Department of Animal Physiology, Faculty of Biology, Philipps University Marburg, Marburg, Germany.
J Neuroendocrinol. 2009 Nov;21(11):961-71. doi: 10.1111/j.1365-2826.2009.01916.x. Epub 2009 Sep 1.
In common forms of obesity, animals and humans become leptin resistant associated with impaired regulation of energy homeostasis. Over the last decade, significant advances in delineating the underlying mechanisms have been achieved. As well as the obvious scientific progress obtained by novel transgenic animals, natural and physiological models of leptin resistance such as the Siberian hamster (Phodoups sungorus), the field vole (Microtus agrestis) or the rat during pregnancy have also provided invaluable insight into the dynamic long-term control of energy homeostasis. Seasonal (in the hamster) and pregnancy-induced leptin resistance are characterised by a modulation of the leptin signalling cascade downstream of its receptor in the hypothalamus. In this state, leptin-induced phosphorylation of the important transcription factor, signal transducer and activator of transcription 3 (STAT3), is impaired in the arcuate nucleus and the ventromedial hypothalamus (only during pregnancy). This is accompanied by elevated levels of leptin signalling inhibitors such as the suppressor of cytokine signalling (SOCS3) and the protein tyrosine phosphatase 1B (PTP1B). The janus kinase 2 (JAK2)-STAT3 signalling pathway might be modulated by a dual function of the tyrosine residue Tyr(985) in the intracellular domain of the leptin receptor. In seasonal animals, SOCS3, most importantly seems to act as a 'molecular switch' enabling a photoperiod-induced alteration in leptin signalling and subsequent adjustments in energy homeostasis to allow attainment of a new body weight set-point. These physiological models show that animals can exhibit leptin resistance as an adaptive response to meet new physiological or environmental challenges, promoting the survival of the species during times of increased metabolic demand. The molecular mechanisms mediating physiological and/or pathological leptin resistance, like during diet induced obesity, might be very similar involving hypothalamic SOCS3. Investigation of these models might further provide new insight into the dynamic complexity of energy homeostasis.
在常见的肥胖形式中，动物和人类会对瘦素产生抗性，从而导致能量稳态调节受损。在过去的十年中，在阐明潜在机制方面取得了重大进展。除了新型转基因动物所获得的明显科学进步外，瘦素抵抗的自然和生理模型，如沙鼠（Phodoups sungorus）、田鼠（Microtus agrestis）或怀孕大鼠，也为能量稳态的动态长期控制提供了宝贵的见解。季节性（在沙鼠中）和妊娠引起的瘦素抵抗的特征是瘦素信号级联在其在下丘脑受体下游的调节。在这种状态下，瘦素诱导的重要转录因子信号转导和转录激活因子 3（STAT3）的磷酸化在弓状核和腹内侧下丘脑（仅在妊娠期间）受损。这伴随着瘦素信号抑制剂如细胞因子信号转导抑制物 3（SOCS3）和蛋白酪氨酸磷酸酶 1B（PTP1B）水平的升高。Janus 激酶 2（JAK2）-STAT3 信号通路可能受到瘦素受体细胞内结构域中酪氨酸残基 Tyr（985）的双重功能的调节。在季节性动物中，SOCS3 似乎最重要的是作为一种“分子开关”，能够在光周期诱导的瘦素信号改变和随后的能量稳态调整中发挥作用，从而达到新的体重设定点。这些生理模型表明，动物可以表现出瘦素抵抗，作为一种适应反应，以满足新的生理或环境挑战，促进物种在代谢需求增加时的生存。介导生理和/或病理瘦素抵抗的分子机制，如在饮食诱导的肥胖中，可能非常相似，涉及下丘脑 SOCS3。对这些模型的研究可能进一步深入了解能量稳态的动态复杂性。
