Appetite Control and Energy Homeostasis
By Sergey Skudaev
Introduction
A human body energy balance depends on the amount of consumed food and energy expenditure. Amount of food we consume depends on one's appetite and activity of the rewarding system. Brain rewarding system is responsible for pleasure. The rewarding system is activated during eating. That is why, even if we are not hungry, we still eat for pleasure.
Energy expenditure depends on activity of the endocrine system. For example, thyroid gland hormone increases energy expenditure because more energy is released as the heat.
During the stress, glucocorticoid hormone of adrenal gland causes gluconeogenesis, a process when proteins are broken down to amino acids and the latter are converted to glucose. That is why stress increases energy expenditure.
Hipothalamus
The hypothalamus is a brain area that is responsible for regulation of all body functions and system such as endocrine system, gastro-intestinal system, cardio-vascular system, reproductive system ect. Hypothalamus is comprised of many nuclei.
Hunger centre and Satiety Centre
It was found that lesion of the ventromedial nucleus (VMN) of hypothalamus increases food intake, while stimulation of the VMN nucleus decreases feeding.
In opposite, lesion of the lateral hypothalamic nucleus (LHA) decreases food intake and stimulation of the nucleus increases food intake.
It was concluded that ventromedial nucleus (VMN) is a 'satiety centre' and lateral hypothalamic nucleus (LHA) is a 'hunger centre'.( Stellar 1994 )
Arcuate Nucleus
Later, there were discovered many endogenous substances which affect appetite and energy expenditure. Neuropeptide Y (NPY) and Agouti-related peptide (AgRP) are produced in the hypothalamus by neurons of Arcuate nucleus.
NPY and AgRP stimulate food intake and decrease energy expenditure by affecting thyroid gland. On the other side, Pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART), which also are produced in Arcuate nucleus, decrease food intake and increase energy expenditure.
Mutation in POMC gene or deficiency of the melanocortin receptors causes obesity. The lateral hypothalamic nucleus (LHA) produces the melanin-concentrating hormone (MCH) and orexins, which stimulate appetite. MCH level is increased with fasting. The intracerebroventricular administration of MCH increases food intake, while antagonists of MCH-1 receptor decreases food intake. (Cone et al 1998, Kristensen et al 1998)
Leptin
Adipose tissue produces a peptide hormone called leptin. Its level in circulatory system reflects the mass of adipose tissue. Intravenous administration of leptin to wild mice reduces food intake, loss of body weight and fat mass.
Leptin also increase energy expenditure. Mutation in ob gene, responsible for producing leptin, causes hyperphagia and obesity. Leptin, circulating in blood, is transported across blood-brain barrier. It transport decreases in fasting and increases after feeding. (Maffey et al. 1995 )
In brain leptin binds to Ob-Rb receptors, which are located in ARC, VMH, DMH and LHA hypothalamic nuclei, mentioned before. Leptin inhibits Neuropeptide Y (NPY) and Agouti-related peptide (AgRP) neurons, which activate feeding. At the same time, leptin activates POMC/CART neurons, which suppress appetite and increase energy expenditure. It is thought that the obesity can be caused not only by low level of leptin but also by deficiency of oB-Rb receptors. (Maffey et al. 1995, Konturek et al 2004)
Adiponectin
One more important peptide is produced by adipose tissue called Adiponectin. It increases energy expenditure by affecting hypothalamus. Adiponectin increases insulin sensitivity. Lack of the Adiponectin causes insulin resistance. In mice, treatment with Adiponectin increases insulin sensitivity and reduces body-weight gain. (Hotta et al. 2001)
Ghrelin
The stomach, duodenum and colon produce a peptide, called Ghrelin, which level is high during a fasting period and decreased after feeding. Ghrelin receptors were found in the hypothalamus and brain stem on the same neurons that produce NPY and AgRP. Ghrelin increases appetite by activating NPY and AgRP neurons in ARC of the hypothalamus.( Wynne et al 2005, Tschop et al 2000, Konturek et al 2004)
The PP-fold peptides
The PP-fold peptides include peptide tyrosine-tyrosine (PYY), Pancreatic Peptide (PP) and neuropeptid Y (NPY).
peptide tyrosine-tyrosine (PYY
The ileum, colon and rectum release PYY peptide. Its level is increased right after feeding and remains elevated for up to 6 hours. PYY delayed gastric emptying, gold bladder emptying and pancreatic and gastric secretion. The peripheral administration of PYY to rodents reduces food intake and weight gain. PYY directly affect ARC nucleus where it binds to Y2 receptors, which inhibit NPY neurons.
PYY reduces appetite in human. Obese patients have relatively low level of PYY in blood and their PYY secretion in response to feeding is reduced. The peripheral administration of PYY reduces appetite and weight gain in obese patients. The intracerebroventricular administration of PYY stimulates food intake in rodent. The peripheral and central administration of PYY may affect different receptors. ( Battrham et al 2002, 2003, Konturek et al 2004, Chaudhri et. al 2006)
Pancreatic peptide (PP)
Pancreatic peptide (PP) mainly is produced by the endocrinal pancreas, and less by colon and rectum. Its release correlates with amount of calories consumed with food. The gastric distension, and gut hormones (ghrelin, motilin and secretin) increase level of PP. The peripheral administration of PP reduces food intake, body weight and energy expenditure in rodents and mice. PP reduces insulin resistance and dyslipidemia, gastric emptying and production of ghrelin by stomach.
