Obesity adipose tissue

Laurell and coworkers have identified an alternatively spliced shorter (80 kDa) form of human HSL that is exclusively expressed in WAT and devoid of both esterase and lipase activities, and is presumably generated by skipping of exon 6, which encodes fhe serine residue of the catalytic triad [295]. Subsequenfly, two HSL immunoreactive bands (88 kDa = L form and 84 kDa = S form) in homogenates from human obese adipose tissue were reported [296]. Immunodetection experiments with an antibody specifically recognizing the domain encoded by exon 6 suggested fhat fhe 80 kDa and S forms correspond to the polypeptide translated... 

Figure 6.3 Infiltration of adipose tissue with macrophages. With progressive obesity, adipose tissue of some subjects accumulates resident tissue macrophages, v ich then secrete inflammatory cytokines, and account for much of the inflammatory condition associated with metabolic syndrome.

Obesity is linked to major adverse health outcomes such as insulin resistance and type 2 diabetes. With obesity, adipose tissue mass expands and adipxxyte (fat cell) size increases. As previously discussed, canonical Wnt signaling pathway is essential for adipwgenesis and type 2 diabetes. Thus, canonical Wnt signaling plays an important role in the genesis of obesity. 

The wide range of inflammation-related factors that adipocytes secrete is linked to the inflammatory response that the tissue exhibits in obesity [1]. Obesity in general, like an increasing number of other diseases, is characterised by a state of mild chronic inflammation, and adipose tissue plays a central role in this. The production of most inflammation-related adipokines increases markedly in obesity and there is an elevated circulating level of a number of these factors as well as of other inflammatory markers such as C-reactive protein (CRP). The increased production of inflammatory adipokines (and decreased production of adiponectin with its anti-inflammatory action) in the obese is considered to play a critical role in the development of the obesity-associated pathologies, particularly type 2 diabetes and the metabolic syndrome [1]. 

An important component of the inflammatory state in adipose tissue in obesity comes from the infiltration of the tissue by macrophages. These are likely to be attracted through the secretion by adipocytes of MCP-1 and MEF. The macrophages in turn secrete factors which both directly add to the total production of inflammatory agents by adipose tissue and also catalyse the production of such agents from adipocytes - and perhaps preadipocytes as well. 

Little attempt has been made to develop drugs targeted specifically to white adipose tissue and the production of adipokines. It is likely, however, that there will be an increasing emphasis on this approach to the pharmacological treatment of obesity-related diseases, given the current views on the centrality of the adipokines to these disorders. It is, of course, the diseases that obesity leads to, rather than obesity itself, that constitute the main medical challenge. 

Obesity results from an energy imbalance, when energy intake exceeds energy expenditure over a prolonged period of time. The excess energy is stored in the form of triglycerides in the adipose tissue. 

The first hormonal signal found to comply with the characteristics of both a satiety and an adiposity signal was insulin [1]. Insulin levels reflect substrate (carbohydrate) intake and stores, as they rise with blood glucose levels and fall with starvation. In addition, they may reflect the size of adipose stores, because a fatter person secretes more insulin than a lean individual in response to a given increase of blood glucose. This increased insulin secretion in obesity can be explained by the reduced insulin sensitivity of liver, muscle, and adipose tissue. Insulin is known to enter the brain, and direct administration of insulin to the brain reduces food intake. The adipostatic role of insulin is supported by the observation that mutant mice lacking the neuronal insulin receptor (NDRKO mice) develop obesity. 

Leptin is a cytokine produced and secreted by adipose tissue in proportion to the body fat content [3]. Mice and humans lacking leptin or its receptor develop a severe hyperphagia and a dramatic degree of obesity which is considerably more pronounced than that of the NDRKO mouse. Thus, leptin is the key adiposity signal in rodents and humans. Leptin secretion appears to reflect the metabolic status of the adipocyte rather than the sheer size of triglyceride deposits, and leptin levels may transiently be dissociated from total body fat. Nonetheless, over the course of a day with unrestricted food supply, plasma leptin levels reliably reflect the amount of total body fat. Local administration of leptin into the brain results in reduced food intake. The vast majority of patients with obesity have elevated serum levels of leptin. Thus, it is believed that the polygenic obesity is due to leptin resistance rather than to inadequate leptin secretion, or to a reduced blood/brain transport of the cytokine. 

