Mechanisms of Appetite Regulation

Mechanisms of Appetite Regulation

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.

Appetite is the desire to eat food, felt as hunger. Appetite exists in all higher life-forms, and serves to regulate adequate energy intake to maintain metabolic needs. It is regulated by a close interplay between the digestive tract, adipose tissue and the brain. Appetite has a relationship with every individual’s behavior. Appetitive and consummatory behaviours are the only processes that involve energy intake, whereas all other behaviours affect the release of energy. When stressed, appetite levels may increase and result in an increase of food intake. Decreased desire to eat is termed anorexia, while polyphagia (or “hyperphagia”) is increased eating. Dysregulation of appetite contributes to anorexia nervosa, bulimia nervosa, cachexia, overeating, and binge eating disorder.

The 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.

Mechanisms of Appetite Regulation

  • Poorly and incompletely understood
  • Genetics 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. Among 289 Czech children with early-onset obesity, prevalence of 2.4% of MC4R gene mutations. One 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.
  • Pleasure-seeking and hedonic responses to feed intake are mediated by humoral substances (endorphins, dopamine, etc)
  • Interaction between hormones, nutrients, and neuronal signals with the CNS 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
  • The Gut Hormones in Appetite Regulation. More than 30 gut hormone genes are known to be expressed, and more than 100 bioactive peptides are distributed in the gastrointestinal tract, which is thus regarded as the largest endocrine organ in the body. Meal anticipation and the presence of food in the upper gastrointestinal tract stimulate the release of gut hormones and neurotransmitters from the gut. These neurohumoral signals are involved in the initiation and maintenance of food intake as well as termination of meals. The satiating effect of stomach distension is revealed by observing that infusion of either saline or nutrients into the rat stomach results in same reduction in food intake . In humans, the effects of intragastric balloon insertion on body weight and food intake are conflicting ; this may reflect differences in the types of balloon used during these studies.
    Both meal duration and size are markedly increased during sham feeding, where ingested food is prevented from distending the stomach or small intestine by surgical intervention, whereas intraluminal gastrointestinal (GI) infusion of macronutrient before food access reduces subsequent meal size in a dose-dependent manner. These findings suggest that the upper GI tract has an important role in negative feedback regulation of food intake, and the upper intestine is critical for nutrient absorption. The vagus nerve is closely implicated in the transmission of the food-induced negative feedback signals which are critical for determining meal size. Transection of all gut sensory vagal fibres results in increased meal size and meal duration but does not block gastric preload-induced feeding suppression; this implies that vagal afferent signals contribute to satiety during spontaneous meals. Perfusion of nutrients into the colon inhibits upper gastrointestinal secretion, motility, and transit; this negative feedback mechanism has been called the “ileal brake” . Fat is the most potent trigger of the ileal brake, and glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) may be among the mediators of this phenomenon
  • The hypothalamic regulation of appetite The past decade has witnessed an upsurge in our understanding of the hypothalamic regulation of appetite. Expression of appetite or the motivational drive toward an energy source is a highly regulated phenomenon in vertebrates. It is considered a cornerstone for maintenance of energy homeostasis and for rigidly guarding the body weight around a set point. Abnormalities in the onset, periodicity, duration, and magnitude of eating episodes generally underlie augmented appetite . Increased appetite, whether temporary, as seen clinically in transient bingeing, or permanent, invariably culminates in an increased rate of body weight gain and obesity. On the other hand, anorexia due to psychobiological causes  or in response to acute and chronic infections, inflammation, and trauma is followed by severe loss of body weight. There is now a growing recognition that expression of appetite is chemically coded in the hypothalamus. A perceived corollary is that subtle and progressive derangement in this neurochemical signaling, produced by environmental, genetic, and hormonal factors, impels either hyperphagia or anorexia. This conceptual advance has led not only to the identification and characterization of a multitude of neurotransmitters/neuromodulators