Patients with Prader-Willi syndrome have low level of PP. In opposite, anorexic patients have high level of PP, though not all researches confirmed such correlation. PP does not cross blood-brain barrier; however it can affect central nervous system (CNS) via area postrema, where blood-brain barrier is deficient. The intracerebroventricular administration of PP increase food intake in rodent. (Wynne et. al 2005)
Glucagon-like Peptide-1 (GLP-1)
Glucagon-like Peptide-1 (GLP-1) and Oxyntomoduline (OXM) are produced in small intestine and pancreas by L-cells and in CNS. GLP-1 and OXM levels increase after food ingestion, proportionally to calorie intake. Administered centrally or peripherally, GLP-1 and OXM reduce food intake and weight gain in rodents and human subjects. GLP-1 potentiates biosynthesis of insulin and can normalize blood glucose level in patients with type 2 diabetes. GLP-1 is broken down very fast and as a result GLP-1 cannot be used for treatment of diabetes. Inhibition of DPPIV enzyme that breaks down GLP-1 prolongs GLP-1 effects.( Konturek et al 2004 )
GLP-1R receptors found on the brain stem NTS neurons, which send their projections to hypothalamic nuclei (ARC, DMN and PVN) involved in appetite control. Recently, new drugs were synthesized: GLP-1 receptor agonists and DPPIV enzyme inhibitors. They are about to be approved by FDA for treatment of diabetes.
Cholecystokinine (CCK)
Gastrointestinal hormone cholecystokinine (CCK) is, mainly, produced by the duodenum and jejunum. CCK level is rising in response to nutrients entering the intestine. It stimulates secretion of pancreatic enzymes, emptying gold bladder, intestinal motility and inhibits gastric emptying. The administration of CCK reduces food intake. The gastric distention increases the CCK effect on feeding. CCK also affects vagal afferents. Since, vagus nerve controls gastrointestinal secretion, motility and blood flow, CCK can affect these functions via the vagus nerve. Konturek et al 2004)
There are two kind of receptors exist for CCK: CCKA and CCKB.
CCKA receptors, which are responsible for appetite control, were found in brain stem NTS, area postrema (AP) and dorsomedial hypothalamus. CCKA receptor antagonists increase calorie intake and reduce satiety. (Wynne et al 2005)The Endocannabinoid system
The Endocannabinoid system has been discovered about twenty years ago. It plays an important role in the regulation of food intake, energy saving and hedonic reward. Neurons, which produce the endogenous cannabinoids of the endocannabinoid system, are located in the hypothalamus, and limbic forebrain.
There are two cannabinoids receptors exist: cannabinoid1 (CB1) and cannabinoids 2 (CB2). CB1 receptors are related to regulation of energy homeostasis and found in the brain, adipose tissue, muscle, liver and gastrointestinal tract. CB2 receptors have different purpose and not related to the topic discussed here.
Figure 1. Endocannabinoid receptors.
Mechanism of action of the endocannabinoids on neurons is different than that of the other neuromediators. Most neurotransmitters are stored in the vesicles, which are located inside axon terminals. On the figure 1, you can see GABA neurotransmitter in the vesicles. When axon fires, Ca++ ions flow inside the terminal, vesicles are moved to presynaptic membrane and released into synaptic cleft. Molecules of GABA diffuse to postsynaptic membrane bind to GABA receptors and cause inhibition of postsynaptic cell. (GABA is an inhibitory mediator).
Cannabinoids (Ecs) are synthesized as needed. In the brain cannabinoids are not stored in presynaptic terminals. Unlike regular neurotransmitters, cannabinoids are released from postsynaptic membrane and diffuse to presynaptic membrane, where CB1 receptors are located. (Stanley et al 2005 )
When cannabinoids bind to CB1 receptors synaptic activity is inhibited. It means that GABA cannot inhibit postsynaptic cell. The cannabinoids inhibit inhibition and as a result activate brain mechanisms stimulating food intake, anabolic processes and hedonic reward.
Conclusion
The hypothalamus is a main brain structure responsible for appetite control and energy expenditure. There are many neuronal circuits, which stimulate appetite and reduce energy expenditure and many neuronal circuits, which suppress appetite and increase energy expenditure.
There are many neuropeptides and hormones that are produced in the hypothalamus and intestinal tract, which stimulate appetite during starvation of fasting or suppress appetite after feeding. The main negative feedback reducing appetite and weight gain is executed by leptin, a peptid produced by adipose tissue. The more fat our body gain, the more leptin is produced. Genetical disorders, which cause leptin shortage or deficiency its receptors, cause obesity. There are many other gut hormones, which participate in the negative feedback execution and which deficiency can lead to obesity.
It seems, that nature cared much more about protecting us from starvation, than from obesity, that is why the appetite stimulating and energy saving mechanisms are represented much greater in our endocrinal and nervous systems than the mechanisms suppressing appetite. As a result, the obesity becomes a great problem for human health. The latest researches in appetite control give us a hope that the solution can be found.
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