AMP-activated protein kinase plays a role in the control of food intake

AMP-activated protein kinase (AMPK) is the downstream component of a protein kinase cascade that acts as an intracellular energy sensor maintaining the energy balance within the cell. The finding that leptin and adiponectin activate AMPK to alter metabolic pathways in muscle and liver provides direct evidence for this role in peripheral tissues. The hypothalamus is a key regulator of food intake and energy balance, coordinating body adiposity and nutritional state in response to peripheral hormones, such as leptin, peptide YY-(3-36), and ghrelin. To date the hormonal regulation of AMPK in the hypothalamus, or its potential role in the control of food intake, have not been reported. Here we demonstrate that counter-regulatory hormones involved in appetite control regulate AMPK activity and that pharmacological activation of AMPK in the hypothalamus increases food intake. In vivo administration of leptin, which leads to a reduction in food intake, decreases hypothalamic AMPK activity. By contrast, injection of ghrelin in vivo, which increases food intake, stimulates AMPK activity in the hypothalamus. Consistent with the effect of ghrelin, injection of 5-amino-4-imidazole carboxamide riboside, a pharmacological activator of AMPK, into either the third cerebral ventricle or directly into the paraventricular nucleus of the hypothalamus significantly increased food intake. These results suggest that AMPK is regulated in the hypothalamus by hormones which regulate food intake. Furthermore, direct pharmacological activation of AMPK in the hypothalamus is sufficient to increase food intake. These findings demonstrate that AMPK plays a role in the regulation of feeding and identify AMPK as a novel target for anti-obesity drugs.     

AMPK: a link between metabolism and reproduction?

5'AMP-activated protein kinase (AMPK) is a serine/threonine kinase that acts as a fuel gauge in regulating energy metabolism. It restores cellular ATP levels by switching on catabolic pathways and switching off anabolic pathways. Some evidence indicates that AMPK could be also implicated in reproductive functions such as granulosa cell steroidogenesis and nuclear oocyte maturation in several species. Some metabolic hormones such as leptin, resistin, adiponectin (three adipokines) and ghrelin may in part act through the AMPK signaling. These hormones are also involved in the control of the reproductive functions at the hypothalamus-pituitary-gonadal axis level in both male and female. Thus, AMPK could be one of the signaling pathways controlling the interactions between energy balance and reproduction. The reproductive system is tightly coupled with energy balance, and thereby metabolic abnormalities can lead to the development of some physiopathological situations such as the polycystic ovary syndrome (PCOS). Women with PCOS show altered fertility mostly associated with metabolic disorders such as insulin-resistance, hyperinsulinemia and/or dyslipidemia. Metformin, an insulin-sensitizer, is used for the treatment of women with PCOS. It restores subnormal fertility and energy balance. Recent studies show that AMPK is involved in the mechanism of action of metformin. Thus, it may be a therapeutic target. However, further investigations are necessary to elucidate the functions of AMPK in both metabolic and reproductive tissues.     

Galanin-like peptide in the brain: effects on feeding, energy metabolism and reproduction

The hypothalamus plays an important role in the regulation of feeding behavior, energy metabolism and reproduction. A novel peptide containing 60 amino acid peptide and a non-amidated C-terminus is produced in the hypothalamic arcuate nucleus (ARC) and has been named galanin-like peptide (GALP) on the basis of a portion of this peptide being homologous with galanin. It acts in the central nervous system (CNS), where it is involved in the regulation of feeding behavior. GALP-producing neurons make neuronal networks with several feeding related peptide-producing neurons. Since GALP is involved in the control of food intake and energy balance, it is possible that it plays an important role in the development of obesity. Furthermore, GALP regulates plasma lateral hypothalamus (LH) levels via the activation of gonadotropin-releasing hormone (GnRH)-producing neurons, suggesting that GALP is active in the reproductive system. Thus, interesting findings on the roles of GALP have made across a number of physiological systems. This review will attempt to summarize the research carried out to date on these areas. Because GALP may be involved in feeding behavior, energy metabolism and reproduction, further studies on the morphology and function of GALP-containing neurons in the CNS should increase our understanding of the role of GALP in brain function.     

