Grasso P, Leinung M C, Ingher S P, Lee D W
Department of Biochemistry and Molecular Biology, Albany Medical College, New York 12208, USA.
Endocrinology. 1997 Apr;138(4):1413-8. doi: 10.1210/endo.138.4.5087.
In C57BL/6J ob/ob mice, a single base mutation of the ob gene in codon 105 results in the replacement of arginine by a premature stop codon and production of a truncated inactive form of leptin. These observations suggest that leptin activity may be localized, at least in part, to domains distal to amino acid residue 104. To investigate this possibility, we synthesized six overlapping peptide amides corresponding to residues 106-167 of leptin, and examined their effects on body weight and food intake in female C57BL/6J ob/ob mice. When compared with vehicle-injected control mice, weight gain by mice receiving 28 daily 1-mg i.p. injections of LEP-(106-120), LEP-(116-130), or LEP-(126-140) was significantly (P < 0.01) reduced with no apparent toxicity. Weight gain by mice receiving LEP-(136-150), LEP-(146-160), or LEP-(156-167) was not significantly different from that of vehicle-injected control mice. The effects of LEP-(106-120), LEP-(116-130), or LEP-(126-140) were most pronounced during the first week of peptide treatment. Within 7 days, mice receiving these peptides lost 12.3%, 13.8%, and 9.8%, respectively, of their initial body weights. After 28 days, mice given vehicle alone, LEP-(136-150), LEP-(146-160), or LEP-(156-167) were 14.7%, 20.3%, 25.0%, and 24.8% heavier, respectively, than they were at the beginning of the study. Mice given LEP-(106-120) or LEP-(126-140) were only 1.8% and 4.2% heavier, respectively, whereas mice given LEP-(116-130) were 3.4% lighter. Food intake by mice receiving LEP-(106-120), LEP-(116-130), or LEP-(126-140), but not by mice receiving LEP-(136-150), LEP-(146-160), or LEP-(156-167), was reduced by 15%. The results of this study indicate 1) that leptin activity is localized, at least in part, in domains between residues 106-140; 2) that leptin-related peptides have in vivo effects similar to those of native leptin; and 3) offer hope for development of peptide analogs of leptin having potential application in human or veterinary medicine.
在C57BL/6J ob/ob小鼠中，ob基因第105位密码子的单个碱基突变导致精氨酸被过早的终止密码子取代，从而产生截短的无活性瘦素形式。这些观察结果表明，瘦素活性可能至少部分定位于氨基酸残基104远端的结构域。为了研究这种可能性，我们合成了与瘦素第106 - 167位残基对应的六种重叠肽酰胺，并检测了它们对雌性C57BL/6J ob/ob小鼠体重和食物摄入量的影响。与注射赋形剂的对照小鼠相比，每天腹腔注射1 mg LEP-(106 - 120)、LEP-(116 - 130)或LEP-(126 - 140)共28天的小鼠体重增加显著(P < 0.01)减少，且无明显毒性。接受LEP-(136 - 150)、LEP-(146 - 160)或LEP-(156 - 167)的小鼠体重增加与注射赋形剂的对照小鼠无显著差异。LEP-(106 - 120)、LEP-(116 - 130)或LEP-(126 - 140)的作用在肽治疗的第一周最为明显。在7天内，接受这些肽的小鼠分别减轻了初始体重的12.3%、13.8%和9.8%。28天后，单独给予赋形剂、LEP-(136 - 150)、LEP-(146 - 160)或LEP-(156 - 167)的小鼠体重分别比研究开始时重14.7%、20.3%、25.0%和24.8%。给予LEP-(106 - 120)或LEP-(126 - 140)的小鼠体重仅分别重1.8%和4.2%，而给予LEP-(116 - 130)的小鼠体重轻3.4%。接受LEP-(106 - 120)、LEP-(116 - 130)或LEP-(126 - 140)的小鼠食物摄入量减少了15%，而接受LEP-(136 - 150)、LEP-(146 - 160)或LEP-(156 - 167)的小鼠则没有。本研究结果表明：1) 瘦素活性至少部分定位于第106 - 140位残基之间的结构域；2) 瘦素相关肽在体内的作用与天然瘦素相似；3) 为开发在人类或兽医学中有潜在应用的瘦素肽类似物带来了希望。
