د. حسين محمد جمعه
اختصاصي الامراض الباطنةالبورد العربي
كلية طب الموصل
2012
Leptin .Adiponectin. Ghrelin
2012Leptin (Greek λεπτός (leptos) meaning thin) is a 16 kDa protein hormone that plays a key role in regulating energy intake and energy expenditure, including appetite and metabolism. It is one of the most important adipose derived hormones.[2] discovered in 1994 . The Ob(Lep) gene (Ob for obese, Lep for leptin) is located on chromosome 7
Human leptin is a protein of 167 amino acids. It is manufactured primarily in the adipocytes of white adipose tissue, and the level of circulating leptin is directly proportional to the total amount of fat in the body.
In addition to white adipose tissue—the major source of leptin—it can also be produced by brown adipose tissue, placenta ,ovaries, skeletal muscle, stomach , bone marrow, pituitary and liver.[
Leptin acts on receptors in the hypothalamus where it inhibits appetite by
• counteracting the effects of neuropeptide Y (a potent feeding stimulant secreted by cells in the gut and in the hypothalamus);• counteracting the effects of anandamide (another potent feeding stimulant that binds to the same receptors as THC), and
• promoting the synthesis of α-MSH, an appetite suppressant. This appetite inhibition is long-term, in contrast to the rapid inhibition of eating by cholecystokinin (CCK) and the slower suppression of hunger between meals mediated by PYY3-36.
The absence of leptin (or its receptor) leads to uncontrolled food intake and resulting obesity. Several studies have shown that fasting or following a very-low-calorie diet (VLCD) lowers leptin levels.[8] It might be that, in the short-term, leptin is an indicator of energy balance. This system is more sensitive to starvation than to overfeeding; leptin levels change more when food intake decreases than when it increases.[9] It might be that the dynamics of leptin due to an acute change in energy balance are related to appetite and eventually to food intake. Although this is a new hypothesis, there are already some data that support it.[10][11]
There is some controversy regarding the regulation of leptin by melatonin during the night. One research group suggested that increased levels of melatonin caused a downregulation of leptin.[12]
However, in 2004, Brazilian researchers found that melatonin increases leptin levels in the presence of insulin, therefore causing a decrease in appetite during sleeping.[13]
Mice with type 1 diabetes treated with leptin alone or in conjunction with insulin did better (blood sugar did not fluctuate as much; cholesterol levels decreased; mice formed less body fat) than mice with type 1 diabetes treated with insulin alone, raising the prospect of a new treatment for diabetes.[
Adiponectin is an abundant protein hormone which belongs to a family of so-called adipokines. Adiponectin is expressed mostly by adipocytes and is important regulator of lipid and glucose metabolism. It is established that adiponectin is a insulin-sensitizing hormone with anti-diabetic, anti-inflammatory and anti-atherogenic properties
Adiponectin
It was shown that decreased serum adiponectin concentration indicates insulin resistance and type 2 diabetes .Besides, hypoadiponectinemia was shown to be associated with coronary artery disease .
Several authors point out that high level of circulating adiponectin reduce risk of coronary heart disease among type 2 diabetes patients (4) and is associated with reduced risk of myocardial infarction in apparently healthy men (5). So, there is growing interest among medical professionals to use adiponectin for insulin resistance diagnosis and predicting of cardiovascular complications in subjects with type 2 diabetes.
Human adiponectin consists of 244 amino acid .
Human adiponectin consists of 244 amino acid residues and has distinct domain structure: it contains both collagen-like and globular C1q-like domains. Collagen-like parts of three adiponectin molecules can interact forming triple coiled coil structure much alike to that in collagen (6). C1q-like domains form a “head” of adiponectin globula (Fig.1) and share a great degree of structural similarity to complement component C1q. Several oligomeric forms of native adiponectin circulating in the blood are described in literature: trimers (low-molecular weight form, LMW), hexamers (medium molecular weight form, MMW) and higher order multimers (high molecular weight form, HMW). Three monomers of adiponectin form a trimer. Trimers linked by disulfide bond form a hexamer.
The exact structure of the HMW form of adiponectin is not yet known. Most likely several combined hexamers and/or trimers constitute high-molecular weight form of adiponectin. It is generally believed that disulfide bonds as well as some bonds with participation of modified amino acid residues in collagen domain of adiponectin, take part in holding subunits of HMW form of adiponectin together (Fig. 1). It is also believed that those oligomeric forms exist in the bloodstream as separate moieties and do not convert into each other.
