AMPK 作为激素信号的调节剂

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AMPK as a mediator of hormonal signalling

Abstract

摘要

AMP-activated protein kinase (AMPK) is a key molecular player in energy homeostasis at both cellular and whole-body levels. AMPK has been shown to mediate the metabolic effects of hormones such as leptin, ghrelin, adiponectin, glucocorticoids and insulin as well as cannabinoids. Generally, activated AMPK stimulates catabolic pathways (glycolysis, fatty acid oxidation and mitochondrial biogenesis) and inhibits anabolic pathways (gluconeogenesis, glycogen, fatty acid and protein synthesis), and has a direct appetite-regulating effect in the hypothalamus. Drugs that activate AMPK, namely metformin and thiazolidinediones, are often used to treat metabolic disorders. Thus, AMPK is now recognised as a potential target for the treatment of obesity and associated co-morbidities.

在细胞和整个身体的能量平衡中,AMP活化蛋白激酶是一个关键的分子参与者。已有研究表明,AMPK 介导瘦素、饥饿素、脂联素、糖皮质激素、胰岛素和大麻素等激素的代谢作用。一般来说,活化的 AMPK 能刺激分解代谢途径(糖酵解、脂肪酸氧化和线粒体生物合成) ,抑制合成代谢途径(糖异生、糖原、脂肪酸和蛋白质合成) ,在下丘脑有直接的食欲调节作用。激活 AMPK 的药物,即二甲双胍和噻唑烷二酮,通常用于治疗代谢性疾病。因此,AMPK 现在被认为是治疗肥胖和相关合并症的潜在目标。Keywords: 关键词:

Introduction

引言

AMP-activated protein kinase (AMPK) has emerged as a key molecular player in energy homeostasis at both cellular and whole-body levels (Kahn et al. 2005). Initially, AMPK was shown to have lipid-related effects: it inactivates acetyl-CoA carboxylase (ACC; Carlson & Kim 1973) and 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase (Beg et al. 1973), the key regulatory enzymes of fatty acid and cholesterol synthesis. Later, the role of AMPK in carbohydrate and protein metabolism, cell cycle regulation and mitochondrial biogenesis was also described. AMPK is an evolutionarily conserved serine/threonine kinase with a catalytic α-subunit and regulatory β- and γ-subunits, forming a heterotrimeric complex. The upstream regulation of AMPK is summarised in Figs 1 and 2.

在细胞和整个身体水平上,AMPK AMP活化蛋白激酶已经成为能量稳态的关键分子参与者。最初,AMPK 被证明具有与脂类相关的作用: 它可以使乙酰辅酶A羧化酶和3- 羟基 -3- 甲基戊二酰辅酶 a 还原酶失活,这两种酶是脂肪酸和胆固醇合成的关键调节酶。后来,AMPK 的作用,碳水化合物和蛋白质代谢,细胞周期调节和线粒体生物发生也被描述。AMPK 是一个进化上保守的丝氨酸/苏氨酸激酶,具有催化亚基和调节亚基,形成异三聚体复合体。AMPK 的上游调节在图1和图2中概述。

Figure 1
Figure 1 图1
Figure 2
Figure 2 图2

Role of AMPK in the central control of appetite

AMPK 在食欲中枢调控中的作用

AMPK is expressed throughout the brain: all isoforms are expressed in neuronal tissues including areas that are involved in the control of food intake and neuroendocrine function, such as the hypothalamus and the hindbrain (Turnley et al. 1999Kola 2008). In the last 5 years, AMPK has emerged as a nutrient and glucose sensor in the hypothalamus (Momcilovic et al. 2006). Hypothalamic AMPK activity is increased during fasting and decreased during refeeding (Minokoshi et al. 2004). Pharmacological activation of AMPK in the rodent hypothalamus with 5-aminoimidazole-4-carboxamide riboside (AICAR) causes an increase in food intake (Xue & Kahn 2006). Alteration in ventromedial hypothalamic AMPK activity with recombinant adenoviruses expressing dominant negative (DN) or constitutively active (CA) AMPK-α1/α2 subunit (Minokoshi et al. 2004) changed body weight and food intake. DN-AMPK adenovirus-treated mice ate less and had lower body weight compared with control mice. DN-AMPK mice also had decreased neuropeptide Y (NPY) and agouti-related peptide (AgRP) mRNA levels in the arcuate nucleus (ARC) under ad libitum fed conditions. In contrast, CA-AMPK adenovirus-treated mice ate significantly more and had higher body weight with increased expression of NPY and AgRP mRNA in ARC, as well as increased orexigenic melanin-concentrating hormone expression in lateral hypothalamus. This suggests that high AMPK activity enhances orexigenic signals, whereas low AMPK activity suppresses these signals under ad libitum fed conditions. In agreement with this, deletion of AMPKα2 in AgRP neurons led to the development of an age-dependent lean phenotype.

AMPK 在整个大脑中都有表达: 所有的亚型都在神经组织中表达,包括控制食物摄入和神经内分泌功能的区域,如下丘脑和后脑(Turnley et al. 1999,科拉半岛2008)。在过去的5年中,AMPK 已经作为一种营养和葡萄糖传感器出现在下丘脑(Momcilovic 等人2006年)。下丘脑 AMPK 活性在禁食期间增加,在再喂食期间降低(Minokoshi 等人,2004年)。5- 氨基咪唑 -4- 羧酰胺核苷(AICAR)对大鼠下丘脑 AMPK 的药理活化导致进食量增加(薛康2006)。表达显性阴性(DN)或持续活性(CA) AMPK-1/2亚基的重组腺病毒(Minokoshi et al. 2004)对下丘脑腹内侧核 AMPK 活性的影响改变了体重和食物摄入量。与对照组小鼠相比,经 DN-AMPK 腺病毒处理的小鼠进食量减少,体重降低。DN-AMPK 小鼠弓状核(ARC)神经肽 y (NPY)和豚鼠相关肽(AgRP) mRNA 水平在自由饮食条件下也明显降低。相比之下,CA-AMPK 腺病毒治疗的小鼠进食量明显增加,体重增加,ARC 中 NPY 和 AgRP mRNA 的表达增加,下视丘外核中产生食欲的黑色素浓缩激素的表达增加。这表明,高 AMPK 活性增强了食欲信号,而低 AMPK 活性抑制这些信号在自由采食条件下。与此一致的是,AgRP 神经元中 ampk 2的缺失导致了年龄依赖性的瘦表型的形成。

Peripheral hormones from the gastrointestinal tract (peptide YY, ghrelin, cholecystokinin, glucagon-like peptide 1 (GLP-1) and oxyntomodulin) and adipose tissue (leptin, resistin and adiponectin) are important in influencing the activity of the appetite-regulating neuronal populations in the hypothalamus. In addition, a number of these hormones have been shown to influence AMPK activity. In the short term, anorectic agents such as glucose, GLP-1 and oxyntomodulin decrease hypothalamic AMPK activity (Andersson et al. 2004Minokoshi et al. 2004Seo et al. 2008), leading to reduction in food intake during satiation, while orexigenic agents such as ghrelin lead to AMPK activation and increased food intake (Andersson et al. 2004Kola et al. 2005). In the long term, the circulating anorectic insulin and leptin determine the energy and adiposity profile.

