Biological Psychiatry - Vol. 2

By Hugo D'Haenen; J.A. Den Boer et al. | Go to book overview

XXIII-3
Neuroendocrinology

Frances Connan


INTRODUCTION

Although over a single day food intake is poorly matched to energy expenditure, longer term food intake and energy expenditure can be extremely well balanced such that weight may remain remarkably stable over time (Edholm, 1977). However, the systems governing energy homeostasis appear to function more effectively to defend against starvation than they do in defence of overweight. Indeed, it has been argued that the capacity of the system to maintain healthy weight in the face of high availability of energy dense food and low physical activity levels is poor: there is a marked tendency to over consume, resulting in a high prevalence of obesity (Pinel et al., 2000). In addition to the significant morbidity associated with obesity in its own right, a tendency toward overweight may be a vulnerability factor for the most common of the eating disorders, bulimia nervosa (BN) and binge-eating disorder (BED). These disorders are associated with elevated subjective reward value of food (Karhunen et al., 1997a; Wisniewski et al., 1997), reduced subjective sense of satiety (Kissileff et al., 1996) and premorbid or family history of obesity (Fairburn et al., 1997, 1998).

At the other end of the weight spectrum, anorexia nervosa (AN) is characterized by reduced food intake, but the question of whether appetite is impaired remains controversial and poorly researched. Studies employing subjective assessment have consistently reported reduced hunger and desire to eat and enhanced satiety and sensation of fullness in people with AN (e.g., Halmi and Sunday, 1991; Robinson, 1989). Furthermore, the subjective reward value of food is reduced (Drewnowski et al., 1987; Sunday and Halmi, 1990), and the rate of eating is slow (Halmi and Sunday, 1991). Some authors argue that these findings reflect tight cognitive control of normal appetite (Palmer, 2000). However, relative to healthy comparison women, those with AN show reduced salivation (LeGoff et al., 1988) and a heightened autonomic response to food (Leonard et al., 1998). Images of food elicit fear and disgust (Ellison et al., 1998). These objective data suggest that appetite may indeed be impaired in AN (Pinel et al., 2000), although some capacity to respond to hunger and satiety cues clearly remains (Cugini et al., 1998; Rolls et al., 1992). A predisposition to leanness may be a risk factor for AN (Hebebrand and Remschmidt, 1995), supporting the notion that heritable risk for the disorder may be exerted through the biological systems regulating appetite and weight.

If we are to understand the neuroendocrinology of appetite and weight regulation in eating disorders, we must first understand the normal function of these systems and their responses to changes in body weight. It is well recognized that starvation causes profound changes in neuroendocrine systems and thus many of the findings associated particularly with AN, are liable to be consequence rather than cause of the disorder. Accordingly, the first section provides an overview of current models for understanding the neuroendocrine regulation of appetite and weight. Subsequent sections examine neuroendocrine data relating to each of the eating disorders in turn before presenting a synthesis and considering the implications for treatment and future research.


SECTION 1: REGULATION OF APPETITE AND WEIGHT

Leptin—A Peripheral Energy Sensor

The discovery of leptin in 1995 led to dramatic advances in the understanding of central pathways regulating appetite and weight. Leptin is a 146 amino acid protein that is synthesized and secreted by fat cells. When energy balance is stable, leptin concentration is proportional to fat mass (Considine et al., 1996). However, acute changes in energy balance modulate leptin expression, such that fasting is associated with a greater fall in leptin than might be expected for the change in fat mass and conversely, overeating results in an enhanced postprandial rise in circulating leptin (Ahima et al., 1996; Kolaczynski et al., 1996a). The leptin system therefore responds to potential weight change before fat mass actually changes.

The importance of leptin as a signal of energy balance is demonstrated by genetic strains of mice lacking functional leptin (ob/ob mice) or its receptor (db/db mice). These animals are hyperphagic, hypothermic, hyperinsulinaemic and obese (Chua-SC et al., 1996; Lee et al., 1996; Zhang et al., 1994). Although rare, genetic deficits of leptin signalling in humans are associated with a similar phenotype (Clement et al., 1998; Montague et al., 1997). Exogenous leptin administration reduces food intake and weight in normal and leptin deficient individuals (Farooqi et al., 1999; Halaas et al., 1997; Pelleymounter et al., 1995). Thus, despite the obese phenotype, genetic leptin deficiency is actually a model of starvation: reduced leptin levels signal reduced fat mass and appetite is appropriately elevated.

Leptin enters the brain via an active transport mechanism and its functional long-arm receptors are located in areas of the hypothalamus, such as the arcuate, ventromedial, paraventricular and dorsomedial nuclei (Elmquist et al., 1998): areas important for the function of neuroendocrine systems, including those regulating appetite and weight. The leptin system is therefore an excellent candidate for a peripheral signal of energy homeostasis and adequacy of fat stores to central systems coordinating the adaptive response to starvation.


Other Peripheral Signals of Energy Homeostasis

Several other peripheral hormones play a significant role in the central regulation of appetite. Insulin was one of the first hormonal signals known to be secreted in proportion to adipose mass. Insulin is actively transported across the blood-brain barrier and both insulin receptor mRNA and specific insulin binding sites

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