Obesity is becoming the most important illness in developed countries, many other ailments derive from this metabolic disorder, and this is the reason why many studies are made to restrain its progression which is becoming exponential. Above all, different kinds of diets are proposed, among which the most used is the diet which intervenes on the concept of “calories”; all of which are in association with physical activity.
The calorie diet is used, keeping in mind the efficacy of a lower in take of food, mathematically calculated, obliging the organism to take advantage of the accumulated energy which is deposited in the adipose tissue, retaining it to be helpless, in a storage place, where one can deposit or remove the goods with only a little influence on organs and glands; without any consideration for the whole physiology of the human body; moving research towards a medicine which can miracolasly make fat disappear. But unfortunately this is not possible, each proposed diet has an affect for a certain period of time, because operate on this little pathological portion that have created the fat mass, but after a while it ceases, and no longer has the desired effect, and the patient finds him/her self back to the initial pathological stages. Therefore, the human organism must be considered in its physiological completeness, and later analyse where the mistake occured. We always see the pathology, but rarely analyse where and when the mistake happenes. For this reason we must begin to understand obesity beginning with the tissue which represent it that is adipose tissue. This should be considered like an endocrine tissue that produces hormones which regulate and keep a metabolic condition in homeostasis, which in turn can influence all the endocrine order to obtain this result, it is an important and central endocrine organ, which all the energy of the body dependson, and to which it contributes, and from which signs that interact with alimentary behaviour, regulative regions of the nervous system and endocrine glands start. Many of the secreting factors of adipose tissue behave in an autocrine, paracrine and endocrine manner, in order to regulate the metabolism, the growth and the self regulation of the same adipocytes, and endocrine, on many remote situations for omeostasi energy. The adipose tissue secretes a large quantity of biologically active molecules, the adipocytokins, leptin, adiponectin, resistin, proinflammatory cytokines Tumor Necrosis Factor, interleukin-6 (IL-6).
Leptin, acts mainly on the hypothalamus, the peripheric and central somministration reduces the intake of food and body weight is averages, at least in part, by neuropeptide Y (NPY), a strong stimulator for the assumption of food, on which in acts in a suppressive way; the synthesis of fatty acid in the adipocytes like the secretion of insulin in the pancreatic cells; it induces the suppression of secretion of grelin, mostly expressed by the stomach, with a contrary effect stimulating appetite. The total lack, resistance or insensibility to leptin, provokes hyperphagia, obesity, diabetes, and a variety of neuroendocrine irregularities and disfunctions of the immunity system. The level of leptin in women is higher than in man, partly due to an inhibition by the estrogenics, and partly it is expressed in greater quantity in the subcutaneous adipose tissue than in the visceral. Women have a high proportion of subcutaneous fat. Leptin rises during the night and lasts until morning, during the day it is reciprocal to glucocorticoid and is secreted in a pulsating way. It guarantees a long term control of the fat mass. Leptin activates the sympatetic nervous system, and is involved in the regulation of blood pressure, angiogenesis, hematopoiesis, development of bone and brain, healing of wounds. Leptin has a multi systemic action, and it is probable the action of leptin or leptin resistance can intermediate metabolic, endocrine and cardiovascular complications associated with obesity. For women who have hypothalamic amenorrhoea and low leptin, its administration improves the reproductive system. Thyroid and the axis of the growth hormone, the markers of formation of bone, suggesting that leptin is necessary not only for energetic homeostasis, but also for a neuroendocrine function.
