The Hypothalamus Gland & Hunger – Motivation, Regulation, and Satiation

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Hunger (motivational state)
The CB1 receptor, a G-protein coupled receptor, is widely expressed in the brain and peripheral tissues, and is thought to mediate the metabolic actions of endocannabinoids. Higher leptin levels are associated with increased basal metabolism and lower levels are associated with decreased basal metabolism. It has been shown to inhibit food intake. Regardless of how physiologically vital ghrelin is in energy homeostasis, however, it offers exciting potential for pharmacologic treatment of cachexia and GI motility disorders. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Restricting food intake can trigger a process by which certain brain cells start to consume fats within their cellular structure, a study found. Molecular biology of taste perception.

Principles of satiation

Understanding Hunger and Fullness Cues

When our stomach is growling for food what is really happening? A number of factors influence whether we experience feelings of hunger or satiation. Signals from our brain, certain chemicals produced by our bodies, and even the amount and type of food we eat interact to cause us to feel hungry or full. Because hunger is a physiologic sensation that prompts us to find food and eat, it is more often felt as a negative or unpleasant sensation in which the physical drive to eat is very strong.

The signal arises from within us, rather than in response to environmental stimuli, and is not typically associated with a specific food. A broad variety of foods appeals to us when we are really hungry. One of the major organs affecting our sensation of hunger is the brain and not the stomach.

Our brain actually tells us when we are hungry. The region of brain tissue that is responsible for prompting us to seek food is called the hypothalamus. It triggers hunger by integrating signals from nerve cells throughout our bodies. One important signal comes from special cells lining the stomach and small intestine that perceive whether these organs are empty or distended by the presence of food.

These cells sense changes in pressure and fullness in the stomach and small intestine and send signals to the hypothalamus. Our blood glucose levels, which reflect our bodies most readily available fuel supply, is another primary signal affecting hunger. Falling blood glucose levels are accompanied by a change in insulin and glucagon levels. Insulin and glucagon are hormones produced in the pancreas and are responsible for maintaining blood glucose levels. These signals are relayed to the hypothalamus in the brain, where they trigger the sense that we need to eat in order to supply our bodies with more energy.

Leptin, insulin and metabolic hormones related to fat stores control body weight through long-term effects on feeding and energy expenditure.

On the other hand, neuronal and hormonal signals from the gastrointestinal tract control and satiety, and rarely impact body weight and adiposity. Food has pleasurable and rewarding qualities which drive appetite beyond metabolic needs. In the next sections, we will discuss how the brain integrates metabolic signals, ensures energy homeostasis and influences the hedonic control of feeding.

The gastrointestinal tract acts not only as a conduit for food, but is also crucial for the digestion and absorption of nutrients. Visual, olfactory and gustatory stimuli stimulate exocrine and endocrine secretions, and gut motility even before food enters the mouth.

Meal ingestion stimulates mechanoreceptors, resulting in a coordinated sequence of distension and propulsion to accommodate the mass of food and ensure digestion and nutrient absorption. The brain receives signals from the gastrointestinal tract through sensory nerves and the circulation [ 11 ].

Afferent nervous signals from mechanoreceptors, e. Other afferents end directly on distal dendrites of gastromotor vagal neurons, or are relayed to the dorsal motor vagal nucleus, which innervates the entire gastrointestinal tract. Projections from the NTS and the parabrachial nucleus in the brainstem innervate the paraventricular, dorsomedial, and arcuate nuclei of the hypothalamus and the lateral hypothalamic area, central nucleus of the amygdala and bed nucleus of the stria terminalis.

NTS projection to the visceral sensory thalamus communicates with the visceral sensory cortex, which mediates the conscious perception of gastrointestinal fullness and satiety.

Neurons located in the visceral sensory cortex also integrate taste sensation. The neural connection between the gut and brain has been investigated using surgical and chemical approaches [ 11 ]. Gastric vagal stimulation or balloon distension induces satiety. Infusion of solutions rich in fat, carbohydrates, and proteins into the proximal small intestine reduces subsequent meal size.

This effect is blocked by application of the sensory neurotoxin capsacin to the vagus, or surgical denervation [ 11 - 13 ]. Surgically disrupting the sensory vagal fibers from the gut increases meal size and duration [ 12 ]. Blockade of brainstem vagal afferent transmission using the N-methyl-d-aspartate receptor antagonist MK also increases meal size [ 14 ].

Together, these studies demonstrate a powerful negative feedback control of vagal afferent innervation on feeding [ 11 - 13 ]. The gastrointestinal tract secretes hormones that control of feeding.