that either propagate and transmit, or terminate appetite-stimulating impulses, but also to the precise tracking of pathways containing these signal molecules and the intricate interconnections among them. Increased knowledge of the molecular events governing synthesis, release, and signal transduction sequelae of each of these appetite-regulating messengers has enhanced our awareness of the phenomenon of coexistence and corelease of these chemicals in the cross-talk that ensues in response to an ever changing internal milieu. Consequently, information amassed during this decade has revised our views on the hypothalamic control of appetite and helped to detail the mechanistic attributes of locally derived signals in regulating energy homeostasis. These attributes have crystallized into the following broad categories: 1) Embedded in the networks controlling a multitude of hypothalamic functions, there is a distinct circuitry regulating appetite. This circuitry is composed of an interconnected network of pathways elaborating and emitting orexigenic and anorexigenic signals. 2) The neurons producing these orexigenic and anorexigenic signal molecules are subject to modulation by the internal milieu comprised of a variety of hormonal and other biologically active molecules. In this respect, the recent identification of the adipocyte protein, leptin, has renewed interest in feedback mechanisms between adipocytes and the appetite-regulating hypothalamic circuitry. 3) A cascade of temporally related neural events in various components of the appetite-regulating network (ARN) precedes feeding episodes. 4) Emerging evidence supports the involvement of a distinct neural device for the timely onset of appetite expression, and disintegration of this control may result in unregulated food consumption. 5) A deficit in availability of orexigenic signal(s) at the signal transduction level, whether temporary or permanent, can perturb the postsynaptic receptor dynamics that eventuate in hyperphagia and increased body weight gain indistinguishable from that produced by excessive production and release of orexigenic signals. 6) Coexistence and corelease of orexigenic signals, along with the redundant overlapping and interconnected orexigenic and anorexigenic signaling pathways within the hypothalamus, provide a microenvironment wherein subtle perturbations shift signaling in favor of unregulated hyperphagia rather than anorexia. The central theme of this article is to critically review our understanding of these fundamentals underlying neural control of appetite and to collate the growing information on several newly identified messenger molecules. Emphasis is placed on the anatomical distribution of signal-producing pathways in the hypothalamus, the site and mode of action of peripheral signals, and the cellular and subcellular events underlying hyperphagia and obesity in experimental and genetic models. In doing so we will present a conceptual model, which encompasses a broad spectrum of appetite-regulating messenger molecules, to explain the dynamics of the neural circuitry involved in stimulation and inhibition of appetite.
  • Appetite stimulus: ghrelin 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 . 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.
  • Appetite inhibition: CCK, leptin, GLP-1 etc)  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). 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. 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. 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. Mutations of the leptin receptor gene and the PC1 gene have also been identified and are characterized by early-onset obesity as well
  • GI volume sensitive feedback loops (ie distention)
  • Anorexigenic neuropeptide neuromedin U (NMU) 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. In the Czech cohort, we identified the first human NMU mutation carrier (Arg165Trp). 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

References:

  • Suzuki K, Simpson KA, Minnion JS, et al. The role of gut hormones and the hypothalamus in appetite regulation. Endocr J 2010; 57:359–372.
  • Satya P. Kalra, Michael G. Dube,Shuye Pu, Bin Xu, Tamas L. Horvath. Pushpa S. KalraInteracting Appetite-Regulating Pathways in the Hypothalamic Regulation of Body Weigh. Endocrine Reviews February 1, 1999 vol. 20 no. 1 68-100
  • Hainerová I, Torekov SS, Ek J, et al. Association between Neuromedin U gene variants and overweight and obesity. J Clin Endocrinol Metab 2006; 91:5057–5063.
  • Hanada R, Teranishi H, Pearson JT, et al. Neuromedin U has a novel anorexigenic effect independent of the leptin signaling pathway. Nat Med 2004; 10:1067–1073.
  • Keisuke Suzuki, Channa N. Jayasena, and Stephen R. Bloom. The Gut Hormones in Appetite Regulation. Journal of ObesityVolume 2011 (2011), Article ID 528401, 10

 

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