来自肠粘膜的外周激素(肽 YY,ghrelin,胆囊收缩素,胰高血糖素样肽1(GLP-1)和氧化调节蛋白)和脂肪组织(瘦素,抵抗素和脂联素)在影响下丘脑调节食欲神经元群的活动中起重要作用。此外,一些这些激素已被证明影响 AMPK 活性。在短期内,厌食剂,如葡萄糖,GLP-1和氧化调节蛋白降低下丘脑 AMPK 活性(Andersson et al. 2004,Minokoshi et al. 2004,Seo et al. 2008) ,导致饱食期间食物摄入量的减少,而食欲刺激剂,如 ghrelin 导致 AMPK 活化和食物摄入量的增加(Andersson et al. 2004,科拉半岛 et al. 2005)。从长远来看,循环缺乏胰岛素和瘦素决定了能量和肥胖程度。

The hypothalamus is not the only location in the brain important for appetite regulation. Emerging data suggest that the nucleus tractus solitarius (NTS) in the hindbrain also has an important role. Fasting increases AMPK activity in the NTS and leptin inhibits it (Hayes et al. 2009a). Ghrelin is known to activate neurons in the NTS (Date et al. 2006). GLP-1 (7–36) amide, an anorectic hormone, acts both in the hypothalamus and the NTS (Goldstone et al. 2000Seo et al. 2008Hayes et al. 2009b).

下丘脑并不是大脑中调节食欲的唯一重要部位。新的研究数据表明,后脑孤束核(NTS)也有重要作用。禁食增加 NTS 中的 AMPK 活性,而瘦素抑制其活性(Hayes 等人,2009a)。已知 Ghrelin 可激活 NTS 的神经元(Date 等人,2006年)。GLP-1(7-36)酰胺,一种厌食性激素,作用于下丘脑和 NTS (Goldstone et al. 2000,Seo et al. 2008,Hayes et al. 2009b)。

Role of AMPK in peripheral tissues

AMPK 在外周组织中的作用

AMPK is ubiquitously expressed and plays an important role in the peripheral metabolism of the skeletal muscle, liver, fat, myocardium and other tissues. In general, activated AMPK switches on catabolic processes that produce ATP and switches off ATP-consuming processes, thus restoring the AMP:ATP ratio.

腺苷酸活化蛋白激酶(AMPK)广泛表达,在骨骼肌、肝脏、脂肪、心肌等组织的外周代谢中起重要作用。一般来说,激活 AMPK 开关分解代谢过程中产生三磷酸腺苷和关闭 ATP 消耗过程,从而恢复腺苷: 三磷酸腺苷的比例。

AMPK plays a key role in regulating lipid metabolism. Activated AMPK phosphorylates and inhibits ACC1 and HMG-CoA, decreases fatty acid synthase (FAS) expression and activates malonyl-CoA carboxylase, thereby leading to a decrease in fatty acid and cholesterol synthesis (Woods et al. 2000Kahn et al. 2005Lopez et al. 2007). Activated AMPK stimulates fatty acid oxidation by decreasing malonyl-CoA levels through the inhibition of ACC2 (Merrill et al. 1997Kahn et al. 2005Lopez et al. 2007). This leads to an increase in carnitine palmitoyltransferase 1 (CPT1) activity and the subsequent activation of fatty acid oxidation (Kahn et al. 2005Lopez et al. 2007). The decreased AMPK activity in visceral fat could enhance lipolysis as well as lipogenesis, although the effect on lipogenesis prevails (Divertie et al. 1991Djurhuus et al. 2002). AMPK thus plays a key role in regulating lipid metabolism. AMPK has been suggested to inhibit catecholamine-stimulated lipolysis in adipocytes (Corton et al. 1995Daval et al. 2005), thus lowering the plasma level of fatty acids. Activated AMPK also stimulates and upregulates the expression of peroxisome proliferator-activated receptor-γ coactivator-1α, which consequently increases mitochondrial biogenesis (Terada et al. 2002Zong et al. 2002).

AMPK 在调节脂质代谢中起着关键作用。活化 AMPK 使 ACC1和 HMG-CoA 磷酸化并抑制其表达,降低 FAS 表达并激活丙二酰辅酶 a 羧化酶,从而导致脂肪酸和胆固醇合成减少(Woods 等人,Kahn 等人,2005年,Lopez 等人,2007年)。激活 AMPK 刺激脂肪酸氧化通过减少丙二酰辅酶 a 水平通过抑制 ACC2(Merrill 等人1997年,Kahn 等人2005年,洛佩兹等人2007年)。这导致增加肉碱棕榈酰转移酶1(CPT1)活性和随后激活脂肪酸氧化(卡恩等人2005年,洛佩兹等人2007年)。内脏脂肪中 AMPK 活性的降低可以促进脂肪分解和脂肪形成,虽然对脂肪形成的影响较为普遍(Divertie 等人1991年,Djurhuus 等人2002年)。因此 AMPK 在调节脂质代谢中起着关键作用。AMPK 被认为可以抑制儿茶酚胺刺激脂肪细胞的脂解作用(Corton et al. 1995,Daval et al. 2005) ,从而降低血浆脂肪酸水平。激活的 AMPK 还刺激和上调过氧化物酶体增殖物激活的受体辅激活因子 -1的表达,从而增加线粒体的生物发生(Terada 等人,2002年 Zong 等人,2002年)。

AMPK also regulates glucose homeostasis. Activation of AMPK by contraction in fast-twitching muscles increases hexokinase II expression (Holmes et al. 1999), and enhances glucose uptake through the translocation of glucose transporter 4 (GLUT4) to the cell membrane and the upregulation of Glut4 gene expression (Holmes et al. 1999Derave et al. 2000Wright et al. 2005). Interestingly, these effects were not observed in slow-twitching soleus muscle (Derave et al. 2000Wright et al. 2005).

