Physiological response to long-term peripheral and central leptin infusion in lean and obese mice

• Jeffrey L. Halaas

  Laboratory of Molecular Genetics and Howard Hughes Medical Institute, The Rockefeller University, 1230 York Avenue, New York, NY, 10021; Department of Medicine, College of Physicians and Surgeons, Columbia University, and Obesity Research Center, St. Luke’s–Roosevelt Hospital Center, New York, NY 10025; and Department of Physiology, University of Melbourne, and Howard Florey Institute of Experimental Physiology and Medicine, Parkville 3052, Melbourne, Australia

• Carol Boozer

  Laboratory of Molecular Genetics and Howard Hughes Medical Institute, The Rockefeller University, 1230 York Avenue, New York, NY, 10021; Department of Medicine, College of Physicians and Surgeons, Columbia University, and Obesity Research Center, St. Luke’s–Roosevelt Hospital Center, New York, NY 10025; and Department of Physiology, University of Melbourne, and Howard Florey Institute of Experimental Physiology and Medicine, Parkville 3052, Melbourne, Australia

• John Blair-West

  Laboratory of Molecular Genetics and Howard Hughes Medical Institute, The Rockefeller University, 1230 York Avenue, New York, NY, 10021; Department of Medicine, College of Physicians and Surgeons, Columbia University, and Obesity Research Center, St. Luke’s–Roosevelt Hospital Center, New York, NY 10025; and Department of Physiology, University of Melbourne, and Howard Florey Institute of Experimental Physiology and Medicine, Parkville 3052, Melbourne, Australia

• Naseem Fidahusein

  Laboratory of Molecular Genetics and Howard Hughes Medical Institute, The Rockefeller University, 1230 York Avenue, New York, NY, 10021; Department of Medicine, College of Physicians and Surgeons, Columbia University, and Obesity Research Center, St. Luke’s–Roosevelt Hospital Center, New York, NY 10025; and Department of Physiology, University of Melbourne, and Howard Florey Institute of Experimental Physiology and Medicine, Parkville 3052, Melbourne, Australia

• Derek A. Denton

  Laboratory of Molecular Genetics and Howard Hughes Medical Institute, The Rockefeller University, 1230 York Avenue, New York, NY, 10021; Department of Medicine, College of Physicians and Surgeons, Columbia University, and Obesity Research Center, St. Luke’s–Roosevelt Hospital Center, New York, NY 10025; and Department of Physiology, University of Melbourne, and Howard Florey Institute of Experimental Physiology and Medicine, Parkville 3052, Melbourne, Australia

• Jeffrey M. Friedman

  Laboratory of Molecular Genetics and Howard Hughes Medical Institute, The Rockefeller University, 1230 York Avenue, New York, NY, 10021; Department of Medicine, College of Physicians and Surgeons, Columbia University, and Obesity Research Center, St. Luke’s–Roosevelt Hospital Center, New York, NY 10025; and Department of Physiology, University of Melbourne, and Howard Florey Institute of Experimental Physiology and Medicine, Parkville 3052, Melbourne, Australia

抄録

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.

収録刊行物

• Proceedings of the National Academy of Sciences

  Proceedings of the National Academy of Sciences 94 (16), 8878-8883, 1997-08-05

  Proceedings of the National Academy of Sciences

キーワード

• Multidisciplinary

詳細情報

• CRID: 1364233268678448000
• NII論文ID: 80009849706
• DOI: 10.1073/pnas.94.16.8878
• ISSN: 10916490
• ISSN: 00278424
• Web Site: https://pnas.org/doi/pdf/10.1073/pnas.94.16.8878
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