These peptides access the brain partly through the area postrema, a circumventricular organ located in the roof of the 4 th ventricle. The area postrema is situated above the NTS, thus allowing neurons to respond directly to circulating gut hormones, and to relay these signals to the neuronal circuits in the brainstem and forebrain. Cholecystokinin CCK was the first gut-secreted peptide to be identified as a satiety factor [ 15 ]. CCK decreases meal size [ 15 , 16 ].

CCK1 receptor antagonists block the satiety effects of nutrient infusions into the gut and stimulate feeding in fed animals [ 17 ]. Chemical or surgical sensory vagotomy eliminated the satiety effects of CCK in rodents [ 12 , 15 , 16 ]. Hyperphagia in this animal was associated with higher expression of neuropeptide Y NPY in the dorsomedial nucleus of the hypothalamus [ 17 ].

In contrast to these results in OLETF rats, high fat-diet increased food intake and induced obesity to the same extent in both wild-type and CCK1 receptor knockout mice [ 17 , 18 ]. Thus, CCK1 receptors have different effects food intake and weight in rodent species. Glucagon-like peptide GLP -1 is cleaved from proglucagon and released from the L-cells of the intestine in response to meals [ 19 ].

GLP-1 and longer-acting GLP-1 receptor agonists, such as exendin-4, decrease food intake in rodents when they are injected in the brain or peripherally [ 19 , 20 ]. Presumably, these compounds target the area postrema, NTS and paraventricular hypothalamic nucleus [ 19 , 20 ].

GLP-1 has a strong incretin effect on insulin secretion, hence the GLP-1 mimetic exenatide is used an anti-diabetic agent [ 19 , 20 ]. Moreover, exenatide causes nausea in some patients. Sitagliptin is currently being used for the treatment of diabetes. Oxyntomodulin is also derived from proglucagon and co-secreted with GLP-1 by intestinal L-cells after nutrient ingestion [ 19 , 20 ]. Oxyntomodulin induces satiety, increases energy expenditure and decreases weight [ 20 ].

However, the satiety effect of PYY may be minimized by stress and has not been confirmed by others [ 23 , 24 ]. Pramlintide, an amylin analog, improves blood glucose and also reduces appetite and weight [ 20 ]. Ghrelin is a 28—amino acid peptide synthesized mainly in the stomach [ 25 , 26 ]. The bioactive peptide has an O-linked octanoyl side group on the 3 rd serine residue.

This modification is necessary for ghrelin's effects on feeding. Ghrelin levels increase during food deprivation in animals and prior to meals in humans, and may serve as a critical signal to induce hunger during fasting.

Peripheral or direct administration of ghrelin into the brain stimulates feeding [ 26 ]. The site of action for ghrelin on feeding is thought to be the hypothalamus, where the growth hormone secretagogue receptor which mediates the cellular action of ghrelin is found in the ventromedial and arcuate nuclei, in particular neurons coexpressing NPY and AGRP [ 25 , 26 ].

Ghrelin induces synaptic plasticity in the midbrain as well as the hippocampus where ghrelin has been implicated in learning [ 27 , 28 ]. Apart from stimulating food intake and promoting weight gain, ghrelin has been implicated in glucose metabolism [ 29 , 30 ].

Deletion of ghrelin in mice increased basal insulin level, enhanced glucose-stimulated insulin secretion, and improved peripheral insulin sensitivity [ 29 , 30 ]. Likewise, growth hormone secretagogue receptor antagonists enhanced insulin secretion in rodents [ 31 ]. Gut-derived peptides are attractive targets for inducing satiety and limiting meal size, but the potential for drug development is fraught with difficulty.

Gut hormones have a short half-life therefore stable analogs are needed, as is the case for exenatide and DPP-IV inhibitors [ 20 ]. GLP-1 and CCK, may induce nausea and other gastrointestinal side effects which may limit their therapeutic use.

Furthermore, because of the redundant neuronal and hormonal mechanisms in the gut, it is doubtful that targeting a limited number of peptides is a viable therapeutic approach. Indeed, genetic manipulation of anorexigenic gut hormones rarely causes overt changes in feeding, weight and metabolism [ 29 , 30 , 32 ]. However, gut hormone alterations may explain the rapid effects of Roux-en-Y gastric bypass surgery to decrease weight and reverse diabetes [ 33 , 34 ].

GLP-1 is increased after gastric bypass surgery, and may inhibit appetite and augment insulin secretion [ 34 ]. Efforts are underway to target ghrelin for the treatment of anorexia and cachexia. Ghrelin antagonists have the potential for obesity and diabetes therapy. As mentioned earlier, the discovery of leptin was a major milestone in elucidation of the communication between the brain and energy stores. Leptin is expressed by adipocytes and the concentrations of leptin in adipose tissue and plasma parallel the mass of adipose tissue and triglyceride content.