AMPK 还调节葡萄糖内环境稳态。通过快速抽搐的肌肉收缩激活 AMPK 增加己糖激酶 II 的表达(Holmes 等人1999年) ,并通过葡萄糖转运子4(GLUT4)移位到细胞膜和 GLUT4基因表达上调提高葡萄糖的摄取(Holmes 等人1999年,Derave 等人2000年,Wright 等人2005年)。有趣的是,这些影响在缓慢抽搐的比目鱼肌中没有观察到(Derave 等人2000,Wright 等人2005)。

AMPK regulates hepatic gluconeogenesis by inhibiting the transcription of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase; Lochhead et al. 2000Cool et al. 2006). AMPKα2-knockout (KO) and LKB1-KO mice were shown to have glucose intolerance and fasting-induced hyperglycaemia, possibly caused by increased gluconeogenesis associated with increased PEPCK and G6Pase activity (Lochhead et al. 2000Cool et al. 2006). Activated AMPK in skeletal muscle phosphorylates and inhibits glycogen synthase, thereby leading to a decrease in glycogen synthesis (Wojtaszewski et al. 2002).

AMPK 通过抑制磷酸烯醇丙酮酸羧化激酶蛋白酶(PEPCK)和葡萄糖 -6- 磷酸酶(G6Pase; Lochhead et al. 2000,Cool et al. 2006)的转录调节肝糖异生。Ampk 2-knockout (KO)和 lkb1-KO 小鼠被证明有葡萄糖耐受不良和空腹诱导的高血糖,可能是由于增加了与 PEPCK 和 G6Pase 活性增加有关的糖异生作用(Lochhead et al. 2000,Cool et al. 2006)。活化 AMPK 在骨骼肌磷酸化和抑制糖原合成酶,从而导致减少糖原合成(Wojtaszewski 等。2002年)。

Hypothalamic AMPK has been linked to the regulation of peripheral metabolism, suggesting that AMPK is a key enzyme in coordinating the interaction between peripheral and central energy regulation. Central AICAR treatment has been shown to increase both insulin-mediated and non-insulin-mediated glycogen synthesis (Perrin et al. 2004), thus implicating the role of hypothalamic AMPK in regulating muscle glycogen synthesis. Central insulin infusion also increased muscle glycogen synthesis and this effect was blocked by the co-administration of glucose, possibly mediated by AMPK (Perrin et al. 2004). Central adiponectin treatment leads to hypothalamic AMPK activation and decreases energy expenditure, possibly via a reduced expression of uncoupling protein-1 (UCP-1) in brown adipose tissue (Kubota et al. 2007). Central α-lipoic acid, which inhibits hypothalamic AMPK activity, increases UCP-1 expression and energy expenditure in brown adipose tissue (Kim et al. 2004b). Central ghrelin treatment, independently from the effect on food intake, has been shown to increase glucose utilisation rate of white and brown adipose tissues and counteract the effects of intracerebroventricular leptin treatment on fat weight, plasma glucose and insulin (Kim et al. 2004aTheander-Carrillo et al. 2006).

下丘脑 AMPK 与外周代谢调节有关,提示 AMPK 是协调外周和中枢能量调节相互作用的关键酶。中央 AICAR 治疗已被证明增加胰岛素介导和非胰岛素介导的糖原合成(佩兰等人2004年) ,因此牵连的作用下丘脑 AMPK 调节肌肉糖原合成。中枢胰岛素输注也增加了肌肉糖原的合成,这种效应被共同管理的葡萄糖,可能介导 AMPK (佩兰等人。2004年)。中央脂联素治疗导致下丘脑 AMPK 激活和减少能量消耗,可能通过减少表达解偶联蛋白1(UCP-1)的褐色脂肪组织。中枢硫辛酸,抑制下丘脑 AMPK 活性,增加褐色脂肪组织的 UCP-1表达和能量消耗。中央胃促生长素治疗,独立于对食物摄入的影响,已被证明可提高白色和棕色脂肪组织的葡萄糖利用率,并抵消侧脑室内瘦素治疗对脂肪重量、血糖和胰岛素的影响(Kim 等人,2004a,Theander-Carrillo 等人,2006年)。

Role of AMPK as mediator of hormonal signals

AMPK 在激素信号调节中的作用

Intriguingly, several hormones have tissue-specific, often opposite, effects on AMPK activity (Fig. 3).

有趣的是,几种激素对 AMPK 活性有组织特异性的影响,通常相反(图3)。

Figure 3
Figure 3 图3

Leptin

瘦素

Leptin increases AMPK activity in the skeletal muscle directly as well as indirectly through stimulation of the hypothalamo-sympathetic axis (Minokoshi et al. 2002). Chronic s.c. administration of leptin also increases the expression of AMPK in skeletal muscle (Steinberg et al. 2003). Leptin- or leptin receptor-deficient rodents showed a decreased AMPK activity in the liver (Yu et al. 2004). In lean animals, leptin has been shown to attenuate hepatic glucose production and insulin resistance under normal conditions and to slightly increase AMPK activity (Brabant et al. 2005). However, these effects are lost in diet-induced obese rats, thereby suggesting an important physiological dysregulation of leptin effects in obese animals. Leptin inhibits triacylglycerol storage and stimulates fatty acid oxidation in the heart, and both AMPK-dependent (Lee et al. 2004) and AMPK-independent (Atkinson et al. 2002) pathways have been suggested.

瘦素直接或间接地通过刺激下丘脑交感轴增加骨骼肌中的 AMPK 活性(Minokoshi 等人,2002年)。瘦素的长期给药也增加骨骼肌中 AMPK 的表达(Steinberg 等人,2003年)。瘦素或瘦素受体缺乏的啮齿动物在肝脏中表现出 AMPK 活性的下降(Yu 等人,2004年)。在瘦肉动物中,瘦素已被证明在正常条件下能够减弱肝脏葡萄糖的产生和胰岛素抵抗,并且能够轻微增加 AMPK 活性(Brabant 等人,2005年)。然而,这些效应在饮食诱导的肥胖大鼠中消失了,因此提示肥胖动物瘦素效应的重要生理调节失调。瘦素抑制甘油三酯储存和刺激心脏中脂肪酸氧化,并且两者依赖于 ampk (Lee 等人,2004年)和 ampk 独立(Atkinson 等人,2002年)的通路已经被提出。

Central injection of leptin into ventromedial hypothalamus (VMH) of rats has been shown to increase glucose uptake in the heart, brown adipose tissue and skeletal muscle, but not in white adipose tissue (Kamohara et al. 1997Haque et al. 1999Minokoshi et al. 1999). Central infusion of leptin decreases hepatic glycogen content (Kamohara et al. 1997Haque et al. 1999).

中央注射瘦素到大鼠的腹内侧下丘脑(VMH)已被证明可以增加心脏、褐色脂肪组织和骨骼肌的葡萄糖摄取,但是在白色脂肪组织没有(Kamohara 等人1997,Haque 等人1999,Minokoshi 等人1999)。中枢灌注瘦素降低肝糖原含量(Kamohara 等人1997,Haque 等人1999)。

In the hypothalamus, leptin has an opposite effect: it decreases AMPK activity in the ARC and paraventricular (PVC) nuclei (Minokoshi et al. 20022004Andersson et al. 2004Mountjoy et al. 2007). By reducing the appetite centrally and increasing the peripheral fatty acid consumption, these tissue-specific effects of leptin lead to an overall negative energy balance and reduction in body weight.

