The Concept of Selective Leptin Resistance

Evidence From Agouti Yellow Obese Mice

  1. Marcelo L.G. Correia,
  2. William G. Haynes,
  3. Kamal Rahmouni,
  4. Donald A. Morgan,
  5. William I. Sivitz and
  6. Allyn L. Mark
  1. From the Hypertension Genetics Specialized Center of Research and Department of Internal Medicine, University of Iowa College of Medicine, Iowa City, Iowa; and the Veterans Administration Medical Center, Iowa City, Iowa


    Leptin, a hormone secreted by adipose tissue, acts to inhibit appetite and promote metabolism, thereby reducing body weight. Leptin also increases sympathetic activity and arterial pressure. Several murine models of obesity, including agouti obese mice, exhibit resistance to the anorexic and weight-reducing effects of leptin. Hypertension in agouti mice has been attributed to hyperleptinemia. These observations pose a seeming paradox. If these mice are leptin-resistant, then how can leptin contribute to hypertension? We tested the novel hypothesis that these mice have selective leptin resistance, with preservation of the sympathoexcitatory action despite resistance to the weight-reducing actions. Leptin-induced decreases in food intake and body weight were less in agouti obese mice than in lean littermates. In contrast, leptin-induced increases in sympathetic nerve activity did not differ in obese and lean mice. These findings support the concept of selective leptin resistance, with resistance to the metabolic actions of leptin but preservation of the sympathoexcitatory actions. This finding may have potential implications for human obesity, which is associated with elevated plasma leptin and is thought to be a leptin-resistant state. If leptin resistance is selective in obese humans, then leptin could contribute to sympathetic overactivity and its adverse consequences in human obesity.


    • Address correspondence and reprint requests to Allyn L. Mark, 220 CMAB, University of Iowa, Iowa City, IA 52242-1101. E-mail: allyn-mark{at}

      Received for publication 29 June 2001 and accepted in revised form 25 October 2001.

      M.L.G.C. is currently affiliated with Hospital Universitario Pedtro Ernesto, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil.

      SNA, sympathetic nerve activity.

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