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Adiposity Signaling and Biological Defense Against Weight Gain: Absence of Protection or Central Hormone Resistance?

Department of Medicine (M.W.S.), Harborview Medical Center and University of Washington, Seattle, Washington, 98104; and Department of Medicine (K.D.N.), Vanderbilt University School of Medicine, Nashville, Tennessee 37232-6303

Address all correspondence and requests for reprints to: Prof. Michael Schwartz, Department of Medicine, Harborview Medical Center, University of Washington, 325 Ninth Avenue, Box 359757, Seattle, Washington 98104. E-mail: mschwart{at}u.washington.edu; or Kevin Niswender, Diabetes, Endocrinology and Metabolism, 715 Preston Research Building, Vanderbilt University Medical Center, 2220 Pierce Avenue, Nashville, Tennessee 37232-6303. E-mail: kevin.niswender{at}vanderbilt.edu.

An abundant and compelling literature supports the existence of a homeostatic system that dynamically adjusts energy intake and energy expenditure to promote stability of body fat mass. In the context of this system, the ease with which many individuals gain weight is difficult to explain. Some have argued that energy homeostasis operates primarily to defend against weight loss and that, over the course of evolution, biological defense against weight gain was not selected for. According to this Absence of Protection model, obesity is seen as the natural result of living in an obesigenic environment. An alternative hypothesis, termed the Central Resistance model, proposes that under normal circumstances, the energy homeostasis system provides an effective defense against weight gain as well as weight loss and that common forms of obesity involve genetic or acquired defects (or interactions between them) that impair the function of this system. Here, we discuss these dichotomous possibilities within the context of current literature regarding energy homeostasis and suggest a strategy for distinguishing between them.

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