在下丘脑,瘦素有相反的作用: 它降低 ARC 和室旁核(PVC)中的 AMPK 活性(Minokoshi 等人,2002,2004,Andersson 等人,Mountjoy 等人,2007)。瘦素通过集中降低食欲和增加外周脂肪酸的消耗,这些组织特异性作用导致整体负能量平衡和体重下降。

Adiponectin

脂联素

Adiponectin activates and stimulates liver and muscle AMPK activity in vivo and in vitro, leading to stimulation of glucose uptake, fatty acid oxidation and PEPCK (Yamauchi et al. 2002). These lead to an improvement in insulin sensitivity. Globular adiponectin was also shown to activate AMPK in primary rat adipocytes (Tomas et al. 2002Yamauchi et al. 2002Wu et al. 2003Huypens et al. 2005).

在体内和体外,脂联素激活和刺激肝脏和肌肉中的 AMPK 活性,导致刺激葡萄糖摄取、脂肪酸氧化和 PEPCK (Yamauchi 等人,2002年)。这些导致胰岛素敏感性的改善。球状脂联素也能激活原代大鼠脂肪细胞中的 AMPK (Tomas 等人,2002,Yamauchi 等人,Wu 等人,2003,Huypens 等人,2005)。

Adiponectin protects the heart from ischaemic injury via AMPK- and cyclooxgenase-2-dependent mechanisms (Shibata et al. 2005). Adiponectin is also suggested to play a beneficial role in cardiac remodelling through multiple mechanisms, one of which is possibly via the activation of AMPK (Liao et al. 2005Shibata et al. 2005). Impaired regulation of AMPK and glucose metabolism in adiponectin-deficient mice result in the development of heart failure (Liao et al. 2005). In endothelial cells, adiponectin stimulates nitric oxide production via AMPK activation, leading to beneficial vasoprotective effects (Chen et al. 2003).

脂联素通过 AMPK 和环氧化酶 -2依赖机制保护心脏免受缺血性损伤(Shibata 等人,2005年)。脂联素也被认为通过多种机制在心脏重构中发挥有益的作用,其中一种可能是通过 AMPK 的激活(Liao 等人,2005年,Shibata 等人,2005年)。在脂联素缺乏的小鼠中,AMPK 和葡萄糖代谢的调节受损导致心力衰竭的发生(廖等人,2005年)。在内皮细胞中,脂联素通过活化 AMPK 刺激一氧化氮的产生,导致有益的血管保护作用(Chen 等人,2003)。

It has been suggested that adiponectin may be involved in the stimulation of food intake (Kadowaki et al. 2008). Serum and cerebrospinal fluid (CSF) adiponectin concentrations increase under fasting conditions, as does expression of adiponectin receptor-1 in ARC. Central adiponectin administration leads to increased phosphorylation of AMPK and ACC in the hypothalamus (Carling 2005Xue & Kahn 2006Kadowaki et al. 2008). Adiponectin KO mice were shown to have reduced food intake and decreased AMPK activity in ARC (Kadowaki et al. 2008). Thus, unlike leptin, adiponectin stimulates both central and peripheral AMPK activity. Adiponectin-transgenic ob/ob mice, which have serum adiponectin levels two- to threefold higher than ob/ob mice, have significantly higher body weight, but an improved metabolic state compared with ob/ob mice (Kim et al. 2007). Adiponectin is considered a starvation hormone: under fasting conditions, high adiponectin levels stimulate central and peripheral AMPK leading to increased food intake and decreased energy expenditure, promoting fat storage. After refeeding, adiponectin levels would fall with a consequent decrease in AMPK activity leading to reduced food intake and an increase in energy expenditure.

有人提出,脂联素可能参与刺激食物摄入(Kadowaki 等人,2008年)。血清和脑脊液中的脂联素浓度在禁食条件下升高,同样在 ARC 中脂联素受体1的表达也升高。中央脂联素管理导致增加磷酸化 AMPK 和 ACC 在下丘脑(Carling 2005,薛 & Kahn 2006,Kadowaki 等人2008年)。脂联素 KO 小鼠在 ARC (Kadowaki 等人,2008年)中表现出食物摄入量减少和 AMPK 活性降低。因此,与瘦素不同,脂联素同时刺激中枢和外周的 AMPK 活性。脂联素转基因 ob/ob 小鼠血清脂联素水平比 ob/ob 小鼠高2ー3倍,体重显著增加,但代谢状态比 ob/ob 小鼠有所改善(Kim 等,2007)。脂联素被认为是一种饥饿激素: 在禁食条件下,高脂联素水平刺激中枢和外周 AMPK,导致增加食物摄入和降低能量消耗,促进脂肪储存。再喂食后,脂联素水平会随着 AMPK 活性的降低而下降,导致食物摄入量减少,能量消耗增加。

Resistin

抵抗素

Resistin is an adipokine secreted in rodents and humans, which generally seems to have opposite effects to those of adiponectin. Resistin induces insulin resistance and stimulates hepatic glucose production. These effects are thought to be mediated by a reduction in liver AMPK activity (Banerjee et al. 2004Muse et al. 2004). It has been shown to decrease fatty acid uptake and oxidation in skeletal muscle via a reduction in the membrane content of fatty acid translocase/CD36, possibly mediated by inhibition of AMPK (Palanivel & Sweeney 2005). Resistin, despite its anorectic effect, has been shown to phosphorylate hypothalamic AMPK and ACC. The consequent inactivation of ACC, after AMPK activation, might represent a physiological compensatory mechanism that prevents deleteriously high levels of malonyl-CoA occurring in the hypothalamus after resistin-induced FAS inhibition in the VMH (Vazquez et al. 2008). Time course-dependent resistin treatments would probably be needed to clarify this issue.

抵抗素是一种由啮齿动物和人类分泌的脂肪细胞因子,与脂联素具有相反的作用。抵抗素诱导胰岛素抵抗并刺激肝细胞产生葡萄糖。这些影响被认为是由于肝脏 AMPK 活性的降低(Banerjee 等人,2004,Muse 等人,2004)。它可能通过抑制 AMPK (Palanivel & Sweeney 2005)介导的脂肪酸转位酶/cd36的膜含量降低,从而减少骨骼肌的脂肪酸摄取和氧化。抵抗素,尽管其厌食作用,已被证明磷酸化的下丘脑 AMPK 和 ACC。AMPK 激活后的 ACC 失活,可能是抵抗素诱导的 FAS 抑制 VMH (Vazquez et al. 2008)后,阻止下丘脑中有害高水平丙二酰辅酶 a 发生的一种生理代偿机制。时程依赖的抵抗素治疗可能需要澄清这个问题。

Ghrelin and cannabinoids

生长素和大麻素

Ghrelin has been shown to regulate AMPK activity in hypothalamus and peripheral tissues (Andersson et al. 2004Kola et al. 2005). Cannabinoids are known to regulate appetite and peripheral metabolism, and AMPK has been shown to mediate these effects (Kola et al. 20052008). Both ghrelin and cannabinoids have similar effects on AMPK activity in various tissues: they stimulate hypothalamic and heart AMPK activity, while inhibit adipose tissue and liver AMPK activity (Kola et al. 20052008).

