Names | |
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IUPAC name (2S)-2-[[(2S)-1-[2-[[(2S)-1-[(2S)-2-aminopropanoyl]pyrrolidine-2-carbonyl]amino]acetyl]pyrrolidine-2-carbonyl]amino]-5-(diaminomethylideneamino)pentanoic acid | |
Other names Procolipase activation peptide; APGPR; L-Alanyl-L-prolylglycyl-L-prolyl-L-arginine | |
Identifiers | |
3D model (JSmol) | |
ChemSpider | |
PubChem CID | |
UNII | |
CompTox Dashboard (EPA) | |
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Properties | |
C21H36N8O6 | |
Molar mass | 496.569 g·mol−1 |
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). |
Enterostatin is a pentapeptide [1] derived from a proenzyme in the gastrointestinal tract called procolipase. It reduces food intake, in particular fat intake, [2] when given peripherally or into the brain. [3]
Enterostatin has the sequence Val-Pro-Asp-Pro-Arg in most mammals, but Val-Pro-Gly-Pro-Arg or Val-Pro-Asp-Pro-Arg in rodents and Ala-Pro-Gly-Pro-Arg in humans [4] . The sequence that it necessary for its anorexic effects is X-pro-Y-pro-arg and conserved among several vertebrate species [5] [6] .
Enterostatin has been detected in gut endocrine cells [7] . It is created in the intestine by pancreatic procolipase, the other colipase serving as an obligatory cofactor for pancreatic lipase during fat digestion. Enterostatin can be created in the gastric mucosa and the mucosal epithelia in the small intestine. A high fat diet will cause the procolipase gene transcription and enterostatin to release into the gastrointestinal lumen. Enterostatin appears in the lymph and circulation after a meal. Enterostatin has been shown to selectively reduce fat intake during a normal meal. The testing has been successful with different species [8] .
The signaling pathway of the peripheral mechanism uses afferent vagal to hypothalamic centers. The central responses are mediated through a pathway including serotonergic and opioidergic components [9] . Enterostatin cuts fat intake, bodyweight, and body fat. This reaction may involve multiple metabolic effects of enterostatin, which include a decrease of insulin secretion, [10] a growth in sympathetic drive to brown adipose tissue, and the stimulation of adrenal corticosteroid secretion. It has been demonstrated that enterostatin stimulates neurons in the amygdala, the arcuate nucleus, the lateral and the ventromedial hypothalamus that have anatomic and functional projections to the paraventricular nucleus (PVN) of the hypothalamus [11] . Additionally, enterostatin regulates the expression of Agouti-related peptide (AgRP) in a complex manner [12] .
A possible pathophysiological role is indicated by studies that have associated low enterostatin output and/or responsiveness to breeds of rat that become obese and prefer dietary fat. Humans with obesity also exhibit a lower secretion from pancreatic procolipase after a test meal, compared with persons of normal weight. [3]
Its effects include a reduction of insulin secretion, an increase in sympathetic drive to brown adipose tissue, and the stimulation of adrenal corticosteroid secretion. At the end level, it initiates a sensation of fullness of stomach which could be the reason for its role in regulation of fat intake and reduction of body weight. For enterostatin to be utilized it needs the presence of CCK A receptors. Studies based on rats who lack these receptors have found them to be un-responsive to enterostatin. [13]
When rats have been injected with high doses of enterostatin into the brain the rats ate progressively less food as the dose was increased. [14] : 969 In rats, examination of experiments involving the effects of peripheral or intracerebroventricular administration of enterostatin show this selectively slows down fat consumption. [15] : 8
Although enterostatin-like immunoreactivities exist in blood, brain, and gut, and exogenous enterostatins decrease fat appetite and insulin secretion in rats, the roles of these peptides in human obesity remain to be examined [16] . It has been hypothesized that resistance to enterostatin impairs its effects in obesity [16] .
Pro-opiomelanocortin (POMC) is a precursor polypeptide with 241 amino acid residues. POMC is synthesized in corticotrophs of the anterior pituitary from the 267-amino-acid-long polypeptide precursor pre-pro-opiomelanocortin (pre-POMC), by the removal of a 26-amino-acid-long signal peptide sequence during translation. POMC is part of the central melanocortin system.
