瘦蛋白信号转导及瘦蛋白抵抗机制

瘦蛋白(leptin)通过结合瘦蛋白受体,启动信号转导,发挥控制摄食和调节能量代谢等重要神经内分泌调节功能。肥胖症患者血浆瘦蛋白水平普遍升高,存在瘦蛋白抵抗,瘦蛋白抵抗是导致肥胖症的关键因素。本文综述了瘦蛋白信号转导作用及瘦蛋白抵抗可能的机制。     

冬眠调节机制或可治疗胰岛素抵抗

储脂类冬眠动物在每年夏季大量进食以储存脂肪,在冬季通过冬眠降低代谢并缓慢消耗脂肪。冬眠动物在育肥晚期或冬眠早期表现出高血糖及胰岛素抵抗等症状,但在冬眠结束后胰岛素敏感性明显增强。冬眠可改善胰岛素抵抗症状,这可能是通过改变Akt信号转导通路、葡萄糖转运蛋白(GLUT)和PPARγ/PGC-1α转录复合体的表达来实现的。在肥胖及相关代谢疾病迅速增长的今天,深入研究冬眠动物改善胰岛素抵抗症状的调控机制,可为治疗肥胖病人的胰岛素抵抗提供新的途径。     

瘦素在育肥后达乌尔黄鼠能量平衡及体温调节中的作用

育肥完成后到冬眠前的阶段被认为是贮脂类冬眠动物从体温常态到冬眠之间的过渡阶段。为研究此阶段瘦素对能量平衡和体温调节的作用,将完成育肥的达乌尔黄鼠随机分成3组,分别在侧脑室植入微渗透泵,持续灌注瘦素（0.5μg/day）、瘦素拮抗剂（0.5μg/day瘦素+5μg/day瘦素拮抗剂）以及人工脑脊液（对照组）,为期4周。为了检测瘦素对动物入眠的影响,我们在药物处理最后一周将动物移入低温（5 ^oC±1^oC）、恒黑条件下诱导蛰眠。药物处理过程中测定动物体重、能量摄入、代谢率和体温,药物处理结束后测定身体脂肪重量、褐色脂肪组织中解偶联蛋白1（UCP1）含量以及血清中与能量平衡相关的激素水平。结果发现：育肥后达乌尔黄鼠能量摄入、体重和每日体温自发降低。低温条件下,对照组中50%个体自发进入冬眠状态。瘦素处理和瘦素拮抗剂处理对能量摄入和体重变化没有显著影响。瘦素处理对入眠率没有影响,瘦素拮抗剂处理减少蛰眠表达。瘦素拮抗剂组血清中T₄水平高于瘦素处理组。育肥后期瘦素以及瘦素拮抗剂处理对脂肪重量、代谢率以及UCP1含量没有显著影响。结果表明,瘦素对育肥结束后达乌尔黄鼠的冬眠表达具有一定调节作用。     

瘦蛋白的研究进展

瘦蛋白的研究进展黄君富房殿春（第三军医大学西南医院分子生物学实验室,重庆６３００３８）关键词瘦蛋白瘦蛋白受体肥胖基因肥胖是机体能量平衡紊乱的结果。当能量摄取超过能量消耗时,多余的能量便贮存于脂肪细胞,最终导致肥胖。对机体能量平衡及脂肪贮存进行更深入的...     

