Physiological response to long-term peripheral and central leptin infusion in lean and obese mice
Physiological response to long-term peripheral and central leptin infusion in lean and obese mice
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DOI：
10.1073/pnas.94.16.8878
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发表时间：
1997-08-05
影响因子：
11.1
通讯作者：
Friedman, JM
中科院分区：
文献类型：
--
作者：
Halaas, JL;Boozer, C;Friedman, JM
最近的数据已经将瘦素确定为调节脂肪组织质量的负反馈回路中的传入信号。在肥胖的人和啮齿动物中观察到高瘦素水平，这表明在某些情况下，肥胖是瘦素不敏感的结果。通过比较瘦小鼠和三种肥胖小鼠品系对外周和中枢施用瘦素的反应来测试该假设：饮食诱导的肥胖AKR/J、新西兰肥胖（NZO）和A（y）。向瘦小鼠皮下输注瘦素导致生理血浆水平的剂量依赖性体重减轻。在3 ng/hr或更高的剂量下，导致可见脂肪组织的完全消耗，这在连续i. c. v.输注的30天中保持。能量平衡的直接测量表明，瘦素治疗不增加总能量消耗，但防止了食物摄入减少后的减少。饮食诱导的肥胖小鼠对外周瘦素的反应是体重减轻，但不如瘦小鼠敏感。NZO小鼠对外周瘦素无反应，但对i. c. v.瘦素有反应。A（y）小鼠对皮下瘦素没有反应，对i. c. v.瘦素的敏感性为1/100。饮食诱导的肥胖、NZO和A（y）小鼠对瘦素的反应降低表明，这些品系的肥胖是瘦素抵抗的结果。在NZO小鼠中，瘦素抵抗可能是由于瘦素向脑脊液中的转运减少，而在A（y）小鼠中，瘦素抵抗可能是由于下丘脑中瘦素受体下游的缺陷。
Recent data have identified leptin as an afferent signal in a negative-feedback loop regulating the mass of the adipose tissue, High leptin levels are observed in obese humans and rodents, suggesting that, in some cases, obesity is the result of leptin insensitivity, This hypothesis was tested by comparing the response to peripherally and centrally administered leptin among lean and three obese strains of mice: diet-induced obese AKR/J, New Zealand Obese (NZO), and A(y). Subcutaneous leptin infusion to lean mice resulted in a dose-dependent loss of body weight at physiologic plasma levels, Chronic infusions of leptin intracerebroventricularly (i.c.v.) at doses of 3 ng/hr or greater resulted in complete depletion of visible adipose tissue, which was maintained throughout 30 days of continuous i.c.v. infusion, Direct measurement of energy balance indicated that leptin treatment did not increase total energy expenditure but prevented the decrease that follows reduced food intake. Diet-induced obese mice lost weight in response to peripheral leptin but were less sensitive than lean mice, NZO mice were unresponsive to peripheral leptin but were responsive to i.c.v. leptin. A(y) mice did not respond to subcutaneous leptin and were 1/100 as sensitive to i.c.v. leptin, The decreased response to leptin in diet-induced obese, NZO, and A(y) mice suggests that obesity in these strains is the result of leptin resistance. In NZO mice, leptin resistance may be the result of decreased transport of leptin into the cerebrospinal fluid, whereas in A(y) mice, leptin resistance probably results from defects downstream of the leptin receptor in the hypothalamus.