See also Leptin Receptor under Signal Transduction
Introduction:
The activities of the gastroinentestinal tract are coordinated by the nervous system and the endocrine system. The nervous system, for example, stimulates salivary and gastric secretions in response to the sight, smell and consumption of food. When food arrives in the stomach, proteins in the food stimulates the secretion of stomach hormone called gastrin, which in turn stimulates the secretion of pepsinogen and HCL from the gastric glands. The secreted HCl then lowers the pH of the gastric juice, which acts to inhibit further secretion of gastrin in a negative feedback loop.
The role of both leptin and insulin is long term regulation of the afferent porition of a signaling entwork. Leptin and insulin are produced by adipose tissue and the pancreas, respectively, in response to the effects of feeding. This leads to cirulating levels of leptin that correlate with the amount of adipose tissue. The extreme example of this is the veyr high level of leptin seen in obese individuals. High levels of leptin and insulin then act on the hyptohalamus to increase levels of alpha-MS. This causes a reduction in appetite and increased energy expenditure and allows reproduction and growth. Low levels of these hormones act on the hypothalamus to reduce alpha-MSH levels and increase NPY levels. This elads ot increased appetide and decreased energy expenditure. If very low elvels of leptin persist, this can inhibit reproduction and grwoth.
The gut hormones CCK and GIP are produced in response to feeding and represent short temr regulators of the afferent portion of the circuit. Their ation is the same that of leptin and insulin. The gut hormone ghrelin is also a short term regulator that stimulates feeding.
The activities of the gastroinestinal tract are coordinated by the nervous system and the endocrine system. The nervous system, for example, stimulates salivary and gastric secretions in response to sigght, smell and consumption of food. When food arrives in the stomach, proteins in the food stimulate the secretion of a stomach hormone gastrin, which in turn stimulates the secretion of pepsingoen and HCL from teh gastric glands. The secretion HCl lowers the pH of the gastric juice, which acts to inhibit additional secretion of gastrin in a negative feedback loop.
The duedenum (the first 25 cm of the small intestine) secretes three hormones; cholecystockinin (CCK) which stimulates contraction of the gallbladder and secretion of pancreatic enzyme, secretin, which stimulates secretion of pancreatic bicarbonate and gastric inhibitory peptide (GIP), which inhibits stomach emptying. The hormones GIP and CCK have receptors in the hypothalamus and seem to send the same kinda of inhibitory signals to the brain as leptin and insulin. The gut homrone ghrelin has the opposite effect of these appetite suppressing hormones Ghrelin also has receptors in the hypothalamus, but ghrelin appears to stimulate food intake. Gastric bypass surgery leads to reduced lelvels of ghrelin and has been sugested that this is one of the reasons for the suppression of appetite seen after this surgery.
The brain neuropeptides neuropeptide Y (NPY) and alphamelanocyte-stimulating hormone (alpha-MSH) are antagonstic, with NPY inducing feeding activity and alpha-MSH suppressing it. The production and release of alpha-MSH has been shown to be stimulated by leptin and the administration of alpha-MSH suppresses feeding. Loss of funciton for the alpha-MSH receptor also leads to obesity. Incontrast, the expression of NPY is negatively regulated by leptin and adminsitraiton of NPY stimulates feeding behavior.
Gut hormones (enterogastrones):
The passage of cyme from the stomach into the duodenum of the small intestine inhibits the contractions of the stomach, so that no additional cyme can enter the duodenum until he previous amount can be processed. The stomach of gastric inhibition is mediated by a neural reflex and by duodenal hormones secreted in the blood collectively known as the enterogastrones. The major enterogastrones include cholecystokinin (CCK), secreti and gastric inhibitory peptide (GIP). Chyme with high fat content is the strongest stimulus for CCK and GIP secretions, wehreas incresaing cyme cidity primarily influences the release of secretin. All three of these enterogastrones inhibit gastric motility (churing action) and gastric juice secretions; the result is that fatty measl remain in the stomach longer tha nonfatty meals, allowing mroe time for digestion of cmoplex fat molecules. In addition to gastric inhibition, CCK and secretin ahve other regulatory functions in digestion. CCK stimualtes increased pancreatic secretions of digestive enzymes and gall-bladder contractions which inject more bile into the duodenum, which enhances the emulsificaiton and efficient digestion of fats. Other major functions of secretin is to stimulate the pancrea to release mroe bicarbonate, which neutralizes the acidity of the chyme.
The hormones GIP and CCK have receptors in the hypothalamus and seem to send the same kind of inhibitory signals to the brain as leptin and insulin. The levels of these gut hormones also vary with feeding behavior in a pattern similar to those of leptin and insulin.
The gut homrone ghrelin has the opposite effect of these appetite suppressing hormones. Ghrelin also has receptors in the hypothalamus, but ghrelin appears to stimulate food intake. This role is supported by studies inr ats showing that chronic adminsitration of ghrelin leads to obesity. Ghrelin levels appear to rise before feeding and may be involved in initiating feeding behavior. One of teh treatments for severe obesity, gastric bypass surgery, leads to reduced levels of ghrelin and this has been suggested for one of the reasons for the suppressin of appetite seen after this surgery.