黑线仓鼠断乳后能量代谢和脂肪累积的适应性调节

小型哺乳动物能量代谢和脂肪累积的适应性调节是其应对自然环境变化的主要能量学策略,但在不同的生活史阶段,脂肪组织适应性调节的特征和能量机理尚不清楚。为探讨不同繁殖阶段能量代谢和脂肪累积的变化及其内分泌机理,本文测定了黑线仓鼠哺乳期和断乳后摄食量、脂肪重量,以及血清瘦素水平、下丘脑瘦素受体（Ob-Rb）和相关神经肽的基因表达。结果显示,哺乳高峰期黑线仓鼠的脂肪重量几乎降低至零,断乳后显著增加;与非繁殖对照组相比,皮下脂肪、肾周脂肪与腹腔脂肪重量分别增长了1.5倍、37.1倍和1.9倍。断乳后摄食量、血清瘦素水平显著高于非繁殖对照组,Ob-Rb基因表达显著下调,而促食与抑食神经肽的基因表达均未发生显著变化。哺育不同胎仔数的黑线仓鼠在断乳后能量摄入、静止代谢率、身体组分未出现显著差异。研究表明,在不同的繁殖阶段脂肪累积呈现显 著的适应性调节,瘦素抵抗是断乳后脂肪累积补偿性增长的重要内分泌机制之一。这对迅速恢复脂肪累积,以应对将来的能量需求增加或者食物资源短缺的环境,进而提高自身的适合度具有重要意义。     

瘦蛋白调控小型哺乳动物产热的分子机制

瘦蛋白(leptin)是由脂肪细胞分泌的、肥胖基因编码的蛋白类激素,其在哺乳动物的体重调节和适应性产热中有重要作用。解偶联蛋白(uncoupling protein,UCP)是动物体内具有解偶联作用的一类蛋白质。UCP-1是分布于褐色脂肪组织(brown adipose tissue,BAT)线粒体内膜上的标志蛋白,其在冷适应和食物资源缺乏等条件下的产热作用已得到印证。UCP-2和UCP-3的生物学功能仍存在争论。瘦蛋白可以通过诱导UCP的表达来促进产热．瘦蛋白诱导UCP表达的机制有二：(1)瘦蛋白通过与下丘脑神经肽Y的拮抗作用诱导UCP的表达;(2)瘦蛋白以交感神经系统为媒介诱导UCP的表达。瘦蛋白诱导UCP-1的表达是调节BAT产热的主要途径。了解瘦蛋白与UCP在产热中的作用对于我们了解动物产热的分子机制和其对低温、营养缺乏等条件下的生理生态适应机制具有重要意义。     

治疗肥胖的新希望

治疗肥胖的新希望长期以来,肥胖困扰着人类,特别是中老年人。单就美国,每年要花掉３００亿美元对付肥胖,效果仍不满意。最近几位美国学者的卓越研究,为治疗肥胖展现了新希望。研究认为,平衡摄食和能量消耗的机制决定谁肥谁瘦。肥胖基因（ｏｂ基因）就是小鼠调节能量...     

温度和高脂食物对黑线仓鼠代谢产热和体脂累积的影响

能量代谢的适应性调节是小型哺乳动物应对环境季节性变化的主要策略之一。为探讨不同温度下动物在代谢产热能量支出与脂肪累积之间的权衡策略,以成年雄性黑线仓鼠为研究对象开展了3 个实验:实验1 将动物驯化于高脂和低脂食物;实验2 将动物暴露于低温(5℃)和暖温(30℃);实验3 将饲喂高脂食物的动物暴露于低温。以食物平衡法测定摄食量、摄入能和消化率,以开放式氧气分析仪测定代谢产热,以索氏抽提法测定脂肪含量。结果发现,取食高脂食物的黑线仓鼠摄食量显著减少,但脂肪累积显著增加;暖温下摄食量显著减少,但体脂含量显著增加,低温下摄食量显著升高,但体脂含量显著减少;饲喂高脂食物的黑线仓鼠在低温下摄入能显著增加,非颤抖性产热增强,但体脂含量显著降低。结果表明高脂食物对黑线仓鼠体脂累积的影响与环境温度有关,低温诱导脂肪动员,暖温促进脂肪贮存;低温下黑线仓鼠增加能量摄入不能完全补偿用于产热的能量支出,导致脂肪动员增加;暖温下代谢产热降低是脂肪累积的主要因素;与能量摄入相比代谢产热的能量支出在体脂累积的适应性变化中发挥更重要的作用。     