Adiponectin: it exclusively sectretes from the adipose tissue, its basic concentration circulating, is diminished in obesity, type 2 diabetes, insulin resistance, the concentration of blood adiponectin is more tightly connected to the degree of resistance to insulin and hyperinsulinemia than to the degree of obesity. Low levels of adiponectin forecastes the devolopment of sequent type 2 diabetes and this reduction has a role in the pathogens of the cardiovascular illnessed, associates with obesity; it improves hyperinsulinemia greatly connecting the adipose tissue and the metabolism of glucose of all the body. It has anti-inflammatory and antiatherogenic properties, working and accumulating itself in the wall ,aof the damaged vasculums, and depending on the dosage, it inibits TNF which induces cell adhesion in the endothelial cells. Increases the oxidation of free fatty acids in the muscle increasing the energetic homeostasis. It has an antidiabetic, anti-atherogenic, anti-inflammatory effects, the plasmatic levels diminish with the accumulation of visceral adipose tissue, and therefore a connection between adiponectin, visceral adipose, insulin-resistance and vascular ailments exists.
Adiponectin is codified by the gene APM1 (Adipose Most Abundant Transcript 1) which is exclusively expressed by adipocytes. It produces the modulation of the secretion of insulin, catabolism of the adipocyte, a relation insulin resistance, it is negatively correlates to the index of body IMC. In pathological situations such as insulin recistance, obesity, type 2 diabetes, adiponectin is very low, it not only has a role in the sensibility to insulin, but it also has a metabolic role in the activity of adipose tissue and insulin resistance. Furthermore, there is a close relationship between insulin resistance and atherosclerosis. In patients with type 2 diabetes and with atherosclerotic complications, adiponectin is reduced. Some studies suggest an anti-inflammatory direct role from adiponectin to the vascular walls. This adipocytokins accumulates on the demages walls and has a restraining effect on the production of TNF produced by macrophages. Adiponectin increases the capture of muscular glucose and lowers its production in the liver, the principle defect responsible for hyperglycemia after feeding in diabetic patients, therefore the effect of adiponectin doesn’t pass throught secretion of insulin, but its strengthening of its tissue effect. Like leptin, adiponectin stimulates AMPK (AMP activated protein kinase) at a muscular level. , a strong inhibitor of the adiponectin expression, has theaTNF capability to stimulate IL-6, resistin production which effects are opposite to the effect of adiponectin.
Resistin is a hormone secreted by the adipocytes that potentially leads obesity to type 2 diabetes; is exclusively secreted in the adipose tissue. ResistinmRNA is strongly produced during the differentiation of the adipocytes, just as in diet obesity induced. Its expression is under the nourishing and hormone regulation, and is very low during fasting, and in insulin deficient-rats, and increases after rialimentation and somministration of insulin. The immune neutralisation of circulating resistin, improves the level of blood glucose and insulin share, suggesting that high levels of resistin have an inhibitory effect on the lowering of insulin sensibility in fat-rat. Interestingly, resistin exercises also an inibitory effect on adipocyte differentiation; may run as feedback signal to limits adipocyte formation. They expresses resistin receptors and resistin has paracrine, autocrine, endocrine functions. Adipose tissue secretes resistin on hyperinsulinemia and hyperglycemia reply. Resistin is expresses on the pancreatic islets, and is overproducted in insulin resistance. During pregnancy, levels of resistin have risen, particularly have way through the gestation. Resistin is influences by gender, thyroid hormon, state of gonad and pregnancy. Resistin can explain the insulin sensibility reduction during puberty and could be the link between sexual steroids and insulin sensibility. Besides this, resistin can mediate thyroid hormone effects on insulin resistance, and the state insulin resistance during pregnancy.
Adiponutrin is a protein mainly expressed by brown rather than the white adipose tissue, has an influence on the adipogenic and lipogenic processes; it is absent in all tussues, including liver, its plasmatic levels are very low during fasting, but they increase considerably with a rich carbo-hydrates diet, there is a correlation between adiponutrin and obesity.It is expressed in a very clear manner in obese people and allows the fibroblast differentiation to mature adipocyte.
Malonyl-CoA, “malonyl-CoA could be the body’s primary appetite controller” (Dan Lane). It is an intermediate of fatty acid bio synthesis and monitors the energetic state as mediator in the nuclear hypothalamic (NPY, AgRP, POMC); it’s hypothalamic level is low during fasting and increases after meals; it is a mediator of the sign which causes suppression of appetite.