已经证明 Ghrelin 可以调节下丘脑和外周组织中的 AMPK 活性(Andersson 等人,2004,科拉半岛等人,2005)。大麻素是众所周知的调节食欲和外周代谢的药物,AMPK 已被证明可以调解这些作用(科拉半岛等人2005年2008年)。生长素和大麻素对各种组织中的 AMPK 活性都有类似的作用: 它们刺激下丘脑和心脏的 AMPK 活性,同时抑制脂肪组织和肝脏的 AMPK 活性(科拉半岛等人,2005年,2008年)。

The mechanism of central effect of ghrelin includes the activation of Ca2+ signalling in NPY neurons in the ARC (Kohno et al. 20032008). The Ca2+ rise leads to CAMKK2 activation, which can stimulate hypothalamic AMPK (Anderson et al. 2008Sleeman & Latres 2008). AMPK activation leads to inhibition of malonyl-CoA and stimulation of CPT1, leading to increased mitochondrial oxidation and activation of the UCP-2, which can increase NPY/AgRP neuronal activity and ultimately stimulate appetite (Andrews et al. 2008Lopez et al. 2008).

Ghrelin 的中枢效应机制包括活化 ARC 中 NPY 神经元的 Ca2 + 信号通路。Ca2 + 的上升导致 CAMKK2激活,可以刺激下丘脑 AMPK (Anderson 等人2008,Sleeman & Latres 2008)。AMPK 的激活导致丙二酰辅酶 a 的抑制和 CPT1的刺激,导致 UCP-2的氧化和激活增加,这可以增加 NPY/AgRP 神经元的活性,并最终刺激食欲(Andrews 等人,2008年,Lopez 等人,2008年)。

Endocannabinoids are synthesised locally on demand, and the level in the hypothalamus varies in response to feeding and fasting (Kirkham et al. 2002). The variation in hypothalamic endocannabinoid levels seems to play an important role in mediating the anorectic effects of leptin (Di Marzo et al. 2001) and the orexigenic effects of ghrelin (Kola et al. 2008). Recently, we have shown that the effects of ghrelin on hypothalamic AMPK activity and appetite are abolished in the absence of cannabinoid type 1 receptor (CB1) or in the presence of a CB1 antagonist rimonabant (Kola et al. 2008). These data suggest that an intact cannabinoid-signalling pathway is required for the effects of ghrelin on AMPK activity and appetite. Interestingly, i.p. injection of cannabinoids in rats results in increased plasma ghrelin levels (Zbucki et al. 2008). This suggests that the stimulation of appetite by cannabinoids may be connected to an increase in ghrelin secretion from the gastric X/A-like cells (Zbucki et al. 2008). Further studies are needed to elucidate the details of the ghrelin–cannabinoid interaction.

内源性大麻素是根据需要局部合成的,下丘脑的水平随喂食和禁食而变化(Kirkham 等人,2002年)。下丘脑内源性大麻素水平的变化似乎在介导瘦素的厌食效应(Di Marzo 等人,2001年)和 ghrelin 的促食效应(科拉半岛等人,2008年)中发挥了重要作用。最近,我们已经表明,缺乏大麻素1型受体(CB1)或存在 CB1拮抗剂利莫那班,ghrelin 对下丘脑 AMPK 活性和食欲的影响就会消失(科拉半岛等人,2008年)。这些数据表明,生长素对 AMPK 活性和食欲的影响需要完整的大麻素信号通路。有趣的是,静脉注射大麻素导致大鼠血浆 ghrelin 水平升高(Zbucki et al. 2008)。这表明大麻素对食欲的刺激可能与胃 x/a 样细胞分泌胃饥饿素的增加有关(Zbucki 等人,2008年)。需要进一步研究来阐明生长素与大麻素相互作用的细节。

Insulin

胰岛素

Insulin has a range of metabolic effects in addition to its main role of stimulating glucose uptake into the cells. Centrally, insulin is an anorectic hormone, which has been shown to inhibit hypothalamic AMPK activity (Minokoshi et al. 2004). Insulin deficiency has been proposed as one of the factors causing hypothalamic AMPK activation and the subsequent increase in food intake seen in streptozotocin-induced diabetic rats (Namkoong et al. 2005). In the periphery, insulin inhibits AMPK in fat by activating protein kinase B/Akt complex, which can phosphorylate alphaAMPK at Ser485/491, thus leading to reduced phosphorylation at Thr172 (Kovacic et al. 2003Horman et al. 2006). Insulin inhibits myocardial AMPK activity during ischaemic events alone or when co-administered with glucose, suggesting that the inhibitory effect of insulin on myocardial AMPK activity might be caused by enhanced glucose metabolism (Russell et al. 2004).

胰岛素除了具有刺激细胞摄取葡萄糖的主要作用外,还具有一系列的代谢效应。中枢地说,胰岛素是一种厌食性激素,它已被证明可以抑制下丘脑 AMPK 活性(Minokoshi 等人,2004)。胰岛素缺乏被认为是导致下丘脑 AMPK 激活和随后链脲佐菌素诱导的糖尿病大鼠食物摄入量增加的因素之一(Namkoong 等人,2005年)。在外周,胰岛素通过激活蛋白激酶 B/Akt 复合物抑制脂肪中的 AMPK,该复合物可以在 Ser485/491磷酸化 alphampk,从而减少 Thr172的磷酸化(Kovacic 等人,2003年,Horman 等人,2006年)。胰岛素单独抑制缺血事件期间或与葡萄糖共同给药时心肌 AMPK 活性,提示胰岛素对心肌 AMPK 活性的抑制作用可能是由于葡萄糖代谢增强(Russell 等人,2004年)。

