Heart and Metabolism

The brain and regulation of body weight

Randy J. Seeley, Stephen C. Woods
Department of Psychiatry, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA Correspondence: Dr Randy Seeley, Department of Psychiatry, University of Cincinnati,
Cincinnati, OH 45267-0559, USA. Tel: +1 513 5586664, fax: +1 513 5588990, e-mail: randy.seeley@uc.edu

Abstract

Over the last decade, increasing evidence supports an important role of the brain in the control of energy balance and disorders of energy balance such as obesity. Total body adipose tissue is carefully regulated by negative feedback from hormonal signals that reflect the status of peripheral fat stores. Adiposity signals, such as leptin and insulin, then act directly upon hypothalamic circuits. These hypothalamic neuropeptide systems can be divided into two categories. Anabolic systems are activated by low levels of adiposity signals and work to increase food intake, decrease energy expenditure, and increase body fat stores. Catabolic systems are activated by high levels of adiposity signals and work to decrease food intake, increase energy expenditure, and decrease body fat stores. Traditional means for losing weight are plagued by very low success rates likely due to these redundant and overlapping neuroendocrine responses that serve to maintain energy balance. The substantial progress in this area has led to the possibility of understanding obesity as a disorder related to these neuroendocrine systems and that effective treatment options can result from targeting the brain rather than just the adipocyte.
- Heart Metab. 2002;17:4-7.

Keywords: Obesity, neuropeptide Y, pro-opiomelanocortin, melanocortin, leptin, insulin,
a-melanocyte stimulating hormone, food intake, energy expenditure

Adiposity signals
The last 10 years has seen a revolution in the scientific understanding of how body weight is regulated. The timing of this revolution is none too soon since the need for therapeutic interventions for disorders of body weight regulation such as obesity is becoming paramount. In the USA, obesity now afflicts 19.8% of the population, with an additional 35.1% classed as overweight; individuals in each of these categories are at increased risk for heart disease, diabetes mellitus, and some cancers [1]. It is currently estimated that 300 000 people die each year in the USA as a result of obesity, ranking it among the most severe public health crises we face [2]. The urgent clinical need to treat obesity has accelerated the pace of research on how energy balance is normally maintained by matching energy intake to energy expenditure over long periods of time.
Under most circumstances, changes of body fat simply reflect the difference between energy intake and energy expenditure. A half-century ago, Kennedy [3] proposed that energy balance is maintained by the monitoring of total body fat stores by the brain, and the brain in turn adjusting caloric intake and/or caloric expenditure to keep body fat stores within a narrow range. A critical issue was determining how the brain monitors the total amount of adipose (fat) tissue, since it is scattered and distributed throughout the body. The answer is that the brain is sensitive to the levels of endocrine signals (hormones), which are proportional to the amount of stored fat. Several hormones meet the criteria for being “adiposity signals” that provide negative feedback to the brain in this process and help maintain relatively constant adipose stores [4]. The two best known are the adipocyte hormone leptin and the pancreatic hormone insulin. Both hormones circulate in direct proportion to the total amount of adipose tissue, both cross the blood—brain barrier by receptor-mediated uptake systems, and both have specific receptors located in regions of the brain associated with the control of body weight [5–9]. Administration of either leptin or insulin directly into the CNS results in a dose-dependent reduction in food intake and body weight loss that is not attributable to incapacitation or illness [10–12]. Importantly, genetic manipulations that result in reduced leptin or insulin signaling in the CNS result in increased food intake and obesity [13, 14].

Brain effectors to regulate energy
Since the discovery of leptin in 1994, considerable attention has been focused on the brain systems that are the target for the actions of adiposity signals to regulate energy balance. These systems can be divided into two broad categories. The first includes “anabolic” effectors: neural circuits that produce an increase in caloric intake, a decrease in caloric expenditure, and a net gain in body energy stores when they are activated. These anabolic systems are activated during times of negative energy balance when levels of adiposity signals are low. The second category comprises “catabolic” effectors: neural circuits that produce a reduction in food intake, an increase in energy expenditure, and a net loss in body energy stores when activated. Catabolic systems are activated during times of positive energy balance when levels of adiposity signals are high (Figure 1).

