THE NEUROENDOCRINOLOGY OF OBESITY

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Obesity is a major public health problem not just in the United States but throughout the world. The Worldwatch Institute, an Internet watchdog group,22 now estimates that there are more obese than malnourished individuals worldwide. This epidemic is not restricted to one ethnic, age, or socioeconomic group, although cultural, environmental, and genetic influences clearly have a role. Obesity has been routinely considered a manifestation of voluntary behavior. Indeed, the US Health Care Financing Administration currently classifies obesity as a behavior and does not endorse insurance coverage for obesity therapies. Stedman's Medical Dictionary defines behavior as “a stereotyped motor response to a physiological stimulus.” What is the physiologic stimulus behind increased caloric intake or decreased energy expenditure? Other behaviors, such as alcoholism, now have identifiable genetic markers, promulgating the notion that they are diseases. Based on twin research3, 86 and recent discoveries of monogenic disorders causing obesity,8 the concept of obesity as a disease is maturing; however, the pathogenesis of obesity is clearly multifactorial. The worldwide incidence of obesity has doubled in the last 30 years, a rapid increase not attributable to changes in the human genetic pool; therefore, one gene or biochemical abnormality cannot explain all obesity. The etiologies of obesity are myriad, as are the potential therapies,19 but a rational approach to obesity is dependent on the development of a useful nosology with consistent and accurate diagnostic criteria. This article proposes that obesity is actually a phenotype of many diseases (most of which have not yet been identified). The focus is on conditions residing within a complex neuroendocrine negative feedback loop regulating energy balance.

Section snippets

NEUROENDOCRINE REGULATION OF ENERGY BALANCE

Within the last 6 years, endocrinologists have been able to close the feedback loop on the regulation of energy balance. This feedback loop has many inputs, neuromodulators, and effectors, a finding logical from a teleologic standpoint because the tight regulation of energy balance is essential to the survival and procreation of the species. In contrast to classic neuroendocrine negative feedback loops, the pituitary has a minor role. Instead, there are three primary neuroendocrine components

SUMMARY

The regulation of energy balance is enormously complex, with numerous genetic, hormonal, neural/behavioral, and societal influences. Although the current epidemic of obesity has its underpinnings in the changes in culture during the last half century, the role of the neuroendocrine system in the genesis of obesity is physiologically and therapeutically unavoidable. Increased understanding of this system has suggested organic etiologies (and therapies) for some rare and not-so-rare forms of

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    Address reprint requests to Robert Lustig, MD, Department of Pediatrics, Room S-672D, University of California San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, e-mail: [email protected]

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    Division of Endocrinology, Department of Pediatrics, University of California San Francisco, San Francisco, California

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