Pathophysiology Molecular Mechanisms of Appetite Regulation Ji Hee Yu, Min-Seon Kim Diabetes & Metabolism Journal 2012;36(6):391-398.
DOI: https://www.frankenthalerfoundation.org
Published online: December 12, 2012
Division of Endocrinology and Metabolism, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Corresponding author: Min-Seon Kim. Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Korea. admin@frankenthalerfoundation.org
Copyright © 2012 Korean Diabetes Association
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://www.frankenthalerfoundation.org which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
The prevalence of obesity continues to increase at an alarming rate around the globe. The World Health Organization has forecasted that approximately 2.3 billion adults worldwide will be overweight and more than 700 million will be obese by 2015. Since obesity is associated with increased risks for type 2 diabetes, cardiovascular events, stroke, certain types of cancer, and neurodegenerative diseases, an obesity epidemic will threaten human health in the upcoming years.Obesity is a state in which energy intake exceeds energy expenditure over a prolonged period. Food intake is promoted by hormones signaling hunger, the availability of high calorie palatable foods, and learned food preferences. It is inhibited by leptin and other hormones that generate satiety, including insulin and gut-derived hormones. A chronic imbalance between hunger and satiety signals leads to long term alterations in food intake and body weight.
The hypothalamus, a small area of the brain located just below the thalamus, is the regulating center of appetite and energy homeostasis. The hypothalamus consists of several interconnecting nuclei: the arcuate nucleus (ARC), paraventricular nucleus (PVN), lateral hypothalamic area (LHA), ventromedial nucleus (VMN), and the dorsomedial nucleus (DMN). The ARC of the hypothalamus is adjacent to the median eminence, a circumventricular organ having defective blood-brain barriers (BBB). Thus, circulating hormones and nutrients can access the ARC without passing the BBB. Moreover, the ARC surrounds the third cerebroventricle. Hormones and nutrients in the cerebrospinal fluid can diffuse into the extracellular fluids of the ARC. Due to these anatomical features, the ARC is considered to be a hypothalamic area primarily sensing peripheral metabolic signals. In the ARC, there are two distinct neuronal populations: one is a group of neurons coexpressing orexigenic neuropeptides, including neuropeptide Y (NPY) and agouti-related peptide (AgRP), and the other is a subset of neurons expressing anorexigenic neuropeptides, including proopiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART). These neurons are first-order neurons where peripheral metabolic signals including leptin, insulin, ghrelin, and nutrients are primarily transferred. Anorexigenic monoamine serotonin also acts on POMC neurons through the 5HT-2C receptor to induce anorexia. POMC neurons send axonal projections to the second-order neurons in other hypothalamic areas, the PVN, VMN, and LHA.
Fig. 1 Hypothalamic nuclei involved in appetite regulation. ARC, arcuate nucleus; AM, amygdala; CC, corpus callosum; CCX, cerebral cortex; DMN, dorsomedial nucleus; FX, fornix; HI, hippocampus; LHA, lateral hypothalamic area; ME, median eminence; OC, optic chiasm; PFA, perifornical area; PVN, paraventricular nucleus; SE, septum; 3V, third ventricle; TH, thalamus; VMN, ventromedial nucleus.
The α-melanocyte-stimulating hormone (α-MSH), an anorexigenic neuropeptide, is produced by the posttranscriptional processing of POMC and released from presynaptic terminals of POMC neurons. By binding to the melanocortin-3 and -4 receptor (MC3R, MC4R) on the second order neurons, α-MSH activates catabolic pathways: reduced food intake and enhanced energy expenditure. Targeted deletion of the MC4R in mice resulted in hyperphagia, reduced energy expenditure, and obesity. In humans, MC4R mutations account for about 6% of severe early-onset obesity, supporting an important role for the central melanocortin system in the control of energy metabolism.Endogenous melanocotin receptor antagonist AgRP is released from the terminals of ARC NPY/AgRP-producing neurons to the synaptic space on the second order neurons where it competes with α-MSH on MC3R and MC4R and antagonizes the effects of α-MSH. Selective ablation of NPY/AgRP neurons in young mice resulted in a significant decrease in food intake and body weight, suggesting that these neurons are critical for promoting food intake and preventing weight loss.The PVN neurons synthesize and secrete neuropeptides that have a net catabolic action, including the corticotrophin-releasing hormone, thyrotropin-releasing hormone, somatostatin, vasopressin, and oxytocin. In addition, PVN sends sympathetic outflow to the peripheral metabolic organs, including liver and adipose tissue, resulting in increased fatty acid oxidation and lipolysis. Destruction of PVN and haploinsufficiency of Sim1, a critical transcriptional factor in the development of PVN, caused hyperphagia and obesity, implying a inhibitory role for PVN in food intake and weight gain.The VMN mainly receives neuronal projections from the ARC, and projects their axons to the ARC, DMN and LHA, as well as brainstem regions. The VMN contains neurons that sense glucose and leptin. Moreover, anorexigenic neuropeptide, a brain-derived neurotrophic factor (BDNF), is produced in the VMN. Destruction of the VMN caused hyperphagia and obesity, as well as hyperglycemia. Thus, the VMN is regarded as a pivotal area in generating satiety and maintaining glucose homeostasis. The DMN contains a high level of NPY terminals and α-MSH terminals originating from the ARC. Destruction of DMN also results in hyperphagia and obesity.In contrast to PVN, VMN, and DMN, destruction of LHA leads to hypophagia and weight loss. Therefore, LHA has been considered to be a feeding center. LHA contains two neuronal populations producing orexigenic neuropeptides, the melanin concentrating hormone (MCH) and orexin, also called hypocretin. NPY/AgRP- and α-MSH-immunoreactive terminals from ARC neurons are in contact with MCH- and orexin-expressing neurons. Orexin-producing neurons are also involved in glucose sensing and the regulation of sleep-awake cycles. Mice with orexin receptor 2 displayed canine narcolepsy. On the other hand, depletion of MCH or the MCH 1 receptor in mice attenuated body weight, suggesting that MCH acts as endogenous orexigenic molecules.
The brainstem is another key brain area involved in regulation of food intake and energy balance. Satiety signals from the gastrointestinal (GI) tract primarily relay to the solitary tract nucleus (NTS) through the sensory vagus nerve, a major neuronal link between the gut and the brain. Transaction of sensory vagal fibers resulted in increased meal size and meal duration, confirming that vagal
