexigenic role of NPFF1R signaling selectively in males, which might modulate the effects of leptin and ghrelin on food intake. In addition, our study is the first to disclose the sex-biased, deleterious impact of the lack of NPFF1R signaling on body weight and fat composition, energy expenditure, locomotor activity and glucose balance, which exaggerates some of the metabolic consequences of concurrent obesogenic insults, such as HFD, in a sexually dimorphic manner.Summary of Translational RelevanceOur data are the first to document the nature and magnitude of the regulatory actions of RFRP-3/NPFF1R signaling in the control of feeding and metabolic homeostasis in a physiological setting. Our results not only suggest an orexigenic action of endogenous RFRP-3, specifically in males, but reveal also the detrimental impact of ablation of NPFF1R signaling on body composition, energy expenditure, locomotor activity or glucose balance, especially when concurrent with other obesogenic insults, as HFD, thereby providing the first evidence for additional metabolic effects of RFRP-3, other that the mere control of feeding. Interestingly, alterations of such key metabolic parameters occurred in a sex-biased manner, with males being more sensitive to deregulation of locomotor activity and glycemic control, while females displayed clearer obesogenic responses and deregulated energy expenditure. While our study cannot discard the possibility of RFRP-3 actions via alternative pathways, such as NPFF2R, our data pave the way for future analyses addressing the eventual contribution of altered RFRP-3/NPFF1R signaling in the development of metabolic alterations (including obesity and its comorbidities), especially in conditions associated to reproductive dysfunction.     

Endocannabinoid system overactivity and the metabolic syndrome: Prospects for treatment

The endocannabinoid system (ECS) plays a physiologic role in modulating energy balance, feeding behavior, lipoprotein metabolism, insulin sensitivity, and glucose homeostasis, which when dysregulated can all contribute to cardiometabolic risk. Evidence has suggested that the ECS is overactive in human obesity and in animal models of genetic and diet-induced obesity. ECS stimulation centrally and peripherally drives metabolic processes that mimic the metabolic syndrome. These findings have led to the development of potential novel therapeutic targets, including the drug rimonabant, a selective CB1 receptor antagonist, which has been shown to promote weight loss, reduce inflammation, improve dyslipidemia, and improve glucose homeostasis.     

Deficiency of adiponectin receptor 2 reduces diet-induced insulin resistance but promotes type 2 diabetes

Adiponectin/adiponectin receptors (AdipoR) are involved in energy homeostasis and inflammatory pathways. To investigate the role of AdipoR2 in metabolic control, we studied the lipid and glucose metabolic phenotypes in AdipoR2-deficient mice. AdipoR2 deletion diminished high-fat diet-induced dyslipidemia and insulin resistance yet deteriorated glucose homeostasis as high-fat feeding continued, which resulted from the failure of pancreatic beta-cells to adequately compensate for the moderate insulin resistance. A defect in the AdipoR2 gene may represent a mechanism underlying the etiology of certain subgroups of type 2 diabetic patients who eventually develop overt diabetes, whereas other obese patients do not.     

Female mice and rats exhibit species-specific metabolic and behavioral responses to ovariectomy

Ovariectomy (OVX) leads to hyperphagia and weight gain in rats, which can be prevented by estradiol (E2) replacement; however, the role of endogenous E2 on feeding and energy homeostasis in female mice has not been well characterized. The primary goal of this study was to assess the relative contribution of increased energy intake and decreased energy expenditure to OVX-induced weight gain in female rats and mice. OVX led to hyperphagia in rats, but did not produce daily, nor cumulative, hyperphagia in mice. OVX decreased mass-specific metabolic rate in mice, but not in rats. OVX decreased home cage locomotor activity in both species. Pair-feeding attenuated OVX-induced weight gain in rats and produced both short- and long-term changes in expression of key hypothalamic genes involved in food intake and energy homeostasis, i.e., the anorexigenic neuropeptide pro-opiomelanocortin (POMC) and the orexigenic neuropeptides: melanin-concentrating hormone (MCH) and agouti-related peptide (AgRP). No differences in hypothalamic gene expression were observed between OVX’d and sham mice. The results suggest that OVX-induced weight gain is mediated by hyperphagia and reduced locomotor activity in rats, but that in mice, it is primarily mediated by reduced locomotor activity and metabolic rate.     

Age-related insulin resistance in hypothalamus and peripheral tissues of orexin knockout mice

Aims/hypothesis Orexin/hypocretin is a hypothalamic neuropeptide that regulates motivated behaviours, such as feeding and arousal, and, importantly, is also involved in energy homeostasis. The aim of this study was to reveal the role of orexin in the regulation of insulin sensitivity for glucose metabolism. Methods Orexin knockout mice fasted overnight underwent oral glucose tolerance testing and insulin tolerance testing. The impact of orexin deficiency on insulin signalling was studied by Western blotting to measure levels of Akt phosphorylation and its upstream and downstream molecules in the hypothalamus, muscle and liver in orexin knockout mice. Results We found that orexin deficiency caused the age-related development of impaired glucose tolerance and insulin resistance in both male mice without obesity and female mice with mild obesity, fed a normal chow diet. When maintained on a high-fat diet, these abnormalities became more pronounced exclusively in female orexin knockout mice that developed severe obesity. Insulin signalling through Akt was disrupted in peripheral tissues of middle-aged (9-month-old) but not young adult (2-to-3-month-old) orexin knockout mice fed a normal chow diet. Moreover, basal levels of hypothalamic Akt phosphorylation were abnormally elevated in orexin knockout mice at every age studied, and insulin stimulation failed to increase the level of phosphorylation. Similar abnormalities were observed with respect to GSK3β phosphorylation in the hypothalamus and peripheral tissues of middle-aged orexin knockout mice. Conclusions/interpretation Our results demonstrate a novel role for orexin in hypothalamic insulin signalling, which is likely to be responsible for preventing the development of peripheral insulin resistance with age. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorised users.