AMPK, an active player in the control of metabolism

Impairment in the regulation of energy homeostasis and imbalance between energy intake and energy expenditure lead to many metabolic disorders and diseases such as obesity and type 2 diabetes. AMP-activated protein kinase (AMPK) is considered as a "fuel-gauge" in the cell and plays a key role in the regulation of energy metabolism. Activated by an increase in the AMP/ATP ratio, AMPK switches on catabolic pathways such as fatty acid oxidation and switches off anabolic pathways such as lipogenesis or gluconeogenesis. Insulin-sensitizing adipokines (leptin and adiponectin) and anti-diabetic drugs (thiazolidinediones and biguanides) are acting in part through the activation of AMPK. More recent findings indicate that AMPK plays also a major role in the control of whole body energy homeostasis by integrating, at the hypothalamus level, nutrient and hormonal signals that regulate food intake and energy expenditure. AMPK provides therefore a potential target for the treatment of metabolic diseases such as obesity and type II diabetes.     

C75, a fatty acid synthase inhibitor, reduces food intake via hypothalamic AMP-activated protein kinase

Energy homeostasis and feeding are regulated by the central nervous system. C75, a fatty acid synthase (FAS) inhibitor, causes weight loss and anorexia, implying a novel central nervous system pathway(s) for sensing energy balance. AMP-activated protein kinase (AMPK), a sensor of peripheral energy balance, is phosphorylated and activated when energy sources are low. Here, we identify a role for hypothalamic AMPK in the regulation of feeding behavior and in mediating the anorexic effects of C75. 5-Aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR), an activator of AMPK, increased food intake, whereas compound C, an inhibitor of AMPK, decreased food intake. C75 rapidly reduced the level of the phosphorylated AMPK alpha subunit (pAMPKalpha) in the hypothalamus, even in fasted mice that had elevated hypothalamic pAMPKalpha levels. Furthermore, AICAR reversed both the C75-induced anorexia and the decrease in hypothalamic pAMPKalpha levels. C75 elevated hypothalamic neuronal ATP levels, which may contribute to the mechanism by which C75 decreased AMPK activity. C75 reduced the levels of pAMPKalpha and phosphorylated cAMP response element-binding protein (pCREB) in the arcuate nucleus neurons of the hypothalamus, suggesting a mechanism for the reduction in NPY expression seen with C75 treatment. These data indicate that modulation of FAS activity in the hypothalamus can alter energy perception via AMPK, which functions as a physiological energy sensor in the hypothalamus.     

AMPK对线粒体功能的调节

5’单磷酸腺苷活化蛋白激酶（AMP—activated protein kinase,AMPK）是细胞的能量感受器,调节细胞能量代谢,在正常细胞和癌细胞中均发挥重要的生物功能,它的激活有助于纠正代谢紊乱,使细胞代谢趋向生理平衡。在细胞应急反应中,细胞感受到能量危机,ATP浓度下降,AMP浓度上升,细胞内AMP／ATP比例上升,AMPK被激活：而在病理状态下,如代谢综合征、肿瘤等,常伴随能量代谢紊乱和AMPK激活抑制,因此,AMPK被视为治疗代谢性疾病与肿瘤的潜在作用靶点。然而,AMPK对能量代谢的调节与线粒体的功能密不可分,线粒体作为细胞的能量工厂,在健康与疾病中也发挥着重要的作用。越来越多的研究表明,线粒体能影响AMPK的活性,同时AMPK也通过多方面对线粒体进行调节,线粒体相关疾病与AMPK的调节有着密切的关系。该文主要针对AMPK是如何对线粒体的合成、线粒体自噬、内源性凋亡及线粒体相关疾病等方面进行综述。     

AMP-activated protein kinase: balancing the scales

AMP-activated protein kinase (AMPK) is the central component of a protein kinase cascade that plays a key role in the regulation of energy control. AMPK is activated in response to an increase in the ratio of AMP:ATP within the cell. Activation requires phosphorylation of threonine 172 within the catalytic subunit of AMPK by an upstream kinase. The identity of the upstream kinase in the cascade remained frustratingly elusive for many years, but was recently identified as LKB1, a kinase that is inactivated in a rare hereditary form of cancer called Peutz-Jeghers syndrome. Once activated, AMPK initiates a series of responses that are aimed at restoring the energy balance within the cell. ATP-consuming, anabolic pathways, such as fatty acid synthesis and protein synthesis are switched-off, whereas ATP-generating, catabolic pathways, such as fatty acid oxidation and glycolysis, are switched-on. More recent studies have indicated, that AMPK plays an important role in the regulation of whole body energy metabolism. The adipocyte-derived hormones, leptin and adiponectin, activate AMPK in peripheral tissues, including skeletal muscle and liver, increasing energy expenditure. In the hypothalamus, AMPK is inhibited by leptin and insulin, hormones which suppress feeding, whilst ghrelin, a hormone that increases food intake, activates AMPK. Furthermore, direct pharmacological activation of AMPK in the hypothalamus by 5-aminoimidazole-4-carboxamide ribose increases food intake in rats, demonstrating that AMPK plays a direct role in the regulation of feeding. Taken together these findings indicate that AMPK has a pivotal role in regulating pathways that control both energy expenditure and energy intake.     