After analysing the main mediators involved in the symptoms of hunger and appetite, one must wonder why do we arrive at a metabolic unbalance which later leads to obesity. At this point, the metabolic syndrome, which is characterised by insulin resistance, hyperinsulinemia, arterial high blood pressure, type 2 diabete, arteriosclerosis, marked increase of cardiovascular risk, periferic vascular and cerebrovascular illnesses must be considered. Therefore, the beginning of this syndrome must be perceived in insulin resistance, hyperinsulinemia. But how do these metabolic alterations begin to establish themselves?
Firstly the adipose tissue must always be considered, that not only has a central role in the energetic homeostasis, producing hormones, but it also produces cytokines, TNF, IL-6. The cytokines have an important metabolic role, which don’t only interact directly with the transmission means of insulin signal, but they also modulate fatty acid metabolism equally. We must however, differentiate the physiological condition from the pathological condition. In the first case it is possible that the weak secretion of TNF and IL-6 (even of other cytokines of the same type) limits their harmful effects in the autocrine and paracrine sphere. The strong secretion of adiponectin and the efficient signal of leptin assures fatty acid oxidation in muscle, avoiding the deposit of ectopic fat, all contributes to a perfect block of the postprandial hepatic glucose production. Everything changes in the situation of weight excess, above all in visceral obesity. Circulating Fand IL-6 overexpressed, triggers undesirable endocrine effect, which increases insulin resistance. Adiponectin production collapses and the leptin resistance starts, increasing insulin resistance. A circle vicious aggravation the metabolic syndrome concerns at this point central nervous system, (interruption of signal produced for leptin and insulin on the centres of energetic controllers and their project on the indipendent Nervous System) and the pancreatic cells (insulin expression disturbance throught glucotoxity, but also capacity lowering to form new Langerhans pancreatic islets). When insulin request increases and overcome the capacity of pancreatic compensation, glycemia begins to rise, mainly after meals, and has a devastating effect on the function on pancreatic cells, and the appearance of type 2 diabetes kind, precipitates and quichly becomes irreversible. Therefore, the metabolic syndrome is defined by a group of risk factors defines which attentively analyzed can in advance its beginning forewarn, forestalling precocious obesity start as concause to rheumatic illnesses, type 2 diabetes, hypertension, cardiovascular events. Therefore, obesity mustn’t be considered as single and sole illness in which the assumption and energy dispersal have a predominant and absolute role, but it must be considered as a part of a syndrome in which many factors intersect, producing metabolic intermediate amongst which Malonyl-CoA considered as a mechanism signal off energy homeostasis. At the end analysis the adipokines, citokines, malonyl-CoA, hypothalamic neuropeptides, influence the insulin resistance and hyperinsulinemia.
Adipocytokines and cytokines are physiologically produced in infinitesimal quantity, for example resistin 38,78ng/ml, could we use this proteins in the same physiological quantity, considerating higher dosage would block/stimulate other important reactions in other tissues, upsetting homeostasis physiological of total body, leading it towards more important illnesses. This is a therapy proposal for study successive, keeping high consideration for basis research and comprehensive physiology, carefully analysing the chain reactions.
In ending, obesity is a phenomenon aggravating the rheumatic pathology. The correct body weight is regulated by a complex homeostasis, in which adipose tissue has been an high-class role and must be considered as an organ, a complete one whose influence expounds to other endocrine tissue. Weight controll is important at all ages. The incidence and degree of obesity in children and adolescence has risen drammatically. The biomarkers of risk increased are always present in children, metabolic syndrome begins always with hyperinsulinemia and insulin resistance, therapy must take into account the physiological aspects of patients without attacking other important reactions, even in children the metabolic syndrome can lead to, or accentuate pathological rheumatism acquired by wrong alimentation. Therefore, the analysis of this pathologies, obesity and rheumatic disorders, must be multi factorial, carefully considering the physiology and pathophisiology of the whole body.
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