达乌尔黄鼠入眠准备期的体温、代谢率及能量特征

贮脂类动物在冬眠前大量积累脂肪来准备冬眠,并在入眠时迅速降低体温和代谢率。为探究入眠准备期达乌尔黄鼠体温、代谢率、呼吸商及能量代谢的变化,将其入眠准备期分为育肥期、体重高峰期、育肥后期和冬眠前的试降期,使用植入式半导体温度记录元件iButton、开放式代谢仪和改进的代谢笼,监测其体温、代谢率及呼吸商和能量摄入的变化。结果显示:(1)达乌尔黄鼠体温在冬眠前13 - 34 d 开始下降,远早于冬眠但晚于体重高峰期;体重高峰期体温有降低的趋势,持续时间为1 - 3 d;育肥后期体温显著下降,体温日波动幅度增加。(2)体重高峰期的静止代谢率高于育肥期,育肥后期有降低的趋势,试降期最低。(3)呼吸商在体重高峰期先升高,之后迅速衰减;入眠准备期的能量摄入在体重达高峰期前达到最大值。结果表明,达乌尔黄鼠在入眠准备期,其体温和代谢率已开始降低,能源物质已开始转变;体重高峰期可能是达乌尔黄鼠入眠的一个转折点或启动入眠的开关。     

哺乳动物生物钟与能量代谢的相关研究进展

生物钟广泛存在于各种生物体中,是生命体的一种内源调节机制。哺乳动物生物钟系统与机体营养代谢和能量平衡有着密切的关系。概述了生物钟系统通过营养途径、限速酶途径、核受体途径对哺乳动物机体代谢活动和能量平衡的调控,以及哺乳动物代谢稳态对生物钟系统的影响,从而为从生物钟调控的角度治疗和防控代谢综合征提供新的思路。     

CNS melanocortin system involvement in the regulation of food intake

Accumulating evidence indicates that the central melanocortin (MC) system plays a key role in the regulation of food intake and energy balance. This evidence includes findings that either spontaneous genetic mutations or targeted gene deletions that impair melanocortin signaling cause disrupted food intake and body-weight control. In addition, expression of the mRNA that encodes the endogenous agonists and antagonists for CNS melanocortin receptors is regulated by changes in energy balance and body-adiposity signals. Finally, administration of both natural and synthetic ligands to MC receptors produces changes in food intake. The data collectively suggest a critical role for melanocortin signaling in the control of energy balance.     

Progesterone and the ovarian-adrenal modulation of energy balance in rats

Intact female rats injected daily with 5 mg progesterone beginning at Day 27 of age weighed more than oil-treated controls on Day 39, i.e., prior to puberty; progesterone did not, however, increase food intake until well after puberty (Day 54). Progesterone may affect body weight independently of its interactions with estrogens and via mechanisms that do not involve the central substrate for food intake or energy balance. The ability of progesterone to influence food intake also depends in part on its modulation of estrogen-sensitive mechanisms that do not become functional until after puberty. Progesterone increased food intake of prepubertal overiectomized-adrenalectomized rats but not that of ovariectomized rats of any age. It was concluded that progesterone mimics the actions of adrenal hormones and that it permissively increases food intake of adrenalectomized rats by improving the health of these animals. Progesterone only partially substitutes for adrenal secretions in ovariectomized-adrenalectomized rats and supplementary sodium ingestion may be necessary for progesterone to produce positive energy balance.     