Figure 1. Model of the regulation of energy balance via neuroendocrine responses to alterations of energy balance.

Modern molecular biology has identified a number of brain neuropeptides that can be categorized as having either a net anabolic or a net catabolic action. For simplicity, we focus on those systems that are directly regulated by leptin. Neurons containing the signaling form of the leptin receptor (LepRb), as well as the insulin receptor, are localized in the arcuate nucleus of the hypothalamus [15, 16]. Within the arcuate, there are two identified populations of neurons. One population comprises neurons that synthesize pro-opiomelanocortin (POMC), a precursor molecule for several important neuropeptides including a-melanocyte stimulating hormone (a-MSH). In the periphery a-MSH regulates skin and hair color, but in the brain a-MSH potently inhibits food intake and increases energy expenditure via its interaction with melanocortin (MC) receptors 3 and 4 [17]. Importantly, POMC neurons express leptin and insulin receptors, and POMC gene expression is inhibited during negative energy balance when insulin and leptin levels are low, and stimulated during positive energy balance [18–20]. A state of positive energy balance can be mimicked by administering either leptin or insulin directly into the CNS, and the response is a reduction of food intake and body weight. Thus POMC/
a-MSH and its associated receptor have all the hallmarks of a catabolic effector system.
The second population of neurons in the arcuate synthesize neuropeptide Y (NPY). Although NPY is synthesized in numerous regions of the brain, only the NPY neurons in the arcuate express leptin receptors, and the expression of NPY is increased during negative energy balance and inhibited by both leptin and insulin [5, 7]. Moreover, administration of NPY directly into the brain elicits a robust increase of food intake and concomitant decrease of energy expenditure. Thus, the NPY system has all the hallmarks of an anabolic effector system. NPY neurons in the arcuate nucleus synthesize a second neuropeptide termed agouti-related peptide (AgRP). AgRP is unique in that it is a potent endogenous antagonist of MC3 and MC4 receptors and therefore works to counter the effects of a-MSH [21]. AgRP expression is elevated during negative energy balance and inhibited by adiposity signals. Like NPY, AgRP potently stimulates food intake when administered into the CNS [22].

The difficulty of maintaining weight loss
The picture that emerges is a powerful set of neuroendocrine responses during negative energy balance that make maintaining sustained weight loss exceedingly difficult. When inadequate food is consumed, energy stored in adipose tissue is used as fuel, and levels of insulin and leptin fall. As a result of the reduced signaling of these hormones in the arcuate, a-MSH activity falls while NPY activity rises. Additionally, a-MSH activity is further diminished by increased release of AgRP that antagonizes a-MSH action at MC3/4 receptors (Figure 2).

Figure 2. Relationship of arcuate nucleus neuropeptide systems that influence food intake and energy expenditure

Most weight loss strategies are likely to fall prey to these neuroendocrine responses that encourage the maintenance of energy stores in mammalian species. Successful treatment of obesity will likely require a more complete understanding of the highly interconnected and redundant CNS systems that normally maintain energy balance. Only when we are able to harness these CNS responses that normally work against the obese patient are we likely to provide effective treatment strategies for obesity.
Needless to say, the advances in understanding the critical role of the brain to regulate body weight opens up the possibility that at least some of the underlying etiologies of obesity are the result of either environmental or genetic influences that either increase anabolic signaling or decrease catabolic signaling within the brain. Exploring these hypotheses in humans is extraordinarily difficult, but some data do provide evidence for substantial genetic links between decreased melanocortin system activity and obesity [23]. However, progress is being made to describe CNS changes in a number of animal models that become obese when exposed to specific dietary regimens [24, 25]. This is an exciting time because no longer are we limited to thinking of obesity as a disease specifically of fat cells. Rather, it is a disease of a body weight regulatory system of which the brain is an essential component. This opens up both new opportunities for understanding why some individuals become obese and how we might treat them.

Acknowledgments
This work was supported by grants from NIH (DK54080, DK17844, DK56863) and funds from the Procter & Gamble Company.

REFERENCES

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