Insulin resistance occurs when the normal response to a given amount of insulin is reduced. Resistance of liver to the effects of insulin results in inadequate suppression of hepatic glucose production insulin resistance of skeletal muscle reduces the amount of glucose taken out of the circulation into skeletal muscle for storage and insulin resistance of adipose tissue results in impaired suppression of lipolysis and increased levels of free fatty acids. Therefore, insulin resistance is associated with a cluster of metabolic abnormalities including elevated blood glucose levels, abnormal blood lipid profile (dyslipidemia), hypertension, and increased expression of inflammatory markers (inflammation). Insulin resistance and this cluster of metabolic abnormalities is strongly associated with obesity, predominantly abdominal (visceral) obesity, and physical inactivity and increased risk for type 2 diabetes, cardiovascular and renal disease, as well as some forms of cancer. In addition to obesity, other situations in which insulin resistance occurs includes... 

Fatty acids are synthesized by an extramitochondrial system, which is responsible for the complete synthesis of palmitate from acetyl-CoA in the cytosol. In the rat, the pathway is well represented in adipose tissue and liver, whereas in humans adipose tissue may not be an important site, and liver has only low activity. In birds, lipogenesis is confined to the liver, where it is particularly important in providing lipids for egg formation. In most mammals, glucose is the primary substrate for lipogenesis, but in ruminants it is acetate, the main fuel molecule produced by the diet. Critical diseases of the pathway have not been reported in humans. However, inhibition of lipogenesis occurs in type 1 (insulin-de-pendent) diabetes mellitus, and variations in its activity may affect the nature and extent of obesity. 

Kanda H, Tateya S, Tamori Y, Kotani K, Hiasa K, Kitazawa R, Kitazawa S, Miyachi H, Maeda S, Egashira K, Kasuga M (2006) MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J Qin Invest 116 1494-1505 Kaul M, Garden GA, Lipton SA (2001) Pathways to neuronal injury and apoptosis in HIV-associated dementia. Nature 410 988-994... 

In addition to fiber and carbohydrate content, protein intake from legumes may have weight-loss benefits for obese individuals just because proteins enhance post-meal satiety (Rolls, 1995). However, a possible specific role for phytoestrogens in obesity has been postulated through the modulation of the satiety response, a neuroendocrine mechanism controlled by leptin (a hormone secreted by adipose tissue and already known to be regulated by... 

Auboeuf D, Rieusset J, Fajas L, Vallier P, Frering V, Riou JP, et al. Tissue distribution and quantification of the expression of mRNAs of peroxisome proliferator-activated receptors and liver X receptor-alpha in humans no alteration in adipose tissue of obese and NIDDM patients. Diabetes 1997 46 1319-1327. 

The major types of adipose tissue are (1) white adipose tissue, which manufactures, stores, and releases lipid and (2) brown adipose tissue, which dissipates energy via uncoupled mitochondrial respiration. Obesity research includes evaluation of the activity of adrenergic receptors and their effect on adipose tissue with respect to energy storage and expenditure or thermogenesis. 

Obesity is associated with higher circulating concentrations of leptin that would be found in non-obese individuals. Although this effect can be explained by expansion of adipose tissue mass, there is reason to believe that obesity may also be due to leptin insensitivity in the target tissues. 

For example, obesity affects Vi because lipid-soluble drugs diffuse into the adipose tissues of the obese person. Vi is a useful parameter for determining the loading dose for a drug to attain equilibrium after the drug is administered. 

Chloroform absorption depends on the concentration in inhaled air, the duration of exposure, the blood/air partition coefficient, the solubility in various tissues, and the state of physical activity which influences the ventilation rate and cardiac output. Pulmonary absorption of chloroform is also influenced by total body weight and total fat content, with uptake and storage in adipose tissue increasing with excess body weight and obesity. 

I have already mentioned leptin. There are several others, notably including adiponectin, a protein present in high concentrations in blood. Adiponectin is an antihyperglycemic agent, acting to increase insulin sensitivity. There is a close relationship between obesity, insulin action, and development of type 2 diabetes. Withont listing additional peptides secreted by adipose tissue, it is important to understand that fat is an important player in human physiology. 

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