Insulin resistance is characterised by the inability of insulin to increase glucose uptake and repress glucose production in the liver, and it often leads to hyperglycaemia. The role of AMPK in this condition has to be considered. While activated AMPK stimulates catabolic pathways and inhibits the energy-consuming anabolic processes, insulin promotes glycogen, lipid and protein synthesis. However, both upregulate glucose uptake in muscle via an effect of GLUT1 or GLUT4 translocation and increase in GLUT4 transcription (Zheng et al. 2001Barnes et al. 2002). In skeletal muscle, the two pathways also phosphorylate the protein AS160, which has a Rab GTPase-activating protein domain that can increase translocation of GLUT4 to the plasma membrane (Kurth-Kraczek et al. 1999Kramer et al. 2006Treebak et al. 2006). These factors will lead to an increase in glucose uptake, which is an important homeostatic feature of plasma glucose regulation. Furthermore, AMPK activation is thought to upregulate insulin receptor substrate-1 (Harrington et al. 2004Shah et al. 2004Um et al. 2004) through inhibition of the insulin–mammalian target of rapamycin (mTOR) pathway (Fisher et al. 2002Inoki et al. 2003). This will improve the insulin sensitivity profile. Both insulin and activated AMPK repress the expression of the gluconeogenic enzymes PEPCK and G6Pase (Lochhead et al. 2000). Phosphorylation of AMPK is thought to result in translocation of the transcriptional coactivator TORC2 to the cytoplasm (Koo et al. 2005), thus repressing the expression of the TORC2-target enzymes

胰岛素抵抗的特点是胰岛素不能增加葡萄糖的摄取和抑制肝脏中葡萄糖的产生,并且常常导致高血糖。AMPK 在这种情况下的作用必须加以考虑。活化的 AMPK 刺激分解代谢途径,抑制能量消耗的合成代谢过程,胰岛素促进糖原、脂质和蛋白质合成。然而,这两个上调葡萄糖摄取肌肉的作用 GLUT1或 GLUT4易位和增加 GLUT4转录(郑等人2001年,巴恩斯等人2002年)。在骨骼肌中,这两条通路也磷酸化了 AS160蛋白,该蛋白有一个 Rab gtpase 激活蛋白结构域,可以增加 GLUT4向质膜的转运(Kurth-Kraczek 等人,1999年,Kramer 等人,2006年 Treebak 等人,2006年)。这些因素将导致葡萄糖摄取增加,这是血糖调节的一个重要的内稳态特征。此外,AMPK 激活被认为通过抑制胰岛素-哺乳动物雷帕霉素靶蛋白(mTOR)通路上调胰岛素受体底物-1(Harrington 等人,2004年 Shah 等人,2004年 Um 等人,2004年)。这将改善胰岛素的敏感性。胰岛素和活化的 AMPK 都抑制了葡萄糖异生酶 pepcck 和 G6Pase 的表达(Lochhead et al. 2000)。磷酸化的 AMPK 被认为是导致转录辅激活子 TORC2转位到细胞质(Koo et al. 2005) ,从而抑制 TORC2靶酶的表达

Glucagon-like peptide-1

胰高血糖素样肽-1

GLP-1 is produced from pre-proglucagon mRNA, which is expressed in NTS cell bodies in the brainstem, with projections to the PVN and other hypothalamic nuclei involved in the control of feeding (Goldstone et al. 2000). Central nervous system GLP-1 is an endogenous inhibitor of feeding acting via the GLP-1 receptor. Hypothalamic GLP-1 peptide content is decreased during fasting. Fasting-induced increase in hypothalamic AMPK activity is inhibited by GLP-1 and this could be the mechanism of its anorectic effects (Seo et al. 2008). It has been shown that the anorectic effects of leptin are at least partly via GLP-1. GLP-1 acts in both the hypothalamus and the NTS, as GLP-1 receptors located in the NTS are also suggested to regulate food intake (Hayes et al. 2009b).

GLP-1是由前胰高血糖素 mRNA 产生的,该 mRNA 在脑干的 NTS 细胞体中表达,投射到 PVN 和参与控制摄食的其他下丘脑核团(Goldstone 等人,2000年)。中枢神经系统 GLP-1是通过 GLP-1受体起作用的内源性喂养抑制剂。下丘脑 GLP-1肽含量在禁食期间下降。禁食诱导的增加下丘脑 AMPK 活性被 GLP-1抑制,这可能是其厌食效应的机制(Seo 等人,2008年)。研究表明,瘦素的厌食作用至少部分是通过 GLP-1。GLP-1作用于下丘脑和 NTS,因为位于 NTS 的 GLP-1受体也被认为可以调节食物摄入(Hayes 等人,2009b)。

Glucocorticoids

糖皮质激素

Glucocorticoids increase appetite and lead to increased availability of metabolic fuels such as amino acids and fatty acids. Chronic or excessive exposure to glucocorticoids will result in insulin resistance, truncal obesity, hyperlipidaemia and symptoms similar to the metabolic syndrome. We have suggested that AMPK is involved in the central and peripheral effects of glucocorticoids. Glucocorticoids activate hypothalamic AMPK activity in vivo (Christ-Crain et al. 2008) either directly or via stimulation of endocannabinoid synthesis (Di et al. 2005Christ-Crain et al. 2008), and these effects could lead to appetite stimulation (Tataranni et al. 1996). In the periphery, glucocorticoids inhibit AMPK activity in adipose tissue, leading to increased lipogenesis and fat storage (Christ-Crain et al. 2008). Glucocorticoids also inhibited AMPK activity in the heart, which might, at least in part, mediate the detrimental effects of glucocorticoid excess on the heart. Surprisingly, and somewhat unexpectedly, glucocorticoids were shown to stimulate AMPK activity in rat liver in vivo as well as in a liver cell line (Viana et al. 2006Christ-Crain et al. 2008). This could be the result of the balance of local lipolysis, lipid oxidation and the flux of fatty acids into the liver (Foretz et al. 2005). It has been shown that an increase in free fatty acids leads to fatty acid esterification, an energy-demanding process, and this can increase the cellular AMP:ATP ratio and therefore AMPK activity (Gauthier et al. 2008).

糖皮质激素增加食欲,导致增加代谢燃料,如氨基酸和脂肪酸的可用性。长期或过度接触糖皮质激素将导致胰岛素抵抗、躯干肥胖、高脂血症和类似代谢症候群的症状。我们认为 AMPK 参与了糖皮质激素的中枢和外周作用。糖皮质激素在体内激活下丘脑 AMPK 活性(Christ-Crain 等人,2008年)直接或通过刺激内源性大麻素合成(Di 等人,2005年,Christ-Crain 等人,2008年) ,这些效应可导致食欲刺激(Tataranni 等人,1996年)。在外周,糖皮质激素抑制脂肪组织中的 AMPK 活性,导致脂肪生成和脂肪储存增加(Christ-Crain et al. 2008)。糖皮质激素还可以抑制心脏中 AMPK 的活性,至少在一定程度上可以调解糖皮质激素过量对心脏的不利影响。令人惊讶的是,有些出乎意料的是,糖皮质激素被证明在大鼠体内和肝细胞系中刺激 AMPK 活性(Viana 等人,2006,Christ-Crain 等人,2008)。这可能是由于局部脂解、脂质氧化和脂肪酸流入肝脏的平衡(Foretz 等人,2005年)。研究表明,游离脂肪酸的增加导致脂肪酸的酯化,这是一个需要能量的过程,这可以增加细胞的 AMP: ATP 比率,因此 AMPK 活性(Gauthier 等人,2008年)。

