ReviewNeuroendocrine control of food intake
Introduction
The prevalence of obesity is increasing worldwide. In the United States, it has increased from 22.9% to 30.6% over 7 years, and according to the National Health and Nutrition Examination Survey (NHANES), which reports data from 1999 to 2002, 29.8% of adults aged at least 20 years were overweight, 30.4% were obese and 4.9% were extremely obese [1]. The prevalence rates in other industrialized countries are similar, and developing countries adopting a “westernized” lifestyle are exposed to a dramatic increase of this disorder. Accordingly, obesity is now considered as a global pandemic with over 300 million adults affected worldwide [2]. As expected, the prevalence of obesity-related disorders has also increased: about 80% of obese adults have at least one and 40% two or more comorbidities including diabetes mellitus, hyperlipidemia, arterial hypertension, cardiovascular disease, gallbladder disease and some forms of cancer [3]. Approximately 300,000 deaths per year may be attributed to obesity [4]. A weight gain of 1 kg has been shown to increase cardiovascular risk by 3.1% and diabetes risk by 4.5–9% [5], while an 11% weight loss reduces cardiovascular disease and diabetes mortality by 25% [6]. Therefore, effective treatments for obesity are urgently needed.
This article will review the present knowledge on the central and peripheral pathways interacting in the regulation of eating behavior as well as the possible role of their alterations in the pathophysiology of obesity. In this context, some promising pharmacological strategies targeting anorexigenic and orexigenic signaling peptides will be described.
Section snippets
Meal onset and termination
Brain is the recognized coordinator of eating behavior. Meal onset, however, does not appear to be chiefly regulated by biochemical signals. According to the old “glucostatic theory”, the “feeding center”, located in the lateral hypothalamic area (LHA), perceived the inter-meal fall of blood glucose and stimulated food intake. The subsequent post-prandial hyperglycemia was believed to activate the “satiety center” in the ventromedial hypothalamus (VMH), which inhibited the “feeding center” with
Arcuate nucleus
The chief pathways regulating meal size are summarized in Figure 1, Figure 2. Arcuate nucleus (ARC), adjacent to the third ventricle, is the chief hypothalamic area involved in the control of food intake and contains two interconnected groups of “first-order” neurons releasing neuropeptide Y (NPY) and agouti-related peptide (AGRP), which enhance food intake, and the anorexigenic substances pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART). The axons of these
Satiety signals
Satiety signals are generated in the gastrointestinal (GI) tract during a meal and regulate food intake on meal-to-meal basis, inducing a sense of fullness. After entering the GI lumen, nutrients trigger the secretion of several peptides which, in addition to other actions, activate vagal and sympathetic pathways afferent to the nucleus of the solitary tract (NTS) in the caudal brainstem (Fig. 2) where they provide information on the chemical and mechanical properties of the nutrients [8]. NTS
Leptin
Leptin, the ob gene product, is produced mainly in the adipose tissue and enters the brain in proportion to its plasma levels. Leptin maintains long-term control on adiposity and regulates adaptive metabolic changes in response to modifications of nutritional [42]. Leptin is also able to regulate short-term energy intake, modulating meal size according to changes in energy balance: with negative energy balance, low leptin signaling activates anabolic and inhibits catabolic circuits, enhancing
NPY
NPY is the most powerful central enhancer of appetite. Its expression is predominant in ARC, from which NPY neurons project to second-order neurons located in PVN, LHA, PFA, ventromedial (VMN) and dorsomedial (DMN) nuclei, and to other brain regions, setting in motion the anabolic pathway [48]. Furthermore, 90% of NPY neurons co-express AGRP [9]. Low leptin levels, hypoglycemia, hypoinsulinemia, and conditions of negative energy balance all enhance NPY mRNA expression in ARC. Central
Hypothalamic releasing hormones
CRH is highly expressed in PVN neurons and, when centrally injected, inhibits food intake and reduces body weight in rats [37]. Peripheral administration of human CRH increases energy expenditure and fat oxidation in humans [72]. Leptin infusion stimulates CRH expression, while pretreatment with a CRH antagonist attenuates the leptin-induced reduction of food intake and body weight [73]. In anorexia nervosa the ACTH response to CRH is inhibited, a finding compatible with enhanced spontaneous
The endogenous cannabinoids
In the regulation of eating behavior, endogenous cannabinoids are emerging as important “carriers” of metabolic information from the central nervous system to the periphery and vice versa.
The orexigenic effect of exogenous cannabinoids, exerted through G-protein-coupled cannabinoid (CB) type 1 and type 2 receptors, is well known. The two principal endocannabinoids in the brain are anandamide (AEA), derived from membrane phospholipids, and 2-arachidonoylglycerol (2-AG), derived from
Monoaminergic neurotransmitters
Monoaminergic neurotransmitters interact with neuropeptides and hormones to control satiety mechanisms and eating behavior. Serotonin, produced in the dorsal raphe nucleus, reduces food intake and body weight by diminishing appetite and increasing energy expenditure [9]. Based on these properties several antiobesity agents have been developed, as the serotonin agonists fenfluramine and dexfenfluramine and the inhibitors of serotonin reuptake fluoxetine and sertraline (Table 2). However,
Conclusions
The concepts on brain sites and mechanisms involved in the regulation of food consumption have evolved remarkably in the recent past, and new pathways have been added to the already complex network of central and peripheral messages controlling eating behavior and nutritional status. Satiety signals such as CCK, GLP-1 and PYY are delivered by the GI tract in concomitance to the meal and reach the brain chiefly through the vagus nerve. They are integrated with the adiposity signals leptin and
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