BCH 560( HORMONES) MASTERSDr. Samina Hyder Haq

Dept. Of Biochemistry

King Saud University

OVERVIEW OF THE GASTROINTESTINE AND ITS FUNCTION

THREE BASIC FUNCTIONS OF GI1. Digestion and absorption:Most nutrients in a normal human diet are macromolecules and thus not readily

permeable across cell membranes. Likewise, nutrients are not usually taken predominantly in the form of solutions, but rather as solid food. Thus, in addition to the physical process of food uptake, the intestine serves to physically reduce the meal into a suspension of small particles mixed with nutrients in solution.These are then chemically altered such that molecules capable of traversing the intestinal lining result. These processes are referred to as digestion, and involve gastrointestinal motility as well as the influences of pH changes, biological detergents, and enzymes.

The final stage in the assimilation of a meal involves movement of digested nutrients out of the intestinal contents, across the intestinal lining, and into either the blood supply to the gut or the lymphatic system, for transfer to more distant sites in the body. Collectively, this directed movement of nutrients is referred to as absorption. The efficiency of absorption may vary widely for different molecules in the diet as well as those supplied via the oral route with therapeutic intent, such as drugs. The barriers to absorption encountered by a given nutrient will depend heavily on its physicochemical characteristics, and particularly on whether it is hydrophilic (such as the products of protein and carbohydrate digestion) or hydrophobic (such as dietary lipids). In the main for substances vitally required by the body, the gastrointestinal tract does not rely solely on diffusion across the lining to provide for uptake, but rather has evolved active transport mechanisms that take up specific solutes with high efficiency.

2. EXCRETION The gastrointestinal system also serves as an important

organ for excretion of substances out of the body. This excretory function extends not only to the obvious nonabsorbable residues of the meal, but also to specific classes of substances that cannot exit the body via other routes. Thus, in contrast to the excretory function of the renal system, which handles predominantly water-soluble metabolic waste products, the intestine works together with the biliary system to excrete hydrophobic molecules, such as cholesterol, steroids, and drug metabolites. As we will see later, the intestine also harbors a complex ecosystem of symbiotic bacteria, even in health, and many members of this community die on a daily basis and are lost to the stool. Finally, the intestinal lining cells themselves turn over rapidly, and the stool also contains residues of these dead cells that are shed from the lining after their function has been fulfilled.

3. HOST DEFENSE The intestine is a long tube, stretching from mouth to anus,

whose inner surface exists in continuity with the exterior of the body. This, of course, is essential to its function of bringing nutrients from the environment into the body: however, this also implies that the intestine, like the skin, is a potential portal into the body for less desirable substances. Indeed, we exploit this property to deliver drugs via the oral route. In addition, the intestine is potentially vulnerable to infectious microorganisms that can enter the gut with the ingestion of food and water. To protect itself and the body, the intestine has evolved a sophisticated system of immune defenses. In fact, the gastrointestinal tract represents the largest lymphoid organ of the body, with significantly more lymphocytes than are found in the circulating immune system. The gastrointestinal immune system is also characterized by specific functional capabilities, most notably by being able to distinguish between "friend" and "foe"; mounting immune defenses against pathogens while being tolerant of dietary antigens and beneficial commensal bacteria.

OVERVIEW OF THE NEURAL CONTROL OF THE GI SYSTEM

MODES OF COMMUNICATIONS IN GI SYSTEMS

ENDOCRINE COMMUNICATION Endocrine hormones are packaged within the secretory granules of

distinct cell types within the wall of the intestinal tract, and released in response to nervous activity as well as chemical and mechanical signals coincident with food ingestion. The endocrine cells of the gut have been identified with letters to describe their hormonal contents; gastrin, secretin, cholecystokinin, and glucose-dependent insulinotropic peptide (also referred to as gastric inhibitory peptide, or GIP) are stored in G, S, I and K cells, respectively. Cells containing motilin have not been named, and indeed, there is some debate as to whether this peptide is stored in an endocrine cell or nerve ending.

Some endocrine cells may have processes that contact the luminal contents and are activated to release their mediators in response to specific features of luminal composition, such as acidity, osmolarity, or nutrients such as amino acids and free fatty acids. In other cases, hormone release in response to changes in luminal composition can also be activated by a reflex that first involves activation of a sensory enteric nerve ending, with subsequent release of specific neurotransmitters close to the surface of the endocrine cell to stimulate exocytosis. Yet other endocrine cells are designed to respond to conditions existing in the interstitium.

