Tritos N A, Elmquist J K, Mastaitis J W, Flier J S, Maratos-Flier E
Elliot P. Joslin Laboratory, Joslin Diabetes Center, Boston, Massachusetts 02215, USA.
Endocrinology. 1998 Nov;139(11):4634-41. doi: 10.1210/endo.139.11.6308.
Brown adipose tissue-deficient [uncoupling protein (UCP)-promoter-driven diphtheria toxin A (DTA)] mice develop obesity as a result of both decreased energy expenditure and hyperphagia. The hyperphagia occurs despite high serum leptin levels. Hence, this is a model of leptin-resistant obesity in which the mechanism driving hyperphagia is unknown. Leptin is a regulator of a number of hypothalamic neuropeptides involved in energy homeostasis. In ob/ob mice, leptin deficiency results in increased expression of neuropeptide Y (NPY), agouti-related protein (AGRP), and melanin-concentrating hormone (MCH), and decreased expression of POMC. We have previously shown that NPY is reduced in the UCP-DTA mouse, suggesting a normal NPY response to leptin. To define other potential sites of leptin resistance, we used in situ hybridization to evaluate the expression of messenger RNAs (mRNAs) encoding a number of peptides, including NPY, AGRP, MCH, and POMC. We confirmed that the decrease in NPY expression previously detected by Northern blots reflects a decrease in NPY expression in the arcuate nucleus. AGRP mRNA was also decreased, whereas POMC mRNA levels in the arcuate nucleus were the same as control. MCH mRNA levels in the lateral hypothalamic area were also decreased. In contrast, there was induction of NPY expression in the dorsomedial hypothalamic nucleus in the UCP-DTA animals but not in the controls. The results indicate that these neuropeptides generally respond to leptin and that the hyperphagia seen in the UCP-DTA mice is likely the result of dysregulated expression of other, as yet unexamined, hypothalamic peptides, or lies at sites distal to the hypothalamus.
棕色脂肪组织缺陷型[解偶联蛋白（UCP）启动子驱动的白喉毒素A（DTA）]小鼠由于能量消耗减少和食欲亢进而发生肥胖。尽管血清瘦素水平很高，但仍会出现食欲亢进。因此，这是一种瘦素抵抗性肥胖模型，其中导致食欲亢进的机制尚不清楚。瘦素是参与能量稳态的多种下丘脑神经肽的调节剂。在ob/ob小鼠中，瘦素缺乏导致神经肽Y（NPY）、刺鼠相关蛋白（AGRP）和促黑素细胞激素（MCH）的表达增加，而阿黑皮素原（POMC）的表达减少。我们之前已经表明，UCP-DTA小鼠中的NPY减少，表明NPY对瘦素有正常反应。为了确定其他潜在的瘦素抵抗位点，我们使用原位杂交来评估编码多种肽的信使核糖核酸（mRNA）的表达，包括NPY、AGRP、MCH和POMC。我们证实，之前通过Northern印迹检测到的NPY表达下降反映了弓状核中NPY表达的减少。AGRP mRNA也减少，而弓状核中的POMC mRNA水平与对照组相同。下丘脑外侧区的MCH mRNA水平也降低。相比之下，UCP-DTA动物的背内侧下丘脑核中有NPY表达的诱导，而对照组中没有。结果表明，这些神经肽通常对瘦素有反应，并且UCP-DTA小鼠中出现的食欲亢进可能是其他尚未研究的下丘脑肽表达失调的结果，或者位于下丘脑远端的位点。