Thus, leptin is increased in obesity and falls with weight loss [ 35 , 36 ]. These changes are partly mediated by insulin. Leptin is transported via a saturable process across the blood-brain barrier.

Moreover, the circumventricular organs, e. The most abundant short leptin receptor, LRa, which lacks the cytoplasmic domain necessary for Janus family of tyrosine kinases JAK -signal transducer and activator of transcription STAT signaling, may mediate leptin transport across brain capillaries. The long leptin receptor, LRb, is highly expressed in the hypothalamus, brainstem, and several regions of the brain that control feeding, energy expenditure and hormones [ 35 ].

Binding of leptin to LRb results in autophosphorylation of JAK2, phosphorylation of the tyrosine residues and on LRb, activation and nuclear translocation of STAT3, and transcription of neuropeptides [ 36 ].

Leptin-mediated activation of STAT5 and protein-tyrosine phosphatase 1B also terminates leptin signaling [ 36 ]. Neuronal targets for leptin have been mapped in the brain using anatomical, pharmacological and molecular genetic techniques. These neurons project to the paraventricular nucleus PVN , which controls feeding and also provides preganglionic autonomic output to the brainstem.

NPY stimulates food intake, reduces energy expenditure and increases weight via Y1 and Y5 receptors. Melanin concentrating hormone MCH and orexins are expressed in distinct populations of neurons in the lateral hypothalamic area.

The targets of the MCH and orexin neurons include the trigeminal, facial, and hypoglossal motor nuclei that control licking, chewing and swallowing, and parasympathetic preganglionic nuclei in the medulla that control salivation, gut motility and gut secretions.

MCH and orexin neurons also communicate with noradrenergic neurons in the locus coeruleus, serotoninergic neurons in the dorsal and median raphe nuclei, and the histaminergic tuberomammillary nucleus.

These monoaminergic systems regulate arousal. In addition, the MCH and orexin neurons project diffusely to the cerebral cortex, likely to regulate complex behaviors in relation to sleep-wake cycles.

The significance of hypothalamic neuropeptides in energy homeostasis has been ascertained using gene ablation methods in mice [ 37 - 42 ].

On the other hand, the lack of POMC or functional melanocortin-4 receptor caused hyperphagia and obesity [ 41 , 42 ]. Reduced leptin levels during fasting also stimulate MCH and orexins in the lateral hypothalamic area.

Hypothalamic leptin signal transduction. These changes in neuropeptide expression culminate in satiety, stimulation of energy expenditure and weight loss. As with other complex diseases, obesity is influenced by polygenic and environmental factors, particularly energy-dense food and sedentary life style. Diet-induced obesity in rodents is characterized by increased leptin levels, reduced leptin transport across the blood-brain-barrier, and impaired leptin signaling in the hypothalamus, related to induction of SOCS3 [ 35 , 36 ].

Deletion of SOCS3 in leptin-responsive neurons in the arcuate nucleus enhanced leptin sensitivity and protected against diet-induced obesity and diabetes [ 43 , 44 ]. Leptin exerts rapid effects on neurotransmission [ 45 ]. This pattern was rapidly reversed by leptin treatment within 6 hours, suggesting that leptin-mediated synaptic plasticity preceded the appetite-suppressing effect of the hormone [ 47 ].

In contrast to leptin, the stimulatory effect of ghrelin on food intake has been associated with a net increase in synaptic activity in the hypothalamus [ 27 ]. These results indicate that peripheral metabolic hormones can alter brain function through modulation of synaptic function [ 27 , 47 ]. Recent studies have focused attention on the actions of leptin in the human brain [ 48 - 50 ]. Restoration of leptin levels maintained the weight reduction, as well as normalized brain activity patterns [ 48 ].

Congenital leptin deficiency is associated with reduced brain activity in regions related to hunger, and increased brain activity in regions linked to satiety [ 49 , 50 ].

The 28 amino acid ghrelin peptide is inactive until it is acetylated on Ser3 by a medium-chain C8—C10 fatty acid. It is believed that the acetylation and secretion of ghrelin are regulated differently. Several mutations and polymorphisms of the GHRL gene have been associated with various degrees of obesity, but reports in literature are inconclusive and inconsistent.

However, increased ghrelin levels have been reported in individuals with anorexia, which suggests ghrelin resistance may play a role in this condition. Cholecystokinin CCK is an incretin.