Protective effects of AMP‐activated protein kinase in the cardiovascular system

Cardiovascular diseases remain the leading cause of mortality worldwide. Recent studies of AMP-activated protein kinase (AMPK), a highly conserved sensor of cellular energy status, suggest that there might be therapeutic value in targeting the AMPK signaling pathway. AMPK is found in most mammalian tissues, including those of the cardiovascular system. As cardiovascular diseases are typically associated with blood flow occlusion and blood occlusion may induce rapid energy deficit, AMPK activation may occur during the early phase upon nutrient deprivation in cardiovascular organs. Therefore, investigation of AMPK in cardiovascular organs may help us to understand the pathophysiology of defence mechanisms in these organs. Recent studies have provided proof of concept for the idea that AMPK is protective in heart as well as in vascular endothelial and smooth muscle cells. Moreover, dysfunction of the AMPK signalling pathway is involved in the genesis and development of various cardiovascular diseases, including atherosclerosis, hypertension and stroke. The roles of AMPK in the cardiovascular system, as they are currently understood, will be presented in this review. The interaction between AMPK and other cardiovascular signalling pathways such as nitric oxide signalling is also discussed.     

Kisspeptin在女性生殖内分泌和辅助生殖技术中的研究进展

近年来研究显示,kisspeptin在大脑的性别分化、性激素正负反馈调节、青春期始动以及机体能量信号转导等生理过程中起到重要作用,表明kisspeptin可能是女性生殖功能成熟及调控的一个关键性信号因子。除下丘脑分泌的kisspeptin之外,生殖器官局部表达的kisspeptin在机体正常生殖过程中的作用也不断得到证实。研究表明,很多生殖内分泌疾病,如单纯性促性腺激素分泌不足的性腺机能减退症(isolated hypogonadotropic hypogonadism, IHH)、多囊卵巢综合征(polycystic ovary syndrome, PCOS)、卵巢早衰(premature ovarian failure, POF)、病理性高泌乳素血症等,都与kisspeptin的异常表达有关。通过给予外源性kisspeptin可解决辅助生殖技术应用中的一些问题。本文主要就kisspeptin在女性生殖内分泌尤其是在辅助生殖领域研究中所取得的进展进行论述。     

Expression profiling of liver receptor homologue 1 (LRH-1) in mouse tissues using tissue microarray

Liver receptor homologue 1 (LRH-1) is a nuclear receptor that plays important roles in lipid homeostasis and embryogenesis. To elucidate systemic physiological functions of LRH-1, we used tissue microarray-based immunohistochemistry to examine the tissue distribution and localization of LRH-1 in adult mouse tissues. LRH-1 immunoreactivity was observed in the nucleus of multiple epithelial lineage cells in the digestive system (including absorptive epithelial cells in the small and large intestines, goblet cells, acinar cells of the exocrine glands, chief cells and mucus neck cells in the stomach, granular and prickle layer cells in the tongue and forestomach, and gall bladder epithelium); respiratory system (alveolar type II cells); and urinary system (transitional epithelium). Nuclear LRH-1 immunoreactivity was also localized in cells involved in fatty acid/glucose metabolism, including hepatocytes, brown adipocytes, and cardiomyocytes, and neurons involved in the regulation of food intake, including the arcuate nucleus in the hypothalamus and paraventricular nucleus of thalamus. Additionally, LRH-1 immunoreactivity was observed in testicular Leydig cells and ovarian follicular cells. These data suggest that LRH-1 functions in multiple organ systems to regulate epithelial cell physiology and differentiation, energy metabolism, and reproduction. Electronic Supplementary Material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

AMP-activated protein kinase--the key role in metabolic regulation

AMP-activated protein kinase (AMPK) is the central component of a protein kinase cascade that acts as an energy sensor maintaining the energy balance at the cellular as well as at the whole body level. Within the healthy cell, metabolic stress leading to an increase in AMP concentration results in AMPK activation. Once activated, AMPK "switches off" many anabolic pathways e.g. fatty acid and protein synthesis while "switches on" catabolic pathways such as fatty acid oxidation or glycolysis which serve to restore intracellular ATP level. Adipocyte derived hormones leptin and adiponectin activate AMPK in peripheral tissues increasing energy expenditure. AMPK also regulates food intake due to response to hormonal and nutrient signals in hypothalamus. Antidiabetic drugs that mimic the action of insulin activate the AMPK signaling pathways. Further studies are needed to clarify the importance of the AMPK activation for therapeutic effects of this drugs.     

