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Special issue: Pharmacology in The Netherlands
Anti-obesity drugs and neural circuits of feeding

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Most of the drugs that have entered the market for treating obesity were originally developed to treat psychiatric diseases. During the past decade, understanding of the neural circuits that underlie food intake has increased considerably. Different aspects of ingestive behavior such as meal termination, meal initiation and overconsumption of highly rewarding and palatable foods are modulated by different neuroanatomical structures. Integration of the action of many signaling molecules (e.g. hormones, neurotransmitters and neuropeptides) in these structures results in a response that, ultimately, modulates food intake. Thus, the type of drug required by an obese patient might depend on the individual cause of obesity. In this article, we summarize the neural circuits that regulate food intake and we provide a framework for understanding how obesity drugs function. Several potential drug targets are expressed in different neural circuits, implying that current and future obesity drugs act on partially overlapping systems that control food intake.

Introduction

Obesity is a risk factor for the development of diseases such as type II diabetes, stroke, cardiovascular disease and certain forms of cancer. We believe that being lean is a physical state to which many overweight individuals aspire. Dieting and exercising to lose weight require effort, willpower and persistence, making weight-reducing drugs an extremely attractive option (Table 1). The obesity epidemic has boosted the interest of the pharmaceutical industry in the development of anti-obesity drugs.

The discovery of drugs that have entered the market for the treatment of obesity is characterized by serendipity. Fenfluramine and sibutramine were discovered during the search for new antidepressants, and rimonabant was developed for smoking cessation, among other indications. When it was discovered that these drugs reduce food intake and induce weight loss, focus was turned towards the treatment of obesity 1, 2, 3.

Obesity is caused by energy intake (by ingestion) exceeding energy expenditure (by basal metabolic rate, diet-induced thermogenesis and exercise), with surplus energy stored in the form of fat. Over the past six decades, research has unraveled neural circuits that are implicated in the regulation of feeding. The entry of food into the stomach and intestines and the delivery of nutrients to the liver generate neural signals to the brainstem, via the vagal nerve, that have a role in the termination of a meal. The destruction of these neural inputs by vagal nerve cutting results in greater food intake (by increased meal size and frequency) [4]. Rats with knife-cut lesions between the brainstem and the midbrain (caudal–hypothalamus) do not increase meal size when food is restricted, as hungry rats normally do [5]. These data implicate the involvement of neural circuits in the brainstem during satiation (the process that limits meal size) but not during hunger, for which more-rostral neural circuits are required.

Electrical lesioning and stimulation studies in the hypothalamus have identified several nuclei that are important in the regulation of feeding behavior. Electrolytic destruction of the ventromedial hypothalamus increases feeding behavior (by causing meals to be eaten more frequently) and induces obesity 6, 7, 8. In addition, lesions of the hypothalamic paraventricular nucleus (PVN) and the arcuate nucleus (ARC), which are highly interconnected nuclei, also result in hyperphagia and obesity 9, 10. Moreover, electrical stimulation studies of the lateral hypothalamus (LH) activated a motor program that elicits feeding and hoarding even when sated [11], emphasizing the role of this nucleus in meal initiation and hunger signaling. Overall, these data implicate the hypothalamus in (the initiation of) feeding behavior.

In addition to the homeostatic control of feeding, which involves the brainstem and the hypothalamus, animals – including humans – also eat because palatable food is rewarding. It is hypothesized that this is because of the hedonic value of food [12]. Food reward and the anticipation of meals implicate the nucleus accumbens (NAcc) – a brain structure that is important in reward processing – in the control of food intake 13, 14. The NAcc is connected to both cortical and limbic brain regions such as the amygdala and orbitofrontal cortex (OFC), the LH and ventral tegmental area (VTA) [15], and is implicated in motivation to eat [16].

In this article, we describe how peripheral signals that affect energy balance modulate neural circuits. We then delineate the functional role of these circuits and describe how they are targets for anti-obesity drugs. Although anti-obesity drugs also have peripheral modes of action, we focus on the central mechanisms by which they affect food intake.

Section snippets

Peripheral hormones involved in satiation

Gastrointestinal and pancreatic hormones such as cholecystokinin (CCK), amylin, insulin and glucagon are released during, or in anticipation of, meals and act to limit meal size (reviewed in Refs 17, 18, 19). Other hormones that affect meal size are peptide YY (PYY)3–36, glucagon-like peptide (GLP)-1 and oxyntomodulin, which are released from distal intestinal L-cells. Levels of these hormones increase following meals and remain elevated for several hours (reviewed in Ref. [18]) (Figure 1a).

Targeting obesity

The discovery of leptin and other hormones involved in energy balance led to new opportunities for developing drugs to treat obesity (Table 2). Drugs that mimic the action of CCK, GLP-1, amylin and PYY3–36 could increase feelings of satiation and satiety, and antagonists of ghrelin receptors could decrease feelings of hunger (reviewed in Ref. [23]). Thus, these drugs would decrease appetite and caloric intake. CCK has an established role in satiation and satiety but, despite treatment with this

Concluding remarks

Research in recent years has further elucidated neural circuits that regulate food intake, providing a framework for understanding how drugs that suppress food intake function. Although these neural circuits do not act independently, from a drug discovery point of view, there are at least three levels at which ingestive behavior can be targeted: brainstem, hypothalamus and limbic corticostriatal system. These neural circuits use partially different signaling molecules. Anti-obesity drugs

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      Similarly in people, inducing suppression of dopamine signaling in ordinary volunteers may actually cause them to eat less rather than to eat more [425]. As a caveat, however, the brain has multiple anatomical dopamine systems, and dopamine and norepinephrine signaling in the paraventricular nucleusof medial hypothalamus can oppositely suppress food intake [426,427]. Appetite-suppressing action of dopamine in the paraventricular nucleus of hypothalamus may explain why amphetamine-type drugs can be dieting aids (i.e., by stimulating hypothalamic dopamine and norepinephrine systems), and conversely why long-term exposure to neuroleptic/anti-psychotic dopamine antagonist drugs can sometimes produce weight gain [428–430].

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