It has been shown recently, that adiponectin oligomers are capable of binding Ca2+ ions which are thought to participate in maintenance of conformational stability of adiponectin (10). Concentration of total adiponectin in the blood is about 3-30 μg/ml, whereas concentration of the closest structural homolog of adiponectin, C1q, is about 80-200 μg/ml. It is therefore of utmost importance that anti-adiponectin antibodies would have no cross-reactivity with human C1q. (8) Some authors describe significant gender differences in adiponectin level in healthy adults and these differences are believed to contribute to discrepancies in adiponectin concentration reported by various authors.
It was shown, that biologic activity of adiponectin is mediated by high-molecular weight form and, not surprisingly, it has been suggested recently that concentration of HMW form of adiponectin or ratio HMW/total adiponectin (sum of three types of oligomers) in serum correlates stronger than total adiponectin with insulin resistance and other measures of type 2 diabetes (9).
HyTest offers new generation of anti-human adiponectin monoclonal antibodies suitable both for research purposes (Western blotting, direct ELISA) and for the development of adiponectin-specific sandwich immunoassays.
Adiponectin affects:
glucose fluxdecreased gluconeogenesis
increased glucose uptake[3][12][20]
lipid catabolism[20]
β-oxidation[12]
triglyceride clearance[12]
protection from endothelial dysfunction (important facet of atherosclerotic formation)
insulin sensitivity
weight loss
control of energy metabolism.[20]
upregulation of uncoupling proteins
Metabolic effects
A low level of adiponectin is an independent risk factor for developing:
Metabolic syndrome[7]Diabetes mellitus[
Hypoadiponectinemia
Because adiponectin is a novel hormone, no therapy has yet been developed with adiponectin and it may be some years before clinical trials commence. One obvious pharmaceutical treatment would be the administration of adiponectin; in mouse models such administration has shown positive effects.[3]
Pharmaceutical therapy
Problems to be overcome prior to human administration include establishing what the biologically active molecule is, what role post-translational modifications have upon the function and associated difficulties in generating biologically active molecules on a large scale. However, this remains a promising area of research for clinical therapy in diseases such as obesity, type 2 diabetes and fatty liver disease.[21] Adiponectin levels may also affect breast cancer risk.[
Ghrelin is a hormone produced mainly by P/D1 cells lining the fundus of the human stomach and epsilon cells of the pancreas that stimulates hunger. Ghrelin levels increase before meals and decrease after meals. It is considered the counterpart of the hormone leptin, produced by adipose tissue, which induces satiation when present at higher levels. In some bariatric procedures, the level of ghrelin is reduced in patients, thus causing satiation before it would normally occur.
Ghrelin is also produced in the hypothalamic arcuate nucleus, where it stimulates the secretion of growth hormone from the anterior pituitary gland.. Receptors for ghrelin are expressed by neurons in the arcuate nucleus and the lateral hypothalamus. The ghrelin receptor is a G protein-coupled receptor, formerly known as the GHS receptor (growth hormone secretagogue receptor).
Ghrelin plays a significant role in neurotrophy, particularly in the hippocampus, and is essential for cognitive adaptation to changing environments and the process of learning. Recently, ghrelin has been shown to activate the endothelial isoform of nitric oxide synthase in a pathway that depends on various kinases including Akt.
Ghrelin exists in an endocrinological inactive (pure peptide) and an active (octanoylated) form (Hexatropin). Side chains other than octanoyl have also been observed.
Ghrelin has emerged as the first circulating hunger hormone. Ghrelin and synthetic ghrelin mimetics (the growth hormone secretagogues) increase food intake and increase fat mass by an action exerted at the level of the hypothalamus. They activate cells in the arcuate nucleus that include the orexigenic neuropeptide Y (NPY) neurons. Ghrelin-responsiveness of these neurones is both leptin- and insulin-sensitive.
Ghrelin also activates the mesolimbic cholinergic-dopaminergic reward link, a circuit that communicates the hedonic and reinforcing aspects of natural rewards, such as food, as well as of addictive drugs, such as ethanol.
Recently, Scripps research scientists have developed an anti-obesityvaccine, which is directed against the hormone ghrelin. The vaccine uses the immune system, specifically antibodies, to bind to selected targets, directing the body's own immune response against them. This prevents ghrelin from reaching the central nervous system, thus producing a desired reduction in weight gain.
The discovery of ghrelin was reported by Masayasu Kojima and colleagues in 1999. The name is based on its role as a ''growth hormone-releasing peptide'', with reference to the Proto-Indo-European root ''ghre'', meaning ''to grow''. The name can also be viewed as an interesting (and incidental) pun, too, as the initial letters of the phrase ''growth hormone-releasing'' give us "ghre" with "lin" as a usual suffix for some hormones.