Leptin also obese protein is a protein hormone predominantly made by adipocytes. Its primary role is likely to regulate long-term energy balance.
Secretin is a hormone that regulates water homeostasis throughout the body and influences the environment of the duodenum by regulating secretions in the stomach, pancreas, and liver. It is a peptide hormone produced in the S cells of the duodenum, which are located in the intestinal glands. In humans, the secretin peptide is encoded by the SCT gene.
Cholecystokinin is a peptide hormone of the gastrointestinal system responsible for stimulating the digestion of fat and protein. Cholecystokinin, formerly called pancreozymin, is synthesized and secreted by enteroendocrine cells in the duodenum, the first segment of the small intestine. Its presence causes the release of digestive enzymes and bile from the pancreas and gallbladder, respectively, and also acts as a hunger suppressant.
The paraventricular nucleus is a nucleus in the hypothalamus. Anatomically, it is adjacent to the third ventricle and many of its neurons project to the posterior pituitary. These projecting neurons secrete oxytocin and a smaller amount of vasopressin, otherwise the nucleus also secretes corticotropin-releasing hormone (CRH) and thyrotropin-releasing hormone (TRH). CRH and TRH are secreted into the hypophyseal portal system and act on different targets neurons in the anterior pituitary. PVN is thought to mediate many diverse functions through these different hormones, including osmoregulation, appetite, and the response of the body to stress.
The arcuate nucleus of the hypothalamus (ARH), or ARC, is also known as the infundibular nucleus to distinguish it from the arcuate nucleus of the medulla oblongata in the brainstem. The arcuate nucleus is an aggregation of neurons in the mediobasal hypothalamus, adjacent to the third ventricle and the median eminence. The arcuate nucleus includes several important and diverse populations of neurons that help mediate different neuroendocrine and physiological functions, including neuroendocrine neurons, centrally projecting neurons, and astrocytes. The populations of neurons found in the arcuate nucleus are based on the hormones they secrete or interact with and are responsible for hypothalamic function, such as regulating hormones released from the pituitary gland or secreting their own hormones. Neurons in this region are also responsible for integrating information and providing inputs to other nuclei in the hypothalamus or inputs to areas outside this region of the brain. These neurons, generated from the ventral part of the periventricular epithelium during embryonic development, locate dorsally in the hypothalamus, becoming part of the ventromedial hypothalamic region. The function of the arcuate nucleus relies on its diversity of neurons, but its central role is involved in homeostasis. The arcuate nucleus provides many physiological roles involved in feeding, metabolism, fertility, and cardiovascular regulation.
Ghrelin is a hormone primarily produced by enteroendocrine cells of the gastrointestinal tract, especially the stomach, and is often called a "hunger hormone" because it increases the drive to eat. Blood levels of ghrelin are highest before meals when hungry, returning to lower levels after mealtimes. Ghrelin may help prepare for food intake by increasing gastric motility and stimulating the secretion of gastric acid.
Neuropeptide Y (NPY) is a 36 amino-acid neuropeptide that is involved in various physiological and homeostatic processes in both the central and peripheral nervous systems. It is secreted alongside other neurotransmitters such as GABA and glutamate.
Octreotide, sold under the brand name Sandostatin among others, is an octapeptide that mimics natural somatostatin pharmacologically, though it is a more potent inhibitor of growth hormone, glucagon, and insulin than the natural hormone. It was first synthesized in 1979 by the chemist Wilfried Bauer, and binds predominantly to the somatostatin receptors SSTR2 and SSTR5.
Amylin, or islet amyloid polypeptide (IAPP), is a 37-residue peptide hormone. It is co-secreted with insulin from the pancreatic β-cells in the ratio of approximately 100:1 (insulin:amylin). Amylin plays a role in glycemic regulation by slowing gastric emptying and promoting satiety, thereby preventing post-prandial spikes in blood glucose levels.
The ventromedial nucleus of the hypothalamus is a nucleus of the hypothalamus. In 2007, Kurrasch et al. found that the ventromedial hypothalamus is a distinct morphological nucleus involved in terminating hunger, fear, thermoregulation, and sexual activity. This nuclear region is involved in the recognition of the feeling of fullness.