TrkB receptor signaling in the nucleus tractus solitarius mediates the food intake-suppressive effects of hindbrain BDNF and leptin

Brain-derived neurotrophic factor (BDNF) and TrkB receptor signaling contribute to the central nervous system (CNS) control of energy balance. The role of hindbrain BDNF/TrkB receptor signaling in energy balance regulation is examined here. Hindbrain ventricular BDNF suppressed body weight through reductions in overall food intake and meal size and by increasing core temperature. To localize the neurons mediating the energy balance effects of hindbrain ventricle-delivered BDNF, ventricle subthreshold doses were delivered directly to medial nucleus tractus solitarius (mNTS). mNTS BDNF administration reduced food intake significantly, and this effect was blocked by preadministration of a highly selective TrkB receptor antagonist {[N2-2-2-Oxoazepan-3-yl amino]carbonyl phenyl benzo (b)thiophene-2-carboxamide (ANA-12)}, suggesting that TrkB receptor activation mediates hindbrain BDNF's effect on food intake. Because both BDNF and leptin interact with melanocortin signaling to reduce food intake, we also examined whether the intake inhibitory effects of hindbrain leptin involve hindbrain-specific BDNF/TrkB activation. BDNF protein content within the dorsal vagal complex of the hindbrain was increased significantly by hindbrain leptin delivery. To assess if BDNF/TrkB receptor signaling acts downstream of leptin signaling in the control of energy balance, leptin and ANA-12 were coadministered into the mNTS. Administration of the TrkB receptor antagonist attenuated the intake-suppressive effects of leptin, suggesting that mNTS TrkB receptor activation contributes to the mediation of the anorexigenic effects of hindbrain leptin. Collectively, these results indicate that TrkB-mediated signaling in the mNTS negatively regulates food intake and, in part, the intake inhibitory effects of leptin administered into the NTS.     

Role of thermogenesis in the regulation of energy balance in relation to obesity

Obligatory thermogenesis is a necessary accompaniment of all metabolic processes involved in maintenance of the body in the living state, and occurs in all organs. It includes energy expenditure involved in ingesting, digesting, and processing food (thermic effect of food (TEF]. At certain life stages extra energy expenditure for growth, pregnancy, or lactation would also be obligatory. Facultative thermogenesis is superimposed on obligatory thermogenesis and can be rapidly switched on and rapidly suppressed by the nervous system. Facultative thermogenesis is important in both thermal balance, in which control of thermoregulatory thermogenesis (shivering in muscle, nonshivering in brown adipose tissue (BAT] balances neural control of heat loss mechanisms, and in energy balance, in which control of facultative thermogenesis (exercise-induced in muscle, diet-induced thermogenesis (DIT) in BAT) balances control of energy intake. Thermal balance (i.e., body temperature) is much more stringently controlled than energy balance (i.e., body energy stores). Reduced energy expenditure for thermogenesis is important in two types of obesity in laboratory animals. In the first type, deficient DIT in BAT is a prominent feature of altered energy balance. It may or may not be associated with hyperphagia. In a second type, reduced cold-induced thermogenesis in BAT as well as in other organs is a prominent feature of altered thermal balance. This in turn results in altered energy balance and obesity, exacerbated in some examples by hyperphagia. In some of the hyperphagic obese animals it is likely that the exaggerated obligatory thermic effect of food so alters thermal balance that BAT thermogenesis is suppressed. In all obese animals, deficient hypothalamic control of facultative thermogenesis and (or) food intake is implicated.     

To be or NUCB2, is nesfatin the answer?

Signals from the hypothalamus govern food intake and energy balance. A new study describes nesfatin-1, a hypothalamic and brainstem peptide whose expression decreases during fasting. Although central treatment with nesfatin-1 inhibited food intake and nesfatin-1 blockade increased food intake, the role and mechanism of nesfatin in energy balance remains unclear.     

Effects of corticocerebellar lesions on taste preferences, body weight gain, food and fluid intake in the rat.

The experiments reported here attempted to examine in two groups of rats the effects on the taste preferences, food and fluid intake, energy balance and body weight gain of corticocerebellar lesions involving, primarily, the Lobulus VI (LVI) or the Lobulus Paramedianus (LP). The results showed that the lesions of LVI or LP did not affect the daily intake of total fluid and salty solution. The intake of sweet solution increased in both groups of lesioned rats, while the intake of deionized water and acid and bitter solutions decreased only in the LVI lesioned rats. Food intake decreased in the LVI-lesioned rats but not in the LP-lesioned animals. Body weight gain, efficiency of food utilization, caloric intake and body surface gain decreased in both groups. It seems therefore that the cerebellar cortex, which probably receives taste fibers, somehow influences taste preferences and water intake, and that it may be involved in the mechanisms of food intake, its utilization and body energy balance.     

