Ventral tegmental area

1 Introduction

The regulation of energy balance involves a matching of energy intake with energy expenditure, in order to maintain a stable body weight over time. The relative stability of body weight in most adults over prolonged periods is testament to the accuracy with which this regulatory system functions. Positive energy balance occurs when intake exceeds expenditure and leads to a progressive increase in body weight and adiposity if the appropriate negative regulation does not occur.

In this situation, prolonged positive energy balance will invariably lead to the development of obesity.

It is apparent within human populations that some individuals are better able to maintain an appropriate body weight than others in the face of an "obesogenic" environment. Studies in animal models have begun to shed some light on key pathways that may, at least in part, determine differential susceptibility to diet-induced obesity (DIO). The central nervous system (CNS) plays an essential role in the regulation of feeding and energy expenditure, integrating signals from gastrointestinal afferents and circulating nutrient-related factors to alter behaviour and neuroendocrine function (Schwartz et al. 2000). Although the discovery of leptin initially highlighted its critical role in the regulation of body weight, leptin receptors (LepRs) have since been identified in virtually every tissue, and diverse roles for this hormone have been shown in reproduction, development, immunity, cardiovascular function, cognition and some forms of cancers (Ahima and Flier 2000; La Cava and Matarese 2004; Harvey et al. 2005; Tune and Considine 2007). In this chapter, we will focus specifically on the role of leptin and LepRs in the regulation of feeding and energy homeostasis.

2 Historical Perspectives on the Discovery of Leptin

The genetically obese ob/ob mice were first described in 1950 by Ingalls and colleagues (Ingalls et al. 1950) who reported that in these animals, affected offspring began to display significant hyperphagia and increased body weight at around 4 weeks of age, and by 3 months, they were approximately twice the weight of non-obese littermates. Subsequent parabiosis experiments in which the circulatory systems of an obese animal were fused with a lean control mouse indicated that it was the lack of a blood-borne signal that caused the massive obesity in ob/ob animals, as this surgery resulted in a correction of hyperphagia and significant reduction in body weight of the obese animals (Coleman 1973). In contrast, the surgical union of an obese diabetic (db/db) mouse to a lean control was ineffective in rescuing the phenotype of these mice, suggesting a failure of these animals to respond to some circulating factor (Coleman 1978).

Almost 20 years later, the mutations responsible for these forms of genetic obesity were identified. In ob/ob mice, Friedman and colleagues identified a nonsense mutation in a gene that is expressed in white adipose tissue and normally produces a peptide hormone of 16 kDa expressed in and secreted by white adipose tissue (Zhang et al. 1994). The mutation causes the production of a truncated protein that is not secreted, and as a consequence of this defective secretion, ob/ob mice are massively obese. In addition, the expression of the ob gene is markedly elevated (approximately 20-fold) compared with wild-type mice (Zhang et al. 1994).

Following this discovery, a number of groups simultaneously investigated the effects of administering recombinant ob protein to ob/ob, wild-type and db/db animals. These studies showed that the treatment reduced food intake and increased oxygen consumption in ob/ob mice (Campfield et al. 1995; Halaas et al. 1995; Pelleymounter et al. 1995) but was without effect in db/db animals (Campfield et al. 1995; Halaas et al. 1995). In db/db mice, a loss-of-function mutation in the receptor for ob was found to be responsible for the obesity in these mice (Tartaglia et al. 1995). Thereafter, a variant of the receptor was identified which is partially responsible for the phenotype of the polygenic New Zealand mouse model of obesity (Igel et al. 1997; Kluge et al. 2000). The product of the ob gene was subsequently named leptin, and its receptor, leptin receptor (LepR), derived from the Greek word for thin, "leptos" (Halaas et al. 1995). Both ob/ob and db/db mice are also infertile and exhibit a reduced longitudinal growth. Thus, leptin clearly has widespread functions in the neuroendocrine regulation of growth and reproduction as well as body weight, the mechanisms of which are discussed in more detail below.

3 Homeostatic Regulation of Feeding in the Central Nervous System

In order to communicate the size of peripheral energy stores to the CNS, a circulating factor needs to be produced in response to changes in energy availability, to be circulated in amounts proportional to energy stores and to be sensed by the brain. Insulin was the first such satiety signal to be identified. Following feeding, circulating concentrations are increased, and insulin enters the brain via a regulated transport mechanism (Baura et al. 1993) where it acts at insulin receptors to bring about changes in feeding-related neuropeptides. Central administration of insulin acts to reduce energy intake and body weight (Woods et al. 1979), indicating a direct effect of this hormone at the level of the brain.

The second key hormone shown to act as a signal of plentiful energy stores was leptin. This peptide hormone is secreted predominantly by adipocytes, and in the adult, circulating levels are related to body mass (Maffei et al. 1995) but more closely correlated with the degree of adiposity (Liuzzi et al. 1999). Leptin, like insulin, is transported across the blood-brain barrier (BBB) by a saturable system (Banks et al. 1996) and also acts within brain regions that regulate feeding behaviour and thermogenic responses.

Numerous early ablation studies indicated a key role for the hypothalamus in the regulation of energy balance. Leptin receptors are widely expressed within the mediobasal hypothalamus (Mercer et al. 1996; Elmquist et al. 1998b). Within the hypothalamus, the arcuate nucleus (ARC) is considered to be a key primary nucleus with respect to reception and relay of nutrient-related signals from the circulation.

Two important populations of ARC cells are considered "first-order" neurons: those co-expressing the anorexigenic pro-opiomelanocortin (POMC) precursor and cocaine- and amphetamine-regulated transcript (CART) neuropeptide, and those co-expressing the orexigenic neuropeptide-Y (NPY) and agouti-related protein

(AgRP). Both of these neuronal populations express the receptors for, and respond to, alterations in concentrations of leptin and insulin (Baskin et al. 1999; Niswender and Schwartz 2003). Raised levels of these hormones, indicative of a fed state and sufficient energy stores, act centrally to increase POMC/CART expression and concomitantly reduce NPY/AgRP levels. Conversely, negative energy balance induced by food shortage has the opposite effects, as depicted in Fig. 1.

These neurons then project to further downstream nuclei within the hypothalamus, where additional information from brainstem and higher cortical centres is integrated. Key hypothalamic targets of ARC projections include the neurons of the paraventricular nucleus (PVN), dorsal medial nucleus (DMH), lateral hypothalamic area (LHA) and the ventromedial nucleus (VMN). Disruption of connections between the ARC and these nuclei is associated with an inability to successfully regulate energy balance (Dawson et al. 1997; Bell et al. 2000; Bouret et al. 2004). However, as discussed in more detail below, although the ARC has received much attention as a primary target in mediating the effects of leptin on energy balance, the role of other sites within the mediobasal hypothalamus and other regions of the brain is increasingly being recognised.

The critical role of neuronal leptin action in body weight regulation was definitively shown through the generation of mice with selective deletion of leptin receptors throughout the CNS (Cohen et al. 2001). These mice exhibit obesity and a peripheral hormone profile very similar to that of db/db mice. Conversely, adenoviral expression of leptin receptors within the ARC in Zucker fa/fa rats, which lack functional leptin receptors, was reported to ameliorate the obesity in these animals (Morton et al. 2003). However, other studies in mice report only a partial

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