"Ectopic fat deposition" appears when the normal buffering capacity of adipose tissue is impaired or exceeded, especially during postprandial periods, and is characterized by diversion of FFAs from adipose depots and lipid deposition in nonadipose tissue (liver, muscle, heart, and pancreatic ^-cells). It may occur by the following mechanisms: 1) increased tissue uptake of chronically elevated FFAs, 2) increased lipogenesis within the tissue or 3) reduced FFA oxidation. Lipid accumulation in liver and muscle is associated with insulin resistance in type 2 diabetic patients (111), and magnetic resonance spectroscopy measurement of intramyocellular triglyceride (IMCT) has been associated with muscle insulin resistance in humans (112-115). IMCT is also elevated in lean, glucose tolerant offspring of two parents with type 2 diabetes compared with individuals without a family history of diabetes, and it is associated with lower glucose disposal (35). However, whether muscle TG accumulation is simply a marker or plays a causative role in the insulin resistance is unclear. The majority opinion at the present time is that IMCT does not itself cause insulin resistance but rather is a marker of some other abnormality that is causally linked to insulin resistance. Accumulation of lipid in the liver (ie non alcoholic hepatosteatosis) is also a feature of insulin resistance (116).
Lipoatrophy, a genetic or acquired reduction or total absence of adipose tissue, in humans and animal models results in accumulation of cytosolic triglycerides to a massive extent in nonadipose tissues, and in extreme insulin resistance (117-120). In A-ZIP/F-1 fatless mice, intramuscular and intrahepatic lipids were significantly reduced and insulin resistance alleviated by surgical re-implantation of adipose tissue (118,119). Shulman has proposed that insulin resistance develops because of an imbalance of fat distribution among tissues (121).
A key issue is whether TGs accumulate in muscle tissue of insulin resistant individuals as a result of a primary defect in fatty acid oxidation, increased total FFA flux to muscle, or owing to an imbalance between FFA uptake, esterification, TG lipolysis, and fatty acid oxidation. Kelley has described inflexibility of insulin resistant skeletal muscle in switching between lipid and carbohydrate oxidation (122), whereas others have implicated inherited and acquired mitochondrial dysfunction in the accumulation of myocellular triglycerides and insulin resistance (123,124).
There appears to be a reciprocal channelling of fuels between muscle and fat when one or the other tissue becomes preferentially insulin resistant. Mice with targeted disruption of GLUT4 in muscle and consequent muscle insulin resistance have a redistribution of substrate from muscle to adipose tissue (4). The converse also appears to be true, where downregulation of GLUT4 and glucose transport selectively in adipose tissue has recently been shown to cause insulin resistance in muscle (5), perhaps by diverting FFAs and other fuels from adipose to nonadipose tissues. This concept of adipose tissue acting as a sink to protect other tissues from the toxic effects of excessive exposure to energy substrates is further supported by the finding that overexpression of GLUT4 in adipose tissue in mice is associated with an increase in adipose tissue mass and improved whole body insulin sensitivity (125,126). Strikingly, adipose-specific overexpression of GLUT4 in muscle-specific GLUT-4-deficient mice reversed insulin resistance (127), and loss of GLUT-4 in both adipose tissue and muscle not only resulted in altered peripheral glucose uptake and insulin resistance, but also in redirected FFA flux through increased hepatic lipogenesis and VLDL production/secretion (128). Clinically, it remains a puzzle as to why some massively obese individuals have surprisingly few manifestations of the insulin resistance syndrome (129,130). One hypothesis is that the more efficient adipose tissue fat storing capacity in these individuals could confer relative protection against lipotoxicity in nonadipose tissues.
In insulin resistant states and type 2 diabetes, enhanced rates of de novo lipogenesis also contribute to lipid deposition in organs such as the liver and, to a lesser extent, in other tissues. In liver and muscle, hyperinsulinemia and/or FFAs per se may chronically induce the expression of the sterol regulatory element-binding protein 1c (SREBP1c) (131), a transcription factor that plays a key regulatory role in de novo lipogenesis. Furthermore, FAs activate other transcription factors of the nuclear receptor family, such as the PPARs and LXRs, which are also involved in the regulation of lipid oxidation and synthesis, respectively (132). Interestingly, activation of LXR has been proposed as an antidiabetic treatment, because pharmacological activation of this nuclear receptor leads to improved peripheral insulin sensitivity and peripheral glucose disposal, although it induces severe hepatic steatosis owing to LXR-triggered de novo TG synthesis (133).
It is noteworthy that adipose tissue-derived hormones may modulate hepatic TG content: leptin overexpression decreases hepatic lipid content in lipodystrophic A-ZIP/F-1 mice (134), as does adiponectin in liver and muscle of obese mice (135), both being accompanied by improved insulin sensitivity. Recently the adipocyte-derived hormone adiponectin has been shown to reverse insulin resistance associated with both lipoatrophy and obesity (135). Adiponectin reduced the triglyceride content of muscle and liver in obese mice by increasing the expression of fatty acid oxidation and energy dissipation in muscle. Unger has argued against the conventional view that the physiological role of leptin is to prevent obesity during overnutrition and proposed that the role of hyperleptinemia in conditions of caloric excess is to protect nonadipocytes from steatosis and lipotoxicity by preventing upregulation of lipogenesis and by increasing fatty acid oxidation (136-138). Adenoviral-mediated expression of the leptin receptor prevents lipid deposition in pancreatic ^-cells (139). In humans, hyperleptinemia characterizes obesity, insulin resistant states, and type 2 diabetes, suggesting that leptin resistance, not leptin deficiency, may be involved in the pathophysiology (140). Elevated plasma FFA could lead to relative suppression of leptin release by adipose tissue, contributing to impaired leptin signaling in insulin resistant states (141). Therefore, hyperleptinemia/leptin resistance may also to a certain extent be a consequence of abnormal FFA partitioning. A more complete discussion of adipose-derived hormones and inflammatory mediators will be presented elsewhere in this book.
In summary, adipose tissue storage and release of fatty acids, and particularly the control of these processes by insulin, is grossly abnormal in insulin resistant states. In the postabsorptive period, basal adipose tissue lipolysis is elevated, and suppression by insulin is diminished. In the postprandial period there is likely to be some diversion of fat away from adipose tissue depots and towards nonadipose tissues owing to less efficient fatty acid uptake and storage by insulin resistant adipocytes. FFA efflux from an enlarged and lipolytically active visceral fat depot may not contribute quantitatively to the majority of circulating FFAs, but because of its anatomical location and intrinsic properties appears to play an extremely important role in the manifestations of insulin resistance and type 2 diabetes. A high capacity for efficient triglyceride accumulation in adipose as well as nonadipose tissue may have presented a survival advantage in the past, during times of starvation, thus accounting for selection of a "thrifty genotype" as originally proposed by Neel in 1962 (142). With current high calorie, high fat diets and sedentary lifestyle, such a thrifty genotype would accumulate excess tissue triglyceride stores, with adverse metabolic consequences. In the presence of positive net energy balance, there is ongoing accumulation of lipids in both adipose and nonadipose tissues. Cytosolic lipid accumulation in nonadipose tissues such as muscle and liver is linked to the development of insulin resistance, as these tissues also attempt to protect themselves from energy overload.
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