ALL OF THE CURRENTLY KNOWN GI HORMONES ARE PEPTIDE., BUT NOT ALL PEPTIDES ISOLATED FROM THE GASTROINTESTINAL TRACT ARE HORMONES. THE GI TRACT IS A VERY RICH SOURCE OF BIOLOGICALLY ACTIVE PEPTIDES, COMPARABLE TO THE CENTRAL NERVOUS SYSTEM, BUT THUS FAR, ONLY FIVE HAVE FULFILLED ALL OF THE CRITERIA TO BE CONSIDERED A HORMONE

HORMONAL REGULATION OF BRAIN GUT AXIX

Leptin, is produced by white adipose tissue and affects feeding behavior,thermogenesis, and neuroendocrine status.

Leptins acts on receptors in the hypothalamus of the brain where it inhibits appetite .

Total lack of leptin or leptin signaling in rodents and humans causes morbid obesity that is accompanied by a wide array of neuro endocrine abnormalities. Circulating levels of leptin levels gives brain the input regarding energy storage so it regulate appetite and metabolisms.

Leptins works by inhibiting the activity of neurons that contains neuropeptide Y(NPY) and other related peptide and by increasing the activity of neurons expressing alpha melanocyte-stimulating hormones.

ROLE OF CCK IN SATIETY AND HUNGER

CCK has also been shown to signal the central nervous system to indicate satiety, or fullness, resulting in considerable efforts to discover small molecule analogues that could be used as appetite suppressants to treat obesity (although as yet without success). CCK also appears to cooperate with a major systemic regulator of food intake, leptin, that is released by adipocytes to signal the status of fat stores throughout the body

GASTRIN /CCK FAMILY

Gastrin and cholecystokinin (CCK) occur in the gastrointestinal system in various forms, and are structurally related peptides that also bind to closely related receptors known as CCK-A and CCK-B receptors. that are G-protein coupled receptors that signal via increases in cytoplasmic calcium. In common with most other biologically- active peptides, both gastrin and CCK are synthesized initially as long propeptides that are sequentially cleaved to generate active forms, which are then stored for release in response to physiologic stimuli.

GHRELIN

ghrelin secretion is inhibited in response to meals; and instead of acting as a satiety signal (like CCK or PYY3-36), ghrelin stimulates appetite,

Recently, another peptide hormone derived from proghrelin, termed obestatin, was demonstrated to inhibit food intake when administered and was proposed to be the ligand for an orphan GPCR, termed GPR39

MOTILIN

full understanding of the biology of motilin has lagged behind that of the other gastrointestinal hormones, most likely because of interspecies variations in the precise structure of the motilin peptide. Human motilin is a 22-amino acid linear peptide that is released cyclically from the gut in the fasting state.

GLP-1 AND GLP-1R NEURONS IN THE CENTRAL NERVOUS SYSTEM(PREPROGLUCAGON-DERIVED PEPTIDES)

They directly associate with several hypothalamic nuclei, including the paraventricular nucleus (PVH), lateral hypothalamic area (LHA).

GIP, or glucose-dependent insulinotropic peptide is released from intestinal K cells in response to all of the major components of a meal—carbohydrates, protein, and fat.

Its primary physiologic actions are to inhibit gastric acid secretion and to stimulate the release of insulin from the endocrine pancreas. The former action represents an example of a feedback regulatory event that contributes to the termination of gastric secretory function once the bulk of the meal has moved into the small intestine.

The latter action accounts for the fact that glucose absorbed across the wall of the gastrointestinal tract is cleared from the circulation more rapidly than an equivalent amount of glucose infused intravenously; thus, the gut augments normal systemic mechanisms of glucose homeostasis to ensure that the body is not overwhelmed during the rapid absorption of glucose originating from a meal rich in sugar.

AMYLIN

Amylin is co-secreted with insulin in response to nutrient intake and insulin secretion.

Amylin readily enters the brain and high affinity a mylin binding sites have been found in several brain regions.

Both peripheral and IV infusions of amylin inhibit food intake acutely and, during chronic infusion, leads to a sustained reduction in body weight.

The precise central neuroendocrine mechanism mediating amylin's anorexic effects has yet to be elucidated.

LHA The lateral hypothalamus includes the lateral

hypothalamic area (LHA) and perifornical hypothalamus. This region of the brain has long been suggested to play a key role in the regulation of ingestive behavior.

These metabolically regulated peptides are melanin concentrating hormone (MCH) and other peptides.

Current data support the view that these LHA neuropeptides play a key role in regulating food intake,

adipose mass, and glucose homeostasis. For example, injection of MCH into the brain increases food intake.

Mice lacking MCH (knockouts) are hypophagic and lean, and mice that over express MCH are obese and hyperleptinemic.