Exercise in rats does not alter hypothalamic AMP-activated protein kinase activity

Recent studies have demonstrated that AMP-activated protein kinase (AMPK) in the hypothalamus is involved in the regulation of food intake. Because exercise is known to influence appetite and cause substrate depletion, it may also influence AMPK in the hypothalamus. Male rats that either rested or ran for 30 or 60 min on a treadmill (22 m/min, 10% slope) were sacrificed immediately after exercise or after 60 min recovery either in the fasted state or after oral gavage with glucose (3g/kg body weight). Exercise decreased muscle and liver glycogen substantially. Hypothalamic total or alpha2-associated AMPK activity and phosphorylation state of the AMPK substrate acetyl-CoA carboxylase were not changed significantly immediately following treadmill running or during fed or fasted recovery. Plasma ghrelin increased (P<0.05) by 40% during exercise whereas the concentration of PYY was unchanged. In recovery, glucose feeding increased plasma glucose and insulin concentrations whereas ghrelin and PYY decreased to (ghrelin) or below (PPY) resting levels. It is concluded that 1h of strenuous exercise in rats does not elicit significant changes in hypothalamic AMPK activity despite an increase in plasma ghrelin. Thus, changes in energy metabolism during or after exercise are likely not coordinated by changes in hypothalamic AMPK activity.     

Cross-talk between estrogen and leptin signaling in the hypothalamus

Obesity, characterized by enhanced food intake (hyperphagia) and reduced energy expenditure that results in the accumulation of body fat, is a major risk factor for various diseases, including diabetes, cardiovascular disease, and cancer. In the United States, more than half of adults are overweight, and this number continues to increase. The adipocyte-secreted hormone leptin and its downstream signaling mediators play crucial roles in the regulation of energy balance. Leptin decreases feeding while increasing energy expenditure and permitting energy-intensive neuroendocrine processes, such as reproduction. Thus, leptin also modulates the neuroendocrine reproductive axis. The gonadal steroid hormone estrogen plays a central role in the regulation of reproduction and also contributes to the regulation of energy balance. Estrogen deficiency promotes feeding and weight gain, and estrogen facilitates, and to some extent mimics, some actions of leptin. In this review, we examine the functions of estrogen and leptin in the brain, with a focus on mechanisms by which leptin and estrogen cooperate in the regulation of energy homeostasis.     

瘦蛋白对繁殖性能的影响

肥胖基因的产物－瘦蛋白可通过下丘脑或直接作用于卵巢,对动物的青春期发育、生殖器的发育以及性激素的分泌都有重要的调节作用。本拟对瘦蛋白的作用机制及其对繁殖功能的影响作一综述。     

Leptin: a possible link between food intake, energy expenditure, and reproductive function

Several regulatory substances participate in the regulation of both food intake/energy metabolism and reproduction in mammals. Most of these neuropeptides originate and act in the central nervous system, mainly at specific hypothalamic areas. Leptin represents a signal integrating all these functions, but originating from the periphery (adipose tissue) and carrying information mainly to central structures. Observations in rodent models of leptin deficiency have suggested that leptin participates in the control of reproduction, in conjunction with that of food intake and energy expenditure. Indeed, leptin administration resulted in the restoration of normal body weight, food intake, and fertility in the ob mouse, lacking circulating leptin. Specific targets of leptin in the hypothalamus are neurons expressing neuropeptide Y, proopiomelanocortin and gonadotropin-releasing hormone, but the presence of leptin receptors in peripheral reproductive structures suggests that leptin might also act at these sites. Human obesity is often associated with reproductive disturbances. The situation in humans is more complex than in the animal models of leptin deficit and the presence of leptin resistance in these subjects is suggested. In conclusion, leptin fits many requirements for a molecule linking the regulation of energy balance and the control of reproduction.     