Neuroendocrine Control:
Experiments with fasting and overfeeding in rats show an increase in food intake over normal levels when fasting ends. This increase restores lost body weight to baseline values and food intake then drops. These experiments indicate the existence of control mechanisms to link food intake to energy balance.
The presence of a hormonal satiety factor produced by adipose tissue has been hypothesized to explain these observations. It has also been shown that regions of the hypothalamus are involved in feeding behavior.
One of the rodent models for obesity, the obese mouse, is caused by a mutation in a single gene named ob (for obese). Animals homozygous for the recessive mutant allele become obese compared with wild type mice. When the gene responsible for this dramatic phenotype was isolated, it proved to encode a peptide hormone named leptin, leading to the hypothesis that the lack of leptin production in mutant individuals is responsible for obesity. Sure enough, when ob/ob animals are injected with leptin, they stop overeating and lose weight. Tehse experiments identified leptin as the main satiety factor, and the key to the control of appetite. The gene for the lpetin receptor (db0 has also been isoalted and is epxressed in neurons in the hypothalamus involved in ernergy intake.
Leptin: is not thought to be the main signaling molecule in the afferent porition of the control circuit for energy sensing, food intake, and energy expenditure. Liptin is produced by adipose tissue in response to feeding, and leptin levels correlate with feeding behavior and amount of body fat. Dietary restriciton reduces leptin levels, signaling the brain that food intake is necessary, whereas refeeding after fasting leads to rapid increase in leptin levels and a loss of appetite. The different part of this control ciruit is complex and includes control of energy expenditure, energy storage and feeding behavior by the CNS.
The leptin gene has also been isoalted in human and appears to function much as it does in mice. However, the blood concentrations of leptin are actually highler in obese than in lean people and leptin produced by obese people appears to be normal. It has been suggested that, in contrast with the mutant mice, most cases of humannn obesity may result from a reduced sensitivity to the ations of leptin int eh brian, rather than from reduced leptin production by adiopose cells. Research on leptin in humans i ongoing and of great ienterest in the pharmaceutical industry.
Leptin is a peptide hormone. which is encoded by the ob (for obese) gene. Leptin is thought to be the main signaling molecule of the control circuit for energy sensing, food intake, and energy expenditure. Leptin is produced by adipose tissue in response to feeding and leptin levels correlate with feeding behavior and amount of body fat. Dietary restriction reduces leptin levels, signaling the brain that food intake is necessary, whereas refeeding after fasting leads to rapid increase in leptin levels and a loss of appetite. Recent studies indicate, however, that most cases of human obesity in humans may result from a reduced sensitivity to the actions of leptin in the brain, rather than from reduced leptin production by adipose cells.
Neuropeptide Y (NPY) and alphamelanocyte-stimulating hormone (alpha-MSH) have been implicated as nueral regulators in the hypothalamus. These peptides are antagonistics, with NPY inducing feeding activity and alpha-MSH suppressing it. Evidence fo this antagonism comes from experiments that show that production and release of alpha-MSH is stimulated by leptin and that adminsitraiton of alpha-MSH suppresses feeding. Loss of function for the alpha-MSH receptor also elads to obesity. In contrast, the expression of NPY is negativley regulated by leptin and admisntiraiton of NPY stimulates feeding behavior.
Gastrin: is secreted by the mucosa of the stomach. It stimulates the secretion of HCl and pepsinogen (which is converted into pepsin).
Insulin: has been implicated in signaling satiety and insulin levels fall with fasting and rise with obesity. Insulin and glucagon are produced in the islets of Langerhans, clusters of endocrine cells scattered throughout the pancreas. After a carbohydrate rich meal, the liver and skeletal muscles remove excess glucose from the blood and stores it as the polysaccharide glycogen. This process is stimulated by the hormone insulin, secreted by the beta cells in the pancreatic islets of Langerhans. When blood glucose levels decrease, as they do between meals, during periods of fasting, and during exercise, the liver secretes glucose into the blood. This glucose is obtained in part from a breakdown of liver glycogen to glucose 6-phosphate, a process called glycogenolysis. The phosphate group is then removed, and free glucose is secreted into the blood. Skeletal muscles lack the enzyme needed to remove the phosphate group, and so, even though they have glycogen stores, they cannot secrete glucose into the blood. However, muscle cells can use this glucose directly for energy metabolism because glucose 6-phosphate is actually the product of the first reaction in glycolysis. The breakdown of liver glycogen is stimulated by another hormone, glucagon, which is created by the alpha cells of the islets of Langerhans in the pancreas. If fasting or exercise continues, the liver begins to convert other molecules, such as amino acids and lactic acid, into glucose. This process is called gluconeogenesis. The amino acids used for glucogenogenesis are obtained from muscle protein, which explains the severe muscle wasting that occurs during prolonged fasting.