SUMMARY OF GASTROINTESTINAL HORMONES

Hormones Cells or Tissue origin

Actions Secretary Stimulus

Amylin ,endocrine cells ofstomach and smallintestine

Inhibits gastricemptying

Inhibits insulinsecretionSatiety factor

Cosecreted with insulin inresponse to oral nutrientingestion

Hormne Cells or Tissue Action Stimulus

CGRPß-CGRP isexpressed inenteric neurons andenteroendocrinecells of the rectum

Produces markedvasodilation in thesplanchnic andperipheralcirculation bystimulating nitricoxide releaseInhibits gastric acidand pancreaticexocrine secretionInduces intestinalsmooth musclerelaxation

Glucose and gastric acidsecretion

Hormones Cells or Tissue origin Actions

CCK Enteroendocrine I cellsand enteric nerves, CNS,pituitary corticotrophs, Ccells of the thyroid,adrenal medulla.

Inhibits proximalgastric motility whileincreasing antraland pyloriccontractionsRegulates meal stimulatedpancreatic enzymesecretion andgallbladderContraction.CCK also acts on vagal neuron leading back to medulla oblongata which gives a satiety signal..

Hormones Cells or tissue of origin

Actions

Galanin neuralstructures of the gut,pancreas, thyroid, andadrenal gland

In the brain,regulation of foodintake, memory andInduces bothcontraction andrelaxation ofintestinal smoothmuscle, Delays gastricemptying andprolongs colonictransit times

Hormoes

Cells or tissue of origin

Actions Secretary stimuls

GIP Neuroendocrine K cellsin the duodenum andproximal jejunum

Inhibits gastric acidsecretion and GImotilityIncreases insulinrelease andregulates glucoseand lipidmetabolismExerts anabolicactions in bone

Oral nutrient ingestion,especially long-chain fattyacids

Gastrin Predominantlyenteroendocrine G cellsof the stomach andduodenal bulb, CNS andPNS, pituitary, adrenalgland, genital tract,respiratory tract, fetalpancreas

secretionAmidated gastrinsare trophic to theoxyntic mucosa ofthe stomachProgastrin andglycine-extendedgastrin inducecolonic epithelialproliferation

Luminal contents,especially partiallydigested aromaticamino acids, smallpeptides, calcium,coffee, and ethanol

Hormones

Cells or tissue of origin

Related peptides

Actions Secretary stimuls

Ghrelin CNS, stomach, smallintestine, colon

Motilin Stimulates GHreleaseStimulates gastrickinetic activityOrexigenic activityStimulates energyproduction andsignalshypothalamicregulatory nucleithat control energyhomeostasis

Fasting

Hormones

Cells or tissue of origin

Actions Secretary stimuls

GLP-1 Enteroendocrine L cellslocated in the ileum andcolon, CNS

Enhances glucosedisposal followingnutrient ingestion byinhibiting gastricemptying,stimulating insulinsecretion, andinhibiting glucagonsecretion Inhibitsfood intakeStimulatespancreatic isletneogenesis andproliferation

Oral nutrientingestion, especiallycarbohydrates andfat-rich meals

Hormones

Cells or tissue of origin

Actions Secretary stimuls

GLP-2 Enteroendocrine L cellslocated in the ileum andcolon, CNS

Induces smallintestinal andcolonic mucosalgrowthEnhances intestinalepithelial barrierfunctionStimulates intestinalhexose transportInhibits short-termcontrol of foodintake

Oral nutrients especiallycarbohydrates andfat-rich meals

Hormones Cells or tissue of origin

Related peptides

Actions

Motilin Brain, bronchoepithelialcells, andenteroendocrine M cellslocated in the duodenumand proximal jejunum

Ghrelin Induces phase IIIcontractions in thestomachStimulates gastricand pancreaticenzyme secretionInduces contractionof the gallbladder,Sphincters.

Hormones

Cells or tissue of origin

Related peptides

Actions Secretary stimuls

NPY CNS and PNS,pancreatic islet cells

PYY. &PP Potent stimulator oforal nutrient intakeInhibits glucosestimulatedinsulinsecretionReduces GI fluidand electrolytesecretionInhibits gastric andsmall intestinalmotility

Oral nutrientsActivation of thesympatheticnervous system

Hormones

Cells or tissue of origin

Actions Secretary stimuls

PYY Enteroendocrine cells,developing endocrinepancreas, subpopulationof pancreatic alpha cellsin mature islets

Enterogastroneinhibits gastric acidsecretion andgastric motilityIncreases intestinaltransit time byreducing intestinalmotilityInhibits pancreaticexocrine secretion

Bile acids and fattyacidsAmino acidsadministeredintracolonically

Hormones

Cells or tissue of origin

Actions Secretary stimuls

Secretin CNS, fetal endocrinepancreas, andenteroendocrine S cellslocated in the duodenumand proximal jejunum

Principal hormonalstimulant ofpancreatic andbiliary bicarbonateand water secretionRegulatespancreatic enzymesecretionStimulates gastricsecretion ofpepsinogen

Gastric acid, bilesalts, and luminalnutrients, especiallyfatty acids, peptides,and ethanol