Halaas J L, Boozer C, Blair-West J, Fidahusein N, Denton D A, Friedman J M
Laboratory of Molecular Genetics, The Rockefeller University, 1230 York Avenue, New York, NY, 10021, USA.
Proc Natl Acad Sci U S A. 1997 Aug 5;94(16):8878-83. doi: 10.1073/pnas.94.16.8878.
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 Ay. 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. Ay 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 Ay 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 Ay mice, leptin resistance probably results from defects downstream of the leptin receptor in the hypothalamus.
近期数据已确定瘦素是调节脂肪组织质量的负反馈回路中的传入信号。在肥胖的人类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品系小鼠（饮食诱导肥胖的AKR/J、新西兰肥胖小鼠（NZO）和Ay小鼠）对外周和中枢给予瘦素的反应来检验这一假设。向瘦小鼠皮下注射瘦素会在生理血浆水平导致体重呈剂量依赖性下降。以3 ng/小时或更高剂量脑室内（i.c.v.）慢性输注瘦素会导致可见脂肪组织完全消耗，在持续30天的i.c.v.输注过程中一直保持这种状态。能量平衡的直接测量表明，瘦素治疗并未增加总能量消耗，但防止了因食物摄入量减少而导致的能量消耗下降。饮食诱导肥胖的小鼠对外周瘦素产生体重下降反应，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。Ay小鼠对皮下注射瘦素无反应，对i.c.v.瘦素的敏感性仅为瘦小鼠的1/100。饮食诱导肥胖的小鼠、NZO小鼠和Ay小鼠对瘦素反应降低表明，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转运减少所致，而在Ay小鼠中，瘦素抵抗可能是由于下丘脑瘦素受体下游的缺陷所致。