Glucagon-like peptide-1 (GLP-1) is a 30- or 31-amino-acid-long peptide hormone deriving from the tissue-specific posttranslational processing of the proglucagon peptide. It is produced and secreted by intestinal enteroendocrine L-cells and certain neurons within the nucleus of the solitary tract in the brainstem upon food consumption. The initial product GLP-1 (1–37) is susceptible to amidation and proteolytic cleavage, which gives rise to the two truncated and equipotent biologically active forms, GLP-1 (7–36) amide and GLP-1 (7–37). Active GLP-1 protein secondary structure includes two α-helices from amino acid position 13–20 and 24–35 separated by a linker region.
Peptide YY (PYY), also known as peptide tyrosine tyrosine, is a peptide that in humans is encoded by the PYY gene. Peptide YY is a short peptide released from cells in the ileum and colon in response to feeding. In the blood, gut, and other elements of periphery, PYY acts to reduce appetite; similarly, when injected directly into the central nervous system, PYY is also anorexigenic, i.e., it reduces appetite.
The lateral hypothalamus (LH), also called the lateral hypothalamic area (LHA), contains the primary orexinergic nucleus within the hypothalamus that widely projects throughout the nervous system; this system of neurons mediates an array of cognitive and physical processes, such as promoting feeding behavior and arousal, reducing pain perception, and regulating body temperature, digestive functions, and blood pressure, among many others. Clinically significant disorders that involve dysfunctions of the orexinergic projection system include narcolepsy, motility disorders or functional gastrointestinal disorders involving visceral hypersensitivity, and eating disorders.
Nesfatin-1 is a neuropeptide produced in the hypothalamus of mammals. It participates in the regulation of hunger and fat storage. Increased nesfatin-1 in the hypothalamus contributes to diminished hunger, a 'sense of fullness', and a potential loss of body fat and weight.
The glucagon-like peptide-1 receptor (GLP1R) is a G protein-coupled receptor (GPCR) found on beta cells of the pancreas and on neurons of the brain. It is involved in the control of blood sugar level by enhancing insulin secretion. In humans it is synthesised by the gene GLP1R, which is present on chromosome 6. It is a member of the glucagon receptor family of GPCRs. GLP1R is composed of two domains, one extracellular (ECD) that binds the C-terminal helix of GLP-1, and one transmembrane (TMD) domain that binds the N-terminal region of GLP-1. In the TMD domain there is a fulcrum of polar residues that regulates the biased signaling of the receptor while the transmembrane helical boundaries and extracellular surface are a trigger for biased agonism.
Neuromedin U is a neuropeptide found in the brain of humans and other mammals, which has a number of diverse functions including contraction of smooth muscle, regulation of blood pressure, pain perception, appetite, bone growth, and hormone release. It was first isolated from the spinal cord in 1985, and named after its ability to cause smooth muscle contraction in the uterus.
Free fatty acid receptor 1 (FFAR1), also known as G-protein coupled receptor 40 (GPR40), is a rhodopsin-like G-protein coupled receptor that is coded by the FFAR1 gene. This gene is located on the short arm of chromosome 19 at position 13.12. G protein-coupled receptors reside on their parent cells' surface membranes, bind any one of the specific set of ligands that they recognize, and thereby are activated to trigger certain responses in their parent cells. FFAR1 is a member of a small family of structurally and functionally related GPRs termed free fatty acid receptors (FFARs). This family includes at least three other FFARs viz., FFAR2, FFAR3, and FFAR4. FFARs bind and thereby are activated by certain fatty acids.
In biology, energy homeostasis, or the homeostatic control of energy balance, is a biological process that involves the coordinated homeostatic regulation of food intake and energy expenditure. The human brain, particularly the hypothalamus, plays a central role in regulating energy homeostasis and generating the sense of hunger by integrating a number of biochemical signals that transmit information about energy balance. Fifty percent of the energy from glucose metabolism is immediately converted to heat.
Jessica Barson is an American neuroscientist and associate professor at Drexel University College of Medicine. Barson investigates neuropeptide signalling in the paraventricular nucleus of the thalamus as well as the nucleus accumbens to understand the neurobiological basis of addiction and elucidate targets for therapy.