Leptin signaling, adiposity, and energy balance
Leptin signaling, adiposity, and energy balance
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DOI：
10.1111/j.1749-6632.2002.tb04293.x
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发表时间：
2002-01-01
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影响因子：
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通讯作者：
Jéquier, E
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作者：
Jéquier, E
能量摄入和能量消耗之间的慢性轻微不平衡可能导致肥胖。瘦人与肥胖者最终都能达到能量平衡，他们的体重调节意味着脂肪组织质量被“感知”，从而产生适当的能量摄入和能量消耗反应。ob基因的克隆及其编码蛋白瘦素的鉴定，提供了一个向大脑发送脂肪能量储存量信号的系统。瘦素是一种由脂肪细胞分泌的激素，通过下丘脑受体在啮齿类动物中起作用，抑制进食并增加产热。已经确定了一个具有三个不同步骤的反馈调节回路：(1)传感器（脂肪细胞产生瘦素）监测脂肪组织块的大小；(2)下丘脑中枢通过瘦素受体（LRb）接收并整合瘦素信号强度；(3)包括交感神经系统在内的效应器系统控制着能量平衡的两个主要决定因素——能量摄入和能量消耗。虽然这种反馈调节回路在啮齿动物中已经很好地建立起来，但关于它在人类体重调节中的适用性，还有许多未解决的问题。瘦素的产生率与肥胖有关，但血浆瘦素浓度的很大一部分个体间变异性与体脂无关。性别是决定血浆瘦素的一个重要因素，对于任何给定的脂肪量，女性的瘦素浓度明显高于男性。糖皮质激素也上调ob mRNA的表达，而交感神经系统的刺激导致其抑制。此外，瘦素不是人类的饱腹感因素，因为食物摄入量的变化不会导致血浆瘦素水平的短期增加。在下丘脑与LRb结合后，瘦素刺激了一个特定的信号级联反应，导致抑制几种厌氧神经肽，同时刺激几种厌氧肽。受瘦素下调的致氧神经肽有神经肽Y （NPY）、黑色素浓缩激素（MCH）、致氧素（orexins）和AGRP （agouti相关肽）。受瘦素上调的厌氧神经肽有α - msh （α -黑色素细胞刺激激素），其作用于MC4R（黑素皮质素-4受体）；CART（可卡因和安非他明管制转录本）；促肾上腺皮质激素释放激素（CRH）。肥胖人群的血浆瘦素浓度与脂肪组织的大小有关，但这种升高的瘦素信号并没有引起预期的反应（即减少食物摄入和增加能量消耗）。这表明肥胖的人对内源性瘦素的作用有抵抗力。在肥胖患者中，外源性瘦素缺乏诱导体重减轻的效果也表明了这种抵抗。可能解释人类肥胖中瘦素抵抗的机制包括血脑屏障运输系统对瘦素的限制和对瘦素敏感的下丘脑神经元中瘦素信号通路的抑制。在能量不足期间，血浆中瘦素水平的下降超过了脂肪储存减少的速度。瘦素信号的减少会引起一些神经内分泌反应，这些反应往往会限制体重减轻，如饥饿、觅食行为和血浆甲状腺激素水平的抑制。相反，当有大量美味食物时，瘦素不太可能进化到预防肥胖的程度，因为脂肪组织质量增加导致的血浆瘦素水平升高并不能预防肥胖的发生。总之，在人类中，瘦素信号系统似乎主要参与在能量不足期间维持足够的能量储存以维持生存。它在人类肥胖病因学中的作用仅在非常罕见的缺乏瘦素信号（瘦素基因或瘦素受体基因突变）的情况下得到证实，这种情况会产生饥饿的内部感知，并导致慢性刺激过量的食物摄入。
A chronic minor imbalance between energy intake and energy expenditure may lead to obesity. Both lean and obese subjects eventually reach energy balance and their body weight regulation implies that the adipose tissue mass is "sensed", leading to appropriate responses of energy intake and energy expenditure. The cloning of the ob gene and the identification of its encoded protein, leptin, have provided a system signaling the amount of adipose energy stores to the brain. Leptin, a hormone secreted by fat cells, acts in rodents via hypothalamic receptors to inhibit feeding and increase thermogenesis. A feedback regulatory loop with three distinct steps has been identified: (1) a sensor (leptin production by adipose cells) monitors the size of the adipose tissue mass; (2) hypothalamic centers receive and integrate the intensity of the leptin signal through leptin receptors (LRb); (3) effector systems, including the sympathetic nervous system, control the two main determinants of energy balance energy intake and energy expenditure. While this feedback regulatory loop is well established in rodents, there are many unsolved questions about its applicability to body weight regulation in humans. The rate of leptin production is related to adiposity, but a large portion of the interindividual variability in plasma leptin concentration is independent of body fatness. Gender is an important factor determining plasma leptin, with women having markedly higher leptin concentrations than men for any given degree of fat mass. The ob mRNA expression is also upregulated by glucocorticoids, whereas stimulation of the sympathetic nervous system results in its inhibition. Furthermore, leptin is not a satiety factor in humans because changes in food intake do not induce short-term increases in plasma leptin levels. After its binding to LRb in the hypothalamus, leptin stimulates a specific signaling cascade that results in the inhibition of several orexigenic neuropeptides, while stimulating several anorexigenic peptides. The orexigenic neuropeptides that are downregulated by leptin are NPY (neuropeptide Y), MCH (melanin-concentrating hormone), orexins, and AGRP (agouti-related peptide). The anorexigenic neuropeptides that are upregulated by leptin are alpha-MSH (alpha-melanocyte-stimulating hormone), which acts on MC4R (melanocortin-4 receptor); CART (cocaine and amphetamine-regulated transcript); and CRH (corticotropin-releasing-hormone). Obese humans have high plasma leptin concentrations related to the size of adipose tissue, but this elevated leptin signal does not induce the expected responses (i.e., a reduction in food intake and an increase in energy expenditure). This suggests that obese humans are resistant to the effects of endogenous leptin. This resistance is also shown by the lack of effect of exogenous leptin administration to induce weight loss in obese patients. The mechanisms that may account for leptin resistance in human obesity include a limitation of the blood-brain-barrier transport system for leptin and an inhibition of the leptin signaling pathways in leptin-responsive hypothalamic neurons. During periods of energy deficit, the fall in leptin plasma levels exceeds the rate at which fat stores are decreased. Reduction of the leptin signal induces several neuroendocrine responses that tend to limit weight loss, such as hunger, food-seeking behavior, and suppression of plasma thyroid hormone levels.Conversely, it is unlikely that leptin has evolved to prevent obesity when plenty of palatable foods are available because the elevated plasma leptin levels resulting from the increased adipose tissue mass do not prevent the development of obesity. In conclusion, in humans, the leptin signaling system appears to be mainly involved in maintenance of adequate energy stores for survival during periods of energy deficit. Its role in the etiology of human obesity is only demonstrated in the very rare situations of absence of the leptin signal (mutations of the leptin gene or of the leptin receptor gene), which produces an internal perception of starvation and results in a chronic stimulation of excessive food intake.