20 YEARS OF LEPTIN: Role of leptin in energy homeostasis in humans

  1. Rudolph L Leibel
  1. Division of Molecular Genetics, Departments of Pediatrics and Medicine, College of Physicians and Surgeons, Columbia University, Russ Berrie Medical Science Pavilion, 6th Floor, 1150 St Nicholas Avenue, New York, New York 10032, USA
  1. Correspondence should be addressed to M Rosenbaum; Email: mr475{at}columbia.edu
  1. Figure 1

    Two models of leptin endocrine action in the context of obesity, which illustrate possible answers to the question as to whether leptin's primary homeostatic role is to restrain adiposity by provoking catabolic responses (reduced energy intake and increased energy expenditure), or to protect body fat in service of reproductive integrity and survival in adverse environmental circumstances? This distinction is critical to integrating the large literature on the biology of leptin and to formulating therapeutic approaches to obesity. 1A depicts a classical linear ‘symmetrical’ catabolic endocrine response (e.g., to thyroid hormone), in which leptin sensitivity is depicted as congenitally reduced in individuals predisposed to obesity. 1B depicts a very different model in which leptin's primary role is to provoke anabolic responses when its circulating concentration reaches a critical minimum (‘threshold’), which is determined by genetic, developmental, and intercurrent metabolic circumstances. The threshold is higher in individuals predisposed to obesity; hence their acquisition and defense of a higher level of body fat. As discussed in the text, physiological and pharmacological studies support the 1B model. Of note is that the leptin concentration ‘thresholds’ for specific physiological processes (e.g., gonadal axis, insulin homeostasis, immune function, and energy intake/expenditure) are not identical, and brain regions and cells, somatic cell types, and signaling mechanisms (e.g., JAK–STAT) also differ (Myers et al. 2008, Villanueva & Myers 2008).

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