Effect of disrupted episodic memory on food consumption: no impact of neuronal loss of endophilin A1 on food intake and energy balance

Food intake is generally assumed to reflect a regulatory tension between homeostatic and hedonic drivers. Information from individuals with memory dysfunction suggests that episodic memory may also play a significant role. We reasoned that if memory influences food intake, then disrupting a genetic factor that is important in episodic memory formation should affect food intake and energy balance. We performed spatial learning tests on neuronal specific endophilin A1 (EENA1) KO mice using the four-arm baited version of the radial arms maze (RAM). Energy regulation has also been evaluated. As anticipated neuronal EENA1 KO mice had impaired spatial memory. However, loss of endophilin A1 did not result in greater food intake, or altered energy absorption efficiency, relative to wild-type (WT) mice, when fed either low or high fat diets. Moreover, loss of EENA1 did not significantly affect other features of energy balance—physical activity and energy expenditure. No statistically significant changes were observed in the expression of hypothalamic neuropeptides related to food intake regulation, or circulating levels of leptin. We conclude that food intake and energy balance are largely governed by homeostatic and hedonic processes, and when these processes are intact memory probably plays a relatively minor role in food intake regulation.     

Leptin and the adaptations of lactation in rodents and ruminants.

Lactation markedly increases nutrient requirements in both rodents and ruminants. This is met mostly by increased food intake, but there are also adaptations to increase metabolic efficiency. Despite such changes, lactating animals usually experience periods of negative energy balance. This is not due to a physical constraint on food intake, at least in the rat. Leptin, a hormone secreted by adipocytes, plays an important role in the regulation of appetite and energy balance. During lactation, serum leptin concentration is decreased in both rodents and ruminants, and the nocturnal rise in concentration is lost in rats. Hypoleptinaemia in lactation is primarily a result of negative energy balance. There is also increased clearance of serum leptin, and the attenuation of the nocturnal rise in leptin in rats is at least partly due to the suckling stimulus. Hypoleptinaemia is not the major factor driving hyperphagia in lactating rats, but it probably facilitates the increased food intake. Leptin may play a more important role in this respect in lactating ruminants. Leptin is probably involved in other adaptations that increase metabolic efficiency during lactation. The ability of hypothalamic neuropeptides to respond to leptin does not appear to be altered by lactation in either rodents or ruminants. The reason why lactating animals do not respond to hypoleptinaemia with a further increase in appetite, thereby achieving energy balance, appears to be due to a failure to respond to changes in neuropeptides which mediate the effects of leptin.     

Divergence of melanocortin pathways in the control of food intake and energy expenditure

Activation of melanocortin-4-receptors (MC4Rs) reduces body fat stores by decreasing food intake and increasing energy expenditure. MC4Rs are expressed in multiple CNS sites, any number of which could mediate these effects. To identify the functionally relevant sites of MC4R expression, we generated a loxP-modified, null Mc4r allele (loxTB Mc4r) that can be reactivated by Cre-recombinase. Mice homozygous for the loxTB Mc4r allele do not express MC4Rs and are markedly obese. Restoration of MC4R expression in the paraventricular hypothalamus (PVH) and a subpopulation of amygdala neurons, using Sim1-Cre transgenic mice, prevented 60% of the obesity. Of note, increased food intake, typical of Mc4r null mice, was completely rescued while reduced energy expenditure was unaffected. These findings demonstrate that MC4Rs in the PVH and/or the amygdala control food intake but that MC4Rs elsewhere control energy expenditure. Disassociation of food intake and energy expenditure reveals unexpected divergence in melanocortin pathways controlling energy balance.     

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.