Obesity free fatty acids

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... 

Lipase Inhibitor Orlistat (Xenical, Roche) is prescribed for the treatment of obesity. It inhibits the gastrointestinal lipase enzymes by binding to the lipase through the serine site and inactivates the enzyme. Fat in the form of triglycerides cannot be hydrolyzed by the lipase and converted to free fatty acids and monoglycerides. Thus, there is no uptake of fat molecules into the cell tissue. 

In a placebo-controlled study in six patients with type 2 diabetes mellitus thalidomide 150 mg/day for 3 weeks reduced insulin-stimulated glucose uptake by 31% and glycogen synthesis by 48% (1115). However, it had no effect on rates of glycolysis, carbohydrate oxidation, non-oxidative glycolysis, lipolysis, free fatty acid oxidation, or re-esterification. The authors concluded that thalidomide increases insulin resistance in obese patients with type 2 diabetes. 

More recently, Bortolotti et al. (2008) provided evidence to refute this calcium-mediated mechanism of weight loss, presenting results from a placebo-controlled crossover study of 10 obese adults with habitually low calcium intakes (<800 mg/day). Results indicated that dietary supplementation of 800 mg of calcium/day had no effect on circulating plasma free fatty acid concentrations or glycerol turnover. Theoretically, a calcium-mediated stimulation of lipolysis would have resulted in an increase in plasma free fatty acid concentrations and glycerol turnover, thus indicating a need for further research. 

Free fatty acids are elevated in the plasma of obese patients and are known to cause muscle and liver insulin resistance. The Wako HR series NEFA-HR(2) is an in vitro enzymatic colorimetric method assay for the quantitative determination of non-esterified fatty acids (NEFA) in serum. Perform the assay on serum collected from mice fasted for a period greater than 4 h, but less than 16 h. Perform the test on samples immediately after collection, without freezing. Also note that hemolysis in the serum samples may interfere with the assay. 

Excess adiposity, particularly the abdominal obesity associated with increased waist circumference, is associated with insulin resistance, hypertension, and proinflammatory states. The prevalence of this complex of comorbidities associated with obesity, now referred to as the metabolic syndrome, is reaching epidemic proportions in the United States (Grundy et al., 2004 Roth et al., 2002). Indeed, increased abdominal adiposity is one of a cluster of factors that are used in the diagnosis of metabolic syndrome. Abdominal tissue in the trunk occurs in several compartments, including subcutaneous and intraperitoneal or visceral fat. Visceral fat in particular appears to contribute to perturbed fuel metabolism by at least two mechanisms. First, hormones and free fatty acids released from visceral fat are released into the portal circulation and impact directly on metabolism of the liver. Second, the visceral adipose depot produces a different spectrum of adipocytokines than that produced by subcutaneous fat (Kershaw and Flier, 2004). 

Table 3 Effect of plasma glucose, triglyceride, and free fatty acids in obese diabetic mice treated with Entry 1 at lOmg/kg per day...

Type 2 DM accounts for as many as 90% of DM cases and is usually characterized by the presence of both insulin resistance and relative insulin deficiency. Insulin resistance is manifested by increased lipolysis and free fatty acid production, increased hepatic glucose production, and decreased skeletal muscle uptake of glucose. )3-Cell dysfunction is progressive and contributes to worsening blood glucose control over time. Type 2 DM occurs when a diabetogenic lifestyle (excessive calories, inadequate exercise, and obesity) is superimposed upon a susceptible genotype. 

Second-hit hypothesis This hypothesis has been proposed as a plausible explanation for the occurrence of NASH. (48, 70) The first hit is considered to be the development offatty liver, particularly due to hyperahmentation and obesity resulting in insulin resistance. As second hit follows the mobilization of free fatty acids from fat depots and their transport to the liver cells. This leads to a massive increase of free radicals due to oxidative stress with lipid peroxidation and induction of cytokines (TNFa, TGFp, IL6, IL8). As a result, there is a reactive formation of uncoupling protein (UCP2) with a subsequent decrease in hepatocyte ATP and a disturbance of macrophage function with higher sensitivity to endotoxin. This leads to an inflammatory reaction, cell death and the formation of fibrosis. (44, 50, 65)... 

Nestel, R J., Ishikawa, T., and Goldrick, R, B, (1978) Diminished plasma free fatty acid clearance in obese subjects, Matalwiism 27, 589-596. 

The most prevalent form of diabetes, which accounts for 85-95% of all cases, is type 2 diabetes, defined by reduced insulin production and insulin resistance. Insulin resistance occurs when increasing quantities of insulin are required to regulate the transport of plasma glucose to body tissues. It is often accompanied by obesity, which elevates the free fatty acid levels in blood serum and is thought to induce insulin resistance. I56l... 

Current evidence suggests that accumulation of fat in NAFLD is a consequence of insulin resistance. A variety of mechanisms may lead to insulin resistance, including genetic predisposition, increased concentrations of free fatty acids, and presence of cytokines such as tumor necrosis factor alpha (TNF-a). Since TNF-a is produced by fat cells, correlates with body fat, and is critical to development of insulin resistance in obesity,it may be a key factor in development of NAFLD. The pathogenesis is likely to be more complicated, however, as a variety of other factors lead to increased fat accumulation in the liver, including increased carbohydrate intake, certain drugs, and mutations in lipid synthesis, but have not been associated with development of NASH. 

P.D. Berk, S.L. Zhou, C. L. Kiang, D. Stump, M. Bradbury, and L.M. Isola, Uptake of long chain free fatty acids is selectively up-regulated in adipocytes of Zucker rats with genetic obesity and noninsulin-dependent diabetes mellitus, /. Biol. Chem., 1997, 272, 8830-8835. 

Santomauro A, Boden G, Silva M, et al. Overnight lowering of free fatty acids with acipimox improves insulin resistance and glucose tolerance in obese diabetic and non-diabetic subjects. Diabetes 1999 48 1836-1841. 

Carpentier A, Mittelman SD, Bergman RN, et al. Prolonged elevation of plasma free fatty acids impairs pancreatic beta-cell function in obese nondiabetic humans but not in individuals with type 2 diabetes. Diabetes 2000 49 399 08. 

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