Pathophysiology of Adipose Tissues Obesity and Insulin Resistance

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Lipid storage in adipose tissue represents excess energy consumption relative to energy expenditure, which in its pathological form has been coined 'obesity'. In recent years, overnutrition has reached epidemic proportions in developed as well as developing countries. This reflects recent lifestyle changes, however there is also a strong genetic component as well. While the biochemical mechanism(s) for this genetic predisposition are still under investigation, the genes that control appetite and regulate energy homeostasis are now better known. For example, adipocytes produce leptin (see above) that suppresses appetite and was initially considered a promising target for drug therapy. However, most overweight individuals overproduce leptin, and no more than 2-4% of the overweight population has defects in the leptin appetite suppression pathway [14]. In contrast, genetic predisposition to obesity and/or T2D when excess calories are consumed is common in the population: for instance, polymorphisms in the peroxisome proliferator-activated receptor-^ (PPAR-^2) gene may have a broad impact on the risk of obesity and insulin resistance. A minority of people is heterozygous for the Pro12Ala variant of PPAR-7 and is less likely to become overweight and less likely to develop DM when overweight than the majority of Pro homozygotes in the population [15].

One striking clinical feature of overweight individuals is a marked elevation of serum NEFAs, cholesterol, and triacylglycerols irrespective of the dietary intake of fat. Obesity is obviously associated with an increased number and/or size of adipose tissue cells. These cells overproduce hormones, such as leptin, and cytokines, such as TNF-a, some of which appear to cause cellular resistance to insulin [16]. At the same time, the lipid-laden adipocytes decrease synthesis of hormones, such as adiponectin, which appear to enhance insulin responsiveness. The insulin resistance in adipose tissue results in increased activity of the hormone-sensitive lipase, which is probably sufficient to explain the increase in circulating NEFAs [17]. The high circulating levels of NEFAs may also contribute to insulin resistance in the muscle and liver (see below). Initially, the pancreas maintains glycemic control by overproducing insulin. Thus, many obese individuals with apparently normal blood glucose control have a syndrome characterized by insulin resistance of the peripheral tissue and high concentrations of insulin in the circulation. This hyperinsulinemia appears to stimulate the sympathetic nervous system, leading to sodium and water retention and vasoconstriction, which increase blood pressure [18]. The excess NEFAs are carried to the liver and converted to triacylglycerol and cholesterol. Excess triacylglycerol and cholesterol are released as very-low-density lipoprotein particles, leading to higher circulating levels of both triacylglycerol and cholesterol. Eventually, the capacity of the pancreas to overproduce insulin declines which leads to higher fasting blood sugar levels and decreased glucose tolerance (see below).

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