Central Nervous System Regulation of Food Intake

Introduction Some 50 years ago, Gordon Kennedy introduced the hypothesis that body fat stores are subject to homeostatic regulation through a process in which afferent signals generated in proportion to body fat mass provide negative feedback to brain areas involved in the control of food intake (1). He further proposed that the central nervous system response to this input is fundamentally catabolic in nature, being characterized by decreased food intake, increased energy expenditure, and weight loss. Accordingly, weight gain caused by a period of excessive food consumption is hypothesized to increase the delivery of “adiposity negative feedback” signals to the brain. This response in turn induces a state of negative energy balance (i.e., energy intake less than energy expenditure) that persists until excess body fat is dissipated, at which point both food intake and body weight return to their original, preintervention levels. Conversely, the effect of energy restriction to reduce body fat stores is predicted to reduce adiposity-related negative feedback to the brain. This response triggers a compensatory increase in the drive to eat that, combined with decreased metabolic rate, favors the recovery of depleted fat stores when food becomes available. The importance of this model lies not only in the light that it sheds on the mechanisms underlying energy homeostasis in normal weight individuals but in the framework it provides for studying obesity as a disorder of a regulated system rather than as the consequence of a lack of restraint or will power. Another attractive feature of this model is that it lends itself to critical hypothesis testing. For example, it predicts that genetic or acquired defects in neuronal sensing or responsiveness to input from adiposity-related signals should be interpreted by the brain as a deficit of body energy stored in the form of fat. In response, hyperphagia, reduced metabolic rate, and pathological expansion of body fat mass should occur. Evidence in support of this prediction first emerged from studies using a technique known as “parabiosis.” In this paradigm, two experimental animals are surgically joined to one another, allowing a shared circulation to develop. With this strategy, Coleman showed that food intake and body weight of genetically obese mice (ob/ob) decrease when they were parabiosed to lean controls and that this weight loss was even more pronounced when they were parabiosed to mice with a different monogenic form of obesity (db/db) (2). From these observations, he inferred that ob/ob mice are obese because they lack a key adiposity negative feedback signal, whereas db/db make this signal (and hence reduce the body weight of parabiosed ob/ob partners) but are obese because they cannot respond to it. Both predictions were realized some 20 years later with the positional cloning of the ob gene locus in 1994 (3) and the demonstration that it encodes the adipocyte hormone, leptin. In this landmark paper, ob/ob mice were also shown to be homozygous for a point mutation that results in a biologically inactive leptin molecule. Thus, severe hyperphagia and obesity in ob/ob mice was hypothesized to arise from leptin deficiency, and indeed, leptin administration was subsequently shown to reverse this obesity phenotype (4,5). Two years later, the leptin receptor was cloned (6), and the obese phenotype of db/db mice was shown to arise from a mutation in the leptin receptor gene. Together, these findings showed that genetic deficiency of either leptin or its receptor is sufficient to induce a severe obesity phenotype in mice. Combined with evidence that leptin circulates at levels proportionate to body fat stores, that it enters the brain from the circulation, that leptin receptors are expressed in brain areas associated with control of food intake and autonomic function, and that leptin administration directly into the brain potently reduces food intake and body weight (7), Kennedy’s model of energy homeostasis, once viewed with understandable skepticism, was rapidly and widely accepted. The intense interest in the biology of energy homeostasis sparked by these and many subsequent findings has yielded Department of Medicine, Harborview Medical Center, University of Washington, Seattle, Washington. Address correspondence to Michael W. Schwartz, Department of Medicine, Harborview Medical Center, University of Washington, 325 Ninth Avenue, Box 359675, Seattle, WA 98104. E-mail: mschwart@u.washington.edu Copyright © 2006 NAASO