Central Exercise Action Increases the AMPK and mTOR Response to Leptin

AMP-activated protein kinase (AMPK) and mammalian Target of Rapamycin (mTOR) are key regulators of cellular energy balance and of the effects of leptin on food intake. Acute exercise is associated with increased sensitivity to the effects of leptin on food intake in an IL-6-dependent manner. To determine whether exercise ameliorates the AMPK and mTOR response to leptin in the hypothalamus in an IL-6-dependent manner, rats performed two 3-h exercise bouts, separated by one 45-min rest period. Intracerebroventricular IL-6 infusion reduced food intake and pretreatment with AMPK activators and mTOR inhibitor prevented IL-6-induced anorexia. Activators of AMPK and fasting increased food intake in control rats to a greater extent than that observed in exercised ones, whereas inhibitor of AMPK had the opposite effect. Furthermore, the reduction of AMPK and ACC phosphorylation and increase in phosphorylation of proteins involved in mTOR signal transduction, observed in the hypothalamus after leptin infusion, were more pronounced in both lean and diet-induced obesity rats after acute exercise. Treatment with leptin reduced food intake in exercised rats that were pretreated with vehicle, although no increase in responsiveness to leptin-induced anorexia after pretreatment with anti-IL6 antibody, AICAR or Rapamycin was detected. Thus, the effects of leptin on the AMPK/mTOR pathway, potentiated by acute exercise, may contribute to appetite suppressive actions in the hypothalamus.     

Olanzapine-induced hyperphagia and weight gain associate with orexigenic hypothalamic neuropeptide signaling without concomitant AMPK phosphorylation

The success of antipsychotic drug treatment in patients with schizophrenia is limited by the propensity of these drugs to induce hyperphagia, weight gain and other metabolic disturbances, particularly evident for olanzapine and clozapine. However, the molecular mechanisms involved in antipsychotic-induced hyperphagia remain unclear. Here, we investigate the effect of olanzapine administration on the regulation of hypothalamic mechanisms controlling food intake, namely neuropeptide expression and AMP-activated protein kinase (AMPK) phosphorylation in rats. Our results show that subchronic exposure to olanzapine upregulates neuropeptide Y (NPY) and agouti related protein (AgRP) and downregulates proopiomelanocortin (POMC) in the arcuate nucleus of the hypothalamus (ARC). This effect was evident both in rats fed ad libitum and in pair-fed rats. Of note, despite weight gain and increased expression of orexigenic neuropeptides, subchronic administration of olanzapine decreased AMPK phosphorylation levels. This reduction in AMPK was not observed after acute administration of either olanzapine or clozapine. Overall, our data suggest that olanzapine-induced hyperphagia is mediated through appropriate changes in hypothalamic neuropeptides, and that this effect does not require concomitant AMPK activation. Our data shed new light on the hypothalamic mechanism underlying antipsychotic-induced hyperphagia and weight gain, and provide the basis for alternative targets to control energy balance.     

瘦蛋白对摄食和能量平衡的调节及其在哺乳动物冬眠中的作用

白色脂肪合成和分泌的瘦蛋白(leptin)作用于下丘脑和外周的代谢产热器官,对摄食和能量平衡起调节作用。摄食和能量平衡的失调,如瘦蛋白抵抗,可以导致肥胖等一系列生理疾病。以体内贮存的脂肪为主要能源物质越冬的冬眠哺乳动物,体重的年周期波动幅度巨大,其摄食和能量平衡调节机制可能不同于一般的非冬眠物种,育肥阶段可能存在瘦蛋白抵抗机制。本文总结了瘦蛋白调节摄食和能量平衡的作用机制以及瘦蛋白对冬眠哺乳动物育肥和冬眠的影响,为进一步研究冬眠哺乳动物的能量平衡提供参考。     

The effect of nutrition on the seasonality of reproduction in ewes

The beneficial effects of nutrition on reproduction in sheep have been described, particularly on ovulation rate. However, the relationships between nutrition and reproductive seasonality are not well known. This review will deal with the effects of body fat or food intake on sexual and hypothalamic/pituitary activity in sheep, mainly focused on Mediterranean genotypes. Although only severe malnutrition can significantly extend the length of the seasonal anestrous period, the level of fat reserves can play a significant role on reproductive seasonality delaying the onset of seasonal anoestrus, particularly on the Mediterranean environment. The effect of overfeeding on LH secretion has also been reported, specially at short term. Several experimental approaches have elucidated that both high body fat and food intake are able to modify the sensitivity of the hypothalamus to oestradiol negative feedback during seasonal anoestrus, with those effects being associated to a reduced amount of NPY mRNA and to an increase of plasma insulin, glucose and leptin concentrations, particularly in the late scenario. However, the highest receptivity to nutritional stimulation in terms of increasing LH occurs when ewes are subjected to a photoperiodic state of early anoestrus or late breeding season rather than under a photoperiod characteristic of the end of anoestrus or the beginning of the breeding season.