Incretin is a group of gastrointestinal hormones that increase insulin in response to intestinal nutrients. CCK is released in the small intestine where it acts in the vagal nervous system to increase satiety. Aromatic amino acids phenylalanine, tryptophan, histidine and tyrosine from dietary protein digestion stimulate CCK release through the extracellular calcium-sensing receptor CaSR.

The signal is then transmitted from the vagus nerve to the brain stem where it is relayed to the hypothalamic region and is integrated with other signals to determine whether to stop or continue eating. Several drugs target the CCK pathway for weight control. Glucagon-like peptide-1 GLP-1 is another incretin hormone. It is synthesized in the gut and released into the bloodstream.

GLP-1 also delays gastric emptying transfer of the partially digested food mixture from the stomach to the small intestine and prolongs the feeling of fullness. The effect of GLP 2 is localized in the gastrointestinal tract. Its main functions include increasing small and large intestinal weight, crypt-villus height and mucosal surface area, and nutrient absorption.

Oxyntomodulin is believed to have the same function as GLP-1, acting via the same receptors. Carbohydrates and fats are the main nutrients that stimulate the release of these hormones. Other signals, such as neurotransmitter acetylcholine and hormones insulin and leptin, also regulate their production Fig.

Through the vagal nerve neurons, it delays gastric emptying and stimulates the anorexigenic neurons in the hypothalamus to suppress appetite. At their highest physiological concentration after a meal , PYY also stimulates the hedonic system in the cortex, generating the sensation of satiation Batterham et al The natural plasma levels of PYY are generally lower in obese people. Pharmaceutical companies have developed synthetic PYY in the form of a nasal spray for weight control.

Amylin is a 37 amino acid pancreatic hormone that helps reduce food intake through the medulla of the brainstem and by delaying gastric emptying. When blood glucose levels are high, amylin is released from the pancreatic beta cells along with insulin.

It is believed to function synergistically with insulin to control blood glucose levels. A human amylin analogue, pramlintide reduces appetite in both lean and obese people Harrold et al, Leptin is a 16 Kd hormone produced by fat tissue. It is a principal long-term regulator of energy balance by functioning on both food intake satiety and body fat metabolism.

Encoded by the LEP gene, leptin is secreted into the bloodstream and delivered to the leptin receptor at the hypothalamus, medulla and other sites. In general, leptin levels in the bloodstream are proportional to body fat, and the amount of leptin entering the CNS is proportional to its plasma concentrations.

Therefore, increased body fat will lead the body to decrease food intake and increase energy expenditure by increasing energy metabolism. However, like insulin resistance, leptin resistance is becoming an epidemic in overweight or obese populations.

Currently, the mechanism of leptin resistance is not well understood. The two CNS centers that control eating are the homeostatic and hedonic systems. The homeostatic system is located in the hypothalamus and the brain stem while the hedonic system is distributed throughout the limbic regions including the cortex and prefrontal cortex Fig.

Several sections of the hypothalamus are at the center of homeostatic regulation Fig. The ARC arcuate nucleus contains two populations of neurons.

Balanced orexigenic and anorexigenic neuron activity ensures the homeostasis of energy balance. The hedonic system controls not only food preferences but also many other emotional and cognitive aspects in relation to happiness. Together, these two systems make the final decision when it comes to what, when and how much to eat. Many obesity risk genes discovered in the last decade, such as those shown in Table 2, are involved in CNS signaling and appetite regulation.

The appetite control system in the brain. B The major appetite signal reception and integration occur in the hypothalamus. Diagram from Schellekens et al AgRP is also highly expressed in the adrenal gland. This prohormone is processed post-translation by a series of cleavages and amino acid modifications in a tissue-specific manner, resulting in different POMC peptides by different cell types.

Its main function in the hypothalamus is to stimulate anorexigenic neurons to suppress appetite. First discovered as a respondent to cocaine and amphetamine administration, CART is believed to play roles in reward and addiction regulations.

Melanin-concentrating hormone MCH is a signaling peptide 19 amino acids expressed in a discrete population of neurons in the hypothalamus. MCH receptors are expressed in the NAcc, amygdala, and hypothalamus. It is hypothesized that MCH mediates the appetite-stimulating effects in response to taste and olfactory signals. The MCH neuron also interacts with the opioid systems, suggesting a connection with the hedonic system. Orexin neurons are stimulated by lower plasma glucose levels and inhibited by high glucose levels.

Orexin is believed to modulate glucose homeostasis by initiating and terminating eating episodes. Orexins are also thought to play a role in reward systems through interaction with dopamine neurons.