Mechanisms of Appetite Regulation

Hainerová, Irena Aldhoon*; Lebl, Jan

Journal of Pediatric Gastroenterology & Nutrition:
doi: 10.1097/MPG.0b013e3181f84208
Original Articles
Author Information

*Department of Pediatrics and Center for Research of Diabetes, Metabolism and Nutrition, Third Faculty of Medicine, Czech Republic

Department of Pediatrics, Second Faculty of Medicine, Charles University, Prague, Czech Republic.

Address correspondence and reprint requests to Irena Aldhoon Hainerová, Department of Pediatrics and Centre for Research of Diabetes, Metabolism and Nutrition, Third Faculty of Medicine, Šrobárova 50, 100 34 Prague 10, Czech Republic (e-mail:

The studies of monogenic obesity are supported by a research project from the Czech Ministry of Education No. MSM 0021620814.

The authors report no conflicts of interest.

Article Outline

Appetite regulation and adequate eating behavior are crucial for survival. To begin and to stop eating is a complex process. Appetite regulation, perception of hunger and satiety, eating behavior, and food preferences are in great part determined by genetic factors. Therefore, if tasty and energy-rich food is freely available in potentially unlimited quantities, overeating may occur due to insufficient defense mechanisms. Pleasure-seeking and hedonic responses to food intake are mediated by humoral substances, for example, endorphins, dopamine, and endocannabinoids.

The regulation of energy balance and appetite regulation is orchestrated by an interaction of peripheral signals (hormones, nutrients, neuronal signals) with the central nervous system (CNS), in which the hypothalamus plays a pivotal role. Receptors for multiple appetite-regulating hormones and neurotransmitters in the hypothalamic nucleus arcuatus are ready to accept and translate the peripheral signals. Hypothalamus disposes with 2 sets of neurons expressing either orexigenic (neuropeptide Y [NPY], agouti-related peptide [AgRP]), or anorexigenic neuropeptides (proopiomelanocortin [POMC], cocaine-amphetamine–related transcript). The orexigenic effectors activate the hunger center located in the lateral hypothalamus, in which orexins and melanin-stimulating hormone are expressed. The anorexigenic mediators activate the satiety center in the ventromedial hypothalamus, in which corticotropin-releasing hormone (CRH), thyrotropin-releasing hormone (TSH), and oxytocin are expressed. The orexigenic pathway leads to an increase of appetite and a decrease of energy expenditure; the anorexigenic pathways act in an opposite way. Both appetite-stimulating substances (ghrelin) and appetite-inhibiting substances (cholecystokinin [CCK], leptin, glucagon-like peptide 1 [GLP-1], and peptide YY3-36 [PYY3-36]) communicate with the brain either to increase or to decrease the feeling of hunger (Fig. 1) (1).

As human beings, we exhibit dietary habits and we learn to become hungry at a precise hour. At this moment, a hunger signal called ghrelin rises. Ghrelin is secreted from the stomach and leads to increased expression of NPY/AgRP and activation of the mesolimbic reward center. When a favorite meal is seen, premeal events occur, such as the cephalic phase–secretion of pancreatic juice, production of satiety signals, and heat. Concurrently, the mesolimbic region that mediates food pleasure activates. Approximately 30 minutes after the initiation of eating, intestinal tract, adipose tissue, and liver release both short-term and long-term satiety signals. The short-term signals as CCK, PYY3-36, and GLP-1 inhibit the orexigenic pathway. Whereas CCK is released by the upper intestine, PYY3-36 is secreted by L cells of the small and large bowel and has high affinity to Y2 receptors of the neurons expressing NPY/AgRP (Fig. 1). GLP-1 is cosecreted with PYY3-36 in response to nutrients in the gut. It enhances insulin secretion and suppresses glucagon secretion after food intake.

Long-term peripheral hormones regulating appetite are represented by insulin and leptin. Insulin reaches the CNS via receptor-mediated transport across the blood-brain barrier. Its increase in response to glucose load is proportional to fat mass. Circulating levels of leptin are proportional to adiposity. Leptin plays a key role in signaling and survival during periods of food deprivation and food excess. In humans, its levels increase after several days of overeating and fall with fasting. Effects of diet-induced thermogenesis and macronutrients are also essential for the regulation of appetite and satiety.

The leptin-melanocortin signaling system is the predominant regulatory system governing appetite and satiety. Leptin crosses the blood-brain barrier and activates its receptor. This action leads to the activation of POMC/cocaine-amphetamine–related transcript and the inhibition of NPY/AgRP. POMC is cleaved by enzymes prohormone convertase 1 and 2. One of its products is α-melanocyte–stimulating hormone that activates melanocortin type 3 and melanocortin type 4 receptors (MC4R) (Fig. 1). MC4R is crucial for body weight regulation because it inhibits orexigenic effectors and stimulates anorexigenic effectors. The importance of this signaling system in energy balance is illustrated by cases of gene mutation in this pathway (2).

Mutations of leptin gene lead to severe obesity due to impaired satiety and hyperphagia. Mutation carriers exhibit hypogonadism, hypothyroidism, and have almost undetectable leptin levels. The daily subcutaneous administration of leptin normalizes body weight, thyroid hormone levels, and induces puberty (3). Mutation carriers of the POMC gene also suffer from early-onset morbid obesity. Mutation carriers have low cortisol levels due to adrenocorticotropic hormone deficiency and present with red hair and pallor due to α-melanocyte–stimulating hormone deficiency (4). Mutations of the leptin receptor gene and the PC1 gene have also been identified and are characterized by early-onset obesity as well (5,6).

Mutations of the MC4R gene are the most common forms of monogenic obesity. Their prevalence among severely obese individuals ranges in different studies between 0.5% and 5.8% and they exhibit diverse weight phenotype. It is well recognized that homozygous mutation carriers suffer from hyperphagia, which leads to morbid obesity from the first months of life (7). Among 289 Czech children with early-onset obesity, we found a prevalence of 2.4% of MC4R gene mutations (8). We identified 1 novel missense mutation (Cys84Arg) and 1 mutation in a homozygous form (Gly181Asp). A comparison of weight, height, and body mass index in mutation carriers with noncarriers through 13 years of follow-up did not reveal any differences. MC4R gene mutation carriers showed a similar response to diet management as noncarriers.

Anorexigenic neuropeptide neuromedin U (NMU) is widely expressed in the CNS with particularly high expression in the hypothalamus. It was shown that knockout mice for this gene demonstrate an increased energy intake and a decreased energy expenditure, leading to a weight gain (9). In the Czech cohort, we identified the first human NMU mutation carrier (Arg165Trp) (10). The mutation cosegregated with childhood-onset obesity in a Czech family in all mutation carriers. We assume that NMU also has an impact on energy homeostasis in humans.

In conclusion, a number of signals contribute to the central regulation of appetite and satiety by acting directly on the hypothalamic arcuate nucleus. Mutations of genes involved in energy balance regulation as the leptin-melanocortin pathway lead to a loss of control over appetite and early-onset severe obesity. Probably more factors that play a role in energy intake regulation exist and so far have not been identified.

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