Appetite Control and Energy Homeostasis

By Sergey Skudaev


Energy balance in the human body depends on the relationship between the amount of consumed food and energy expenditure. Any amount of food we consume depends on one's appetite and activity of the rewarding system. Our brain rewarding system is responsible for pleasureand is activated during eating. This explains why even if we are not hungry, we still eat for pleasure.

Energy expenditure depends on activity of the endocrine system. For example, hormones released by the thyroid gland increase energy expenditure because more energy is released as the heat.

During stress, the glucocorticoid hormone secreted by the adrenal gland promotes gluconeogenesis, a process while proteins are broken down into amino acids and the latter are converted to glucose. That is why stress increases energy expenditure.


The hypothalamus is an area of the brain that responsible for regulation of all body functions and systems such as the endocrine system, gastro-intestinal system, cardio-vascular system, reproductive system etc. The hypothalamus is comprised of many nuclei.

Hunger center and Satiety center

It was found that lesions of the ventromedial nucleus (VMN) of the hypothalamus increases food intake, while stimulation of the VMN nucleus decreases feeding.

On the contrary, lesions 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 center' and lateral hypothalamic nucleus (LHA) is a 'hunger center'( Stellar 1994 ).

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The Arcuate Nucleus

Later, many endogenous substances, were discovered which affect appetite and energy expenditure. Neuropeptide Y (NPY) and Agouti-related peptide (AgRP) are produced in the hypothalamus by neurons of the Arcuate nucleus.

NPY and AgRP stimulate food intake and decrease energy expenditure by affecting the thyroid gland. On the other side, Pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART), which also are produced by the Arcuate nucleus neorons, decrease food intake and increase energy expenditure.

Mutations in POMC gene or deficiency of the melanocortin receptors causes obesity. The lateral hypothalamic nucleus (LHA) produces melanin-concentrating hormone (MCH) and orexins, which stimulate appetite. MCH level is increased with fasting. Intracerebroventricular administration of MCH increases food intake, while antagonists of MCH-1 receptor decreases food intake (Cone et al 1998, Kristensen et al 1998).


Adipose tissue produces a peptide hormone called leptin. Its level in the circulatory system reflects the mass of adipose tissue. Intravenous administration of leptin to wild mice reduces food intake and causes a loss of body weight and fat mass.

Leptin also increases energy expenditure. Mutations in Obese (ob) gene, responsible for producing leptin, causes hyperphagia and obesity. Leptin, circulating in blood, is transported across blood-brain barrier. Its transport decreases in fasting and increases after feeding (Maffey et al. 1995, F. LONNQVIST 1996 ).

In the brain, leptin binds to leptin receptor (Ob-Rb) receptors, which are located in ARC, VMH, DMH and LHA hypothalamic nuclei, previously mentioned. 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 increases energy expenditure. It is thought that 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)


One more important peptide produced by adipose tissue is called Adiponectin. It increases energy expenditure by affecting the hypothalamus. Adiponectin increases insulin sensitivity. Lack of Adiponectin causes insulin resistance. In mice, treatment with Adiponectin increases insulin sensitivity and reduces body-weight gain(Hotta et al. 2001).


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 the PYY peptide. Its level is increased right after feeding and remains elevated for up to 6 hours. PYY delayed gastric emptying, gallbladder emptying and pancreatic and gastric secretion. The peripheral administration of PYY to rodents reduces food intake and weight gain. PYY directly affects the ARC nucleus where it binds to Y2 receptors, which inhibit NPY neurons.

PYY reduces appetite in humans. Obese patients have relatively low levels of PYY in the 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 rodents. 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) is mainly produced by the endocrine pancreas, and less by both the colon and rectum. Its release correlates with amount of calories consumed in food. The gastric distension and gut hormones (ghrelin, motilin and secretin) increase the level of PP. The peripheral administration of PP reduces food intake, body weight and energy expenditure in rodents and mice. PP reduces insulin resistance, dyslipidemia, gastric emptying and production of ghrelin by stomach.

Patients with Prader-Willi Syndrome have a low level of PP. On the other hand, anorexic patients have high levels of PP, though not all research confirm such correlation. PP does not cross the blood-brain barrier; however, it can affect the central nervous system (CNS) via area postrema, where the 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 the small intestine and pancreas by intestine L-cells and in the 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 levels 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 the Dipeptidyl peptidase-IV (DPP IV) enzyme that breaks down GLP-1 prolongs GLP-1 effects.( Konturek et al 2004 )

GLP-1R receptors are found on the brain stem´s 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 rises in response to nutrients entering the intestine. It stimulates secretion of pancreatic enzymes, emptying gallbladder, 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, the 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 that exist for CCK: CCKA and CCKB.

CCKA receptors responsible for appetite control, were found in the 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 was 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 a different purpose and not related to the topic discussed here.


Figure 1. Endocannabinoid receptors.

The 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. The figure 1, shows the GABA neurotransmitter in the vesicles. When an 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 are synthesized as needed. In the brain cannabinoids are not stored in presynaptic terminals. Unlike regular neurotransmitters, cannabinoids are released from the postsynaptic membrane and diffuse to the presynaptic membrane where CB1 receptors are located (Stanley et al 2005 ).

When cannabinoids bind to CB1 receptors synaptic activity is inhibited. This means that GABA cannot inhibit the postsynaptic cell. The cannabinoids prevent inhibition and as a result, activate brain mechanisms stimulating appetite, anabolic processes and hedonic reward.


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. Also, there are many neuronal circuits, which suppress appetite and increase energy expenditure.

Various neuropeptides and hormones that are produced in the hypothalamus and intestinal tract 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. Genetic disorders, that may cause leptin shortage or deficiency of its receptors, lead to obesity. There are many other gut hormones, that can participate in the negative feedback execution and if deficient can also 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 endocrine and nervous systems than the mechanisms for suppressing appetite. As a result, obesity becomes a great problem for human health. The latest research in appetite control give us a hope that a solution will be found.


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