Cholycystokinin elicits satiety in rats with open gastric fistulas. Cross-talk between insulin and leptin signaling in the hypothalamus. Leptin is a 16 Kd hormone produced by fat tissue. Amylin, insulin and pancreatic polypeptide are made in the pancreas. Evidence of interactions between melanocortin and opioid systems in regulation of feeding. We also highlight new insights regarding mechanisms by which enteroendocrine cells sense and respond to nutrients.
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 ]. Insulin is secreted in response to meals and increases the storage of glycogen, fat and protein. In peripheral tissues, insulin autophosphorylates the insulin receptor, leading to activation of the insulin receptor substrate IRS -phosphatidylinositol 3-kinase PI3K enzyme system.
Studies by Porte and his colleagues, preceding the discovery of leptin revealed a blood-to-brain insulin transport, and binding of insulin to several regions in the brain [ 51 ]. Most significantly, injection of insulin into the cerebral ventricle or directly into the brain parenchyma profoundly inhibited food intake [ 51 ]. We now know that insulin signaling molecules are expressed in key hypothalamic nuclei involved in energy metabolism [ 52 ]. Insulin induces tyrosine phosphorylation of the insulin receptor and IRS-1 and -2, increases binding of activated IRS-1 and -2 to the regulatory subunit of PI3 kinase, and activates Akt Fig.
Pharmacological inhibition of PI3 kinase prevented the satiety effect of central insulin [ 52 ]. Studies also indicate a cross-talk between leptin and insulin signaling in the hypothalamus [ 52 ] Fig. Deletion of insulin receptors in neurons resulted in a mildly obese phenotype in female mice [ 54 ]. However, it was subsequently revealed that deficiency of insulin receptors or PI3 kinase in POMC and AGRP neurons did not affect feeding or weight [ 53 , 55 , 56 ], suggesting that central insulin does not play a critical role in the long-term regulation of energy homeostasis.
Cross-talk between insulin and leptin signaling in the hypothalamus. The endocannabinoid system has significant effects on appetite and metabolism [ 57 ]. Endocannabinoids bind to cannabinoid receptors type 1 and type 2 CB1 and CB2 receptors. 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.
Overnutrition activates the endocannaboid system, which results in hyperphegia, reduction in energy expenditure and obesity [ 57 ]. Stimulation of CB1 receptor with anandamide increases food intake and weight in rodents. Conversely, CB1 receptor antagonists suppress feeding and decrease weight [ 57 ]. Rimonabant, a CB1 receptor blocker, inhibits appetite and decreases weight in obese patients [ 58 ]. In addition, rimonabant decreases glucose and lipids [ 58 ].
Adiponectin is secreted by adipocytes and circulates in the plasma in the form of homotrimers, low-molecular weight hexamers and high-molecular weight HMW complexes [ 59 ]. In contrast to leptin, adiponectin is reduced in obesity and increased in response to fasting [ 59 ]. Adiponectin deficiency induces insulin resistance and hyperlipidemia, and is associated with increased susceptibility toward vascular injury and atherosclerosis [ 59 ].
AMPK signaling in energy balance regulation. During times of energy shortage, AMPK is activated in peripheral tissues to favor local ATP production, and in the brain, to stimulate neuroendocrine pathways that increase food intake.
AMPK is also regulated by exercise, metabolic stressors and hormones, and cytokines that affect whole-body energy balance such as leptin, adiponectin, resistin, ghrelin and cannabinoids. Agonists of AMPK have been under development by pharmaceutical companies as potential treatments for obesity Hardie, Peripheral signals are generated in response to food ingestion.
They are classified as either episodic or tonic signals. Episodic signals are short-term and produced between meals eating episodes. They impact our decisions about when and how much to eat. Tonic signals are generated by the body's response to nutrition status in the long term days or weeks. They potentiate the magnitude of episodic signals and cause us to subconsciously adjust meal frequency and size Fig.
Variations of the genes involved in these signaling processes, such as LEP and LEPR, are normally rare but are associated with severe obesity symptoms when they occur. The main energy balance control signals in human body adopted from Blundell et al, When blood glucose levels drop below a threshold comparable to hypoglycemia level, about 1mM , the expression of ghrelin is activated.
It is released into the bloodstream and eventually reaches the arcuate nucleus of the hypothalamus ARC where it activates the expression of agouti-related protein AgRP and neuropeptide Y NPY.
For example, hormones such as epinephrine and norepinephrine stimulate ghrelin release while insulin and somatostatin a peptide hormone produced in the hypothalamus inhibit release Fig 3. Ghrelin is encoded by the GHRL gene. Obestatin is involved in satiety and decreased food intake in rats Zhang et al, , but its function in the human body is less understood. 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.
Satiety After finishing a meal, the feeling of satiety continues to suppress hunger over a period of hours, regulating the frequency of meals. Hormones, nervous signals, and the brain work in harmony to sustain feelings of fullness. Leptin, one of the adipokine hormones, is produced in direct proportion to body fatness. Energy Nutrients and Satiety The composition of a meal seems to affect satiation and satiety, but the relationships are complex. Of the three energy-yielding nutrients, protein seems to have the greatest satiating effect during a meal.
Many carbohydrate-rich foods, such as those providing slowly digestible carbohydrate and soluble fiber, also contribute to satiation and satiety. Researchers have also reported increased satiety from foods high in water and even from foods that have been puffed up with air. Many theories have emerged to explain these mysteries of obesity in terms of metabolic function and energy expenditure—this section just touches the surface of a few of them.