Inflammatory mediators and AMPK

炎症介质与 AMPK

Interleukin-6 (IL-6) treatment was shown to increase AMPK phosphorylation in cultured rodent myocytes and adipocytes, as well as in muscle, liver and adipose tissue in vivo (Keller et al. 2001Park et al. 2002Kahn et al. 2005). Moreover, IL-6-KO mice have decreased AMPK activity in muscle (Kelly et al. 2004). Conversely, adiponectin was shown to increase IL-6 production in human synovial fibroblasts partly via AMPK regulation (Tang et al. 2007). Exercise increases AMPK activity in skeletal muscle primarily in response to changes in the AMP:ATP ratio (Ruderman et al. 2006). Exercise affects AMPK activity in fat and liver tissue (Takekoshi et al. 2006) possibly due to an increase in circulating levels of IL-6 (Keller et al. 2001). Furthermore, AMPK activity is often still increased after exercise at times when the energy state of the muscle is presumably no longer altered, and IL-6 is suggested to be involved in AMPK activation during this ‘late-phase’ stage (Ruderman et al. 2006).

白细胞介素 -6(IL-6)治疗显示增加培养的啮齿动物肌细胞和脂肪细胞以及肌肉、肝脏和脂肪组织中的 AMPK 磷酸化(Keller et al. 2001,Park et al. 2002,Kahn et al. 2005)。此外,IL-6-KO 小鼠已降低 AMPK 活性在肌肉(凯利等人,2004年)。相反,脂联素被证明能部分通过调节 AMPK 增加人滑膜成纤维细胞 IL-6的产生(Tang et al. 2007)。运动增加 AMPK 活性的骨骼肌主要是响应的变化,在 AMP: ATP 比率(鲁德曼等人。2006年)。运动影响脂肪和肝组织中的 AMPK 活性(takekshi 等人,2006年) ,可能是由于循环中 IL-6水平的增加(Keller 等人,2001年)。此外,当肌肉的能量状态假设不再改变时,运动后 AMPK 活性往往仍然增加,并且 IL-6被认为参与了 AMPK 在这个‘晚期’阶段的激活(Ruderman 等人,2006年)。

Ciliary neurotrophic factor (CNTF) is a cytokine, which was found to induce severe anorectic effect (Miller et al. 1996), possibly via hypothalamic neurogenesis that leads to sustained reduction in caloric intake and prolonged maintenance of weight loss (Kokoeva et al. 2005). CNTF was shown to activate AMPK through the CNTFRα-IL-6R-gp130β receptor complex and ultimately increasing fatty acid oxidation and reducing insulin resistance in skeletal muscle (Steinberg et al. 2006b). CNTF can also suppress inflammatory signalling cascades associated with lipid accumulation in the liver and skeletal muscle (Febbraio 2007).

CNTF 是一种细胞因子,被发现可以诱导严重的厌食效应(Miller 等人,1996年) ,可能通过下丘脑的神经发生,导致热量摄入的持续减少和体重减轻的长期维持(Kokoeva 等人,2005年)。CNTF 通过 cntfr-il-6r-gp130受体复合物激活 AMPK,并最终增加脂肪酸氧化和降低骨骼肌的胰岛素抵抗(Steinberg 等人,2006b)。CNTF 还可以抑制与肝脏和骨骼肌脂质堆积有关的炎症信号级联反应(Febbraio,2007年)。

The ischaemic heart releases macrophage inhibitory factor (MIF), an upstream regulator of inflammation. MIF stimulates AMPK through CD74 during ischaemia, and shows impaired ischaemic AMPK signalling in the heart of mice with germline deletion of the MIF gene (Miller et al. 2008). MIF promotes glucose uptake and protects the heart during ischaemia–reperfusion injury (Miller et al. 2008). Human fibroblasts with a low-activity MIF promoter polymorphism also have diminished MIF release and AMPK activation during hypoxia, thus linking inflammation with metabolism in the heart (Miller et al. 2008).

缺血性心脏释放巨噬细胞抑制因子(MIF) ,炎症的上游调节因子。MIF 在缺血期间通过 CD74刺激 AMPK,并在缺失 MIF 基因胚系的小鼠心脏中显示受损的缺血性 AMPK 信号(Miller 等人,2008年)。MIF 在缺血-再灌注损伤时促进葡萄糖摄取和保护心脏(Miller 等人,2008年)。具有低活性 MIF 启动子多态性的人成纤维细胞也减少了 MIF 的释放和缺氧时 AMPK 的激活,从而将炎症与心脏的代谢联系起来(Miller 等人,2008年)。

Tumour necrosis factor α (TNFα) signalling via TNF-receptor has been shown to suppress skeletal muscle AMPK activity both in vivo and in vitro(Steinberg et al. 2006a). This happens via upregulation of protein phosphatase 2C transcription, which in turn reduces ACC phosphorylation and fatty acid oxidation as well as increasing diacylglycerol accumulation in the muscle. Suppressive effects of TNFα on AMPK activity, seen in obese mice with pathologically elevated levels of TNFα, could be reversed in null mice for both TNF receptor-1 and -2 or following treatment with a TNFα-neutralising antibody (Steinberg et al. 2006a). This indicates that AMPK is an important target for TNFα signalling.

通过肿瘤坏死因子受体发出的肿瘤坏死因子-α 信号抑制了骨骼肌 AMPK 的活性,无论是在体内还是体外(Steinberg et al. 2006a)。这通过蛋白磷酸酶2C 转录上调发生,这反过来又减少 ACC 磷酸化和脂肪酸氧化,以及增加二酰甘油在肌肉中的积累。TNF 对 AMPK 活性的抑制作用,可以在 TNF 水平高于正常水平的肥胖小鼠中观察到,在 TNF 受体 -1和 -2缺失的小鼠中或者在用 TNF 中和抗体治疗后可以逆转(Steinberg 等人,2006a)。这表明 AMPK 是肿瘤坏死因子信号转导的重要靶点。

Metabolic syndrome and AMPK

代谢症候群和 AMPK

The metabolic abnormalities observed in metabolic syndrome are insulin resistance, hypertriglyceridaemia, abdominal obesity, hypertension, reduced levels of the beneficial high-density lipoprotein and disturbances in glucose metabolism (Trevisan et al. 1998). Patients with metabolic syndrome have higher risks of developing cardiovascular disease (Isomaa et al. 2001) and have higher rates of mortality from all causes (Trevisan et al. 1998). Downstream targets of AMPK such as genes regulating carbohydrate metabolism (e.g. glycogen synthetase, ChREBP) or lipid metabolism (e.g. HMG-CoA, FAS, ACC, SREBP1) play an important role in features of the metabolic syndrome. Therefore, AMPK emerged as a target for treatment of the metabolic syndrome. Two major anti-diabetic drugs that exert effects via the AMPK pathway will be considered in this review: metformin and rosiglitazone.

