Leptin overexpression in VTA trans-activates the hypothalamus whereas prolonged leptin action in either region cross-desensitizes.
Leptin overexpression in VTA trans-activates the hypothalamus whereas prolonged leptin action in either region cross-desensitizes.
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DOI：
10.1016/j.neuropharm.2012.09.005
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发表时间：
2013-02
影响因子：
4.7
通讯作者：
Zhang Y
中科院分区：
文献类型：
--
作者：
Scarpace PJ;Matheny M;Kirichenko N;Gao YX;Tümer N;Zhang Y
高脂肪喂养或中枢神经系统瘦素过度表达会导致下丘脑内侧基底区和腹侧被盖区 (VTA) 出现区域特异性细胞瘦素抵抗。本研究探讨了与内侧基底下丘脑相比，VTA 中靶向慢性瘦素过度表达对长期体重稳态的影响。该研究还检查了这种有针对性的干预措施是否可以保留区域瘦素敏感性或导致局部瘦素抵抗。通过瘦素刺激的信号转导子和转录激活子 3 (STAT3) 的磷酸化来评估细胞瘦素抵抗。在下丘脑和 VTA 中测量酪氨酸羟化酶以及棕色脂肪组织解偶联蛋白 1。VTA 中的瘦素过度表达可以缓和 HF 诱导的肥胖，但程度略小于下丘脑中瘦素过度表达。此外，VTA中瘦素的过度表达刺激了下丘脑内侧基底几个区域的细胞STAT3磷酸化，而下丘脑中的过度表达并没有激活VTA中的STAT3信号传导。这种单向转刺激似乎不涉及载体或基因产物的迁移。内侧基底下丘脑或 VTA 中的长期瘦素过度表达导致治疗区域瘦素信号传导脱敏和未治疗区域瘦素信号传导交叉脱敏。这些结果证明了 VTA 中的瘦素受体在长期体重调节中的作用，但 VTA 瘦素刺激后下丘脑的反式激活表明涉及两个大脑区域的综合反应可能解释了观察到的生理结果。
High-fat feeding or CNS leptin overexpression in chow-fed rats results in a region-specific cellular leptin resistance in medial basal hypothalamic regions and the ventral tegmental area (VTA). The present investigation examined the effects of targeted chronic leptin overexpression in the VTA as compared with the medial basal hypothalamus on long-term body weight homeostasis. The study also examined if this targeted intervention conserves regional leptin sensitivity or results in localized leptin resistance. Cellular leptin resistance was assessed by leptin-stimulated phosphorylation of signal transducers and activators of transcription 3 (STAT3). Tyrosine hydroxylase was measured in hypothalamus and VTA along with brown adipose tissue uncoupling protein 1. Leptin overexpression in VTA tempered HF-induced obesity, but to a slightly lesser extent than that with leptin overexpression in the hypothalamus. Moreover, the overexpression of leptin in the VTA stimulated cellular STAT3 phosphorylation in several regions of the medial basal hypothalamus, whereas verexpression in the hypothalamus did not activate STAT3 signaling in the VTA. This unidirectional trans-stimulation did not appear to involve migration of either the vector or the gene product. Long-term leptin overexpression in either the medial basal hypothalamus or VTA caused desensitization of leptin signaling in the treated region and cross-desensitization of leptin signaling in the untreated region. These results demonstrate a role of leptin receptors in the VTA in long-term body weight regulation, but the trans-activation of the hypothalamus following VTA leptin stimulation suggests that an integrative response involving both brain regions may account for the observed physiological outcomes.
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影响因子：
4.7
作者：
Matheny, M.;Shapiro, A.;Tuemer, N.;Scarpace, P. J.
通讯作者：
Scarpace, P. J.
影响因子：
4.7
作者：
Scarpace, PJ;Matheny, M;Zolotukhin, S
通讯作者：
Zolotukhin, S
DOI：
10.1152/ajpendo.1998.275.2.e259
发表时间：
1998-08-01
影响因子：
5.1
作者：
Scarpace, PJ;Matheny, M
通讯作者：
Matheny, M
影响因子：
3.3
作者：
Scarpace, PJ;Matheny, M;Tümer, N
通讯作者：
Tümer, N
影响因子：
29
作者：
Myers MG Jr;Münzberg H;Leinninger GM;Leshan RL
通讯作者：
Leshan RL