在代谢症候群中观察到的代谢异常包括胰岛素抵抗、高甘油三酯血症、肚腩赘肉、高血压、有益高密度脂蛋白水平降低以及葡萄糖代谢紊乱。代谢症候群患者患心血管疾病的风险较高(Isomaa 等人,2001年) ,各种原因导致的死亡率也较高(Trevisan 等人,1998年)。AMPK 的下游目标,如调节糖代谢的基因(如糖原合成酶,ChREBP)或脂质代谢的基因(如 HMG-CoA,FAS,ACC,SREBP1)在代谢症候群的特征中起着重要作用。因此,AMPK 成为代谢症候群的治疗靶点。两种主要的抗糖尿病药物,通过 AMPK 途径发挥作用,将在本文中考虑: 二甲双胍和罗格列酮。

Metformin

二甲双胍

Metformin, a biguanide agent, is widely used as an anti-diabetic drug. The biguanide class of anti-diabetic drugs originates from the French lilac (Galega officinalis) plant, known for several centuries to reduce the symptoms of diabetes mellitus (Witters 2001). These were first introduced in 1957 and marketed in France in 1979.

二甲双胍是一种双胍类药物,被广泛用作抗糖尿病药物。双胍类抗糖尿病药物来源于法国的丁香(山羊豆)植物,几个世纪以来众所周知的减轻糖尿病症状(Witters 2001)。这些产品于1957年首次推出,并于1979年在法国上市。

Metformin is shown to stimulate AMPK in the liver and in the muscle (Zhou et al. 2001Zang et al. 2004Shaw et al. 2005). This consequently stimulates glucose uptake in the muscle, induces hepatic fatty acid oxidation and inhibits hepatic glucose production and expression of lipogenic enzymes. Metformin does not activate AMPK directly, but indirectly via inhibition of complex I of the respiratory chain and the consequent increase in AMP:ATP ratio. LKB1 has also been reported to mediate the activation of AMPK in the liver by metformin (Zhou et al. 2001Zang et al. 2004Shaw et al. 2005).

二甲双胍能够刺激肝脏和肌肉中的 AMPK (Zhou 等人,臧等人,2004,Shaw 等人,2005)。因此刺激肌肉对葡萄糖的摄取,引起肝脏脂肪酸氧化,抑制肝脏葡萄糖的产生和脂肪生成酶的表达。二甲双胍不直接激活 AMPK,而是通过抑制呼吸链的复合物 i 和随之增加的 AMP: ATP 比例间接激活 AMPK。LKB1也被报道通过二甲双胍介导 AMPK 在肝脏的激活(Zhou 等人,臧等人,2004,Shaw 等人,2005)。

In contrast, metformin inhibits AMPK in the hypothalamus (Chau-Van et al. 2007). Metformin inhibits low glucose-induced AMPK phosphorylation and NPY mRNA expression. These may explain the anorectic effects of metformin.

相反,二甲双胍抑制 AMPK 在下丘脑(Chau-Van 等人,2007年)。二甲双胍抑制葡萄糖诱导的 AMPK 磷酸化及 NPY mRNA 表达。这些可以解释二甲双胍的无感觉作用。

Metformin is shown to reduce mitochondrial ATP synthesis in the pancreatic β-cell, resulting in impaired glucose responsiveness, inhibition of insulin release and possibly apoptosis (Kefas et al. 2004Leclerc et al. 2004). These findings of metformin are clearly undesired and further studies are needed to reassess the long-term effects of metformin on β-cells.

二甲双胍显示可减少胰腺细胞中线粒体 ATP 的合成,导致葡萄糖反应性受损,抑制胰岛素释放并可能导致细胞凋亡(Kefas 等人,2004年,Leclerc 等人,2004年)。这些发现二甲双胍显然是不希望和进一步的研究需要重新评估的长期效果二甲双胍对细胞。

Rosiglitazone

罗格列酮

Rosiglitazone belongs to a class of anti-diabetic drugs known as thiazolidinediones (TZDs). TZDs are used to reverse insulin resistance and improve glucose tolerance. It is known that TZDs improve insulin sensitivity by activating nuclear PPAR-γ and the consequent regulation of gene transcription. However, it is also believed that TZDs can improve insulin sensitivity via PPAR-γ-independent mechanisms, one of which is AMPK activation (Kahn et al. 2005).

罗格列酮属于噻唑烷二酮类药物。TZDs 用于逆转胰岛素抵抗和提高葡萄糖耐量。TZDs 通过激活细胞核 ppar- 和随之而来的基因转录调控来改善胰岛素敏感性。然而,它也相信 TZDs 可以改善胰岛素敏感性通过 ppar- 独立的机制,其中之一是 AMPK 激活(卡恩等。2005年)。

Rosiglitazone was shown to increase AMPK activity in muscle cell lines (Fryer et al. 2002), and chronic rosiglitazone treatment was reported to restore skeletal muscle AMPKα2 activity in obese, insulin-resistant Zucker rats (Lessard et al. 2006). Rosiglitazone activates AMPK indirectly by inhibiting complex I of the respiratory chain, which consequently leads to an increase in cellular AMP:ATP ratio (El-Mir et al. 2000Owen et al. 2000Brunmair et al. 2004).

罗格列酮显示增加肌肉细胞系中的 AMPK 活性(Fryer 等人,2002年) ,据报道,慢性罗格列酮治疗可恢复肥胖的胰岛素抵抗 Zucker 大鼠的骨骼肌 AMPK 2活性(Lessard 等人,2006年)。罗格列酮通过抑制呼吸链的复合物 i 间接激活 AMPK,从而导致细胞内 AMP: ATP 比例的增加(El-Mir 等人,2000年 Owen 等人,Brunmair 等人,2004年)。

TZDs also decrease the levels of resistin and stimulate release of adiponectin via action on PPAR-γ in adipocytes (Samaha et al. 2006). These effects might also contribute to the stimulatory effect of TZDs on AMPK.

TZDs 还通过作用于脂肪细胞中的 ppar- 而降低抵抗素水平并刺激脂联素的释放(Samaha 等人,2006)。这些效应也可能有助于 TZDs 对 AMPK 的刺激作用。

Conclusion

总结

AMPK is one of the key regulators in energy homeostasis and is known to mediate the effects of several metabolic hormones. AMPK is now recognised as a potential target for the treatment of obesity and the metabolic syndrome.

AMPK 是能量稳态的关键调节因子之一,并且已知介导几种代谢激素的影响。AMPK 现在被认为是治疗肥胖和代谢症候群的潜在靶标。

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