The mechanism behind the benefits of omega-3 PUFAs on energy metabolism is at present not completely understood. There are, however, many possibilities since these fatty acids have many different roles in a cell. For example, apart from being an energy source, fatty acids build up the cellular membranes, regulate gene expression and function as signalling molecules and as precursors for complex biologically active molecules such as, for example, eicosanoids (Simopoulos, 1999, Ruxton et al., 2004). Since omega-3 PUFAs exert positive effects in many different diseases there have been implications for a common pathway for the effects. One mechanism that has been presented is the ability of omega-3 PUFAs to affect the biochemical composition of biological membranes (Ma et al., 2004). Indeed, the cellular fatty acids composition is a mirror of the ingested types of fatty acids. Incorporation of PUFAs into lipid membranes results in altered interaction between the lipids and the membrane proteins (Ma et al., 2004). There are, however, other possibilities that need to be considered - including the digestion and absorption of the fatty acids.
The length and the degree of saturation of fatty acids influence the biophysical properties of the lipids. This has, for example, effects on the digestion and absorption of the fatty acids from the intestine (Small, 1991). Different sources of fat are composed of different types of triglycerides. Triglycerides are digested in the intestinal lumen by lipases to produce fatty acids and monoacylglycerol and the absorption of fatty acids from the intestinal lumen is generally an efficient process. After absorption, the fatty acids are taken up by the enterocytes where the triglycerides are reconstructed, packed in chylomicrons and very-low-density lipoproteins (VLDLs) and secreted into the lymph. From the lymph, the triglycerides are transported to various capillary beds where they bind to the capillary surface. Here, they are hydrolysed by lipoprotein lipase and the surrounding adipocytes or muscle cells take up the free fatty acids. However, the triglycerides containing long-chain PUFAs like arachidonic acid or EPA are poor substrates for lipoprotein lipase. Instead, they appear to be good substrates for hepatic lipase, and thus acylglycerols containing long-chain PUFAs are returned and metabolised by the liver. To be able to study the uptake and the destiny of the PUFAs, rats were fed purified triglycerides containing oleic acid and long-chain PUFAs (Fahey et al., 1985). The results showed that the uptake of the PUFAs was significantly slower than the uptake of saturated or monounsaturated fatty acids. This demonstrates that the PUFAs are absorbed and metabolised at a lower rate, which may influence both appetite and satiety, two factors that are of great importance in weight control.
Studies in cell culture systems have demonstrated that fatty acids have effects on adipocyte proliferation and differentiation (Azain, 2004). Feeding rats a high-fat diet rich in PUFAs demonstrated no difference in pre-adipocyte replication compared with rats fed a normal diet, while a diet rich in saturated fats accelerated the replication (Shillabeer and Lau, 1994). Furthermore, the size of the adipose tissue was reduced in PUFA-fed rats compared with rats fed saturated fat and this was due to less efficient storage of triglycerides (Shillabeer and Lau, 1994). Thus, the diet containing saturated fat induced expansion of the adipose tissue more efficiently than the diet containing PUFAs; possible mechanisms for these effects are that PUFAs do not induce pre-adipocyte replication to the same extent and are less efficiently incorporated in triglycerides.
Feeding a diet rich in saturated fats results in accumulation of triglycerides, not only in adipose tissue but also in non-adipocytes and this phenomenon, called lipotoxicity, has been found to correlate to the onset of insulin resistance (Unger, 1995; Boden and Shulman, 2002). There are, however, studies indicating that diets enriched with PUFAs improve insulin sensitivity in both rodents and humans (Storlien et al., 1991; 2000, Summers et al., 2002). One possible mechanism of action is that PUFAs prevent the accumulation of lipids in non-adipocytes. In rodents, fish oil prevented lipid accumulation in adipose tissue more efficiently compared with other dietary oils, and it was suggested that omega-3 PUFAs increase fatty acid oxidation and inhibit triglyceride synthesis through affecting expression of specific genes involved in these metabolic pathways (Jump et al., 1994).
13.3.3 Regulation of gene expression by polyunsaturated fatty acid
Fatty acids are converted to fatty acyl coenzyme A (CoA) rapidly after entering a cell. The fatty acid derivatives are then shunted into different cellular pathways such as oxidation for production of energy, membrane synthesis, elongation and/or desaturation, or production of signalling molecules. PUFAs have an important function in regulating gene expression. Several transcription factors such as PPARs, SREBPs, hepatocyte nuclear factor-4a (HNF-4a) and liver X receptors (LXRa) have PUFAs as ligands (Krey et al., 1997; Worgall et al., 1998). The fatty acids bind to PPARs resulting in altered expression of genes involved in fatty acid degradation and oxidation, which in turn leads to reduced intracellular accumulation of triglycerides. Transcription of genes encoding lipogenic enzymes such as fatty acid synthase (FAS), acetyl-CoA carboxylase (ACC), and stearoyl-CoA desaturase (SCD) is down-regulated, while transcription of enzymes involved in fatty acid oxidation such as acyl-CoA oxidase (ACO), medium-chain acyl-CoA dehydrogenase (MCAD), carnitine palmitoyl transferase 1 (CPT-1), acyl-CoA synthase (ACS) and uncoupling protein 2 (UCP-2) is up-regulated (Krey et al., 1997; Nakatani et al., 2003; Levy et al., 2004; Ide, 2005). This leads to pleiotrophic and complex actions of PUFAs involving a large variety of intracellular regulatory pathways. SREBP-1 is another transcription factor that regulates fatty acid metabolism in the liver in that its activation results in increased transcription of genes involved in lipogenesis (Horton et al., 2002). Recent data have shown that rats fed a diet enriched with fish oil had reduced effect and expression of SREBPs in the liver (Xu et al., 2001; Nakatani et al., 2003). The overall effect of PUFAs on gene expression results in accelerated oxidation of fat and reduced lipogenesis.
13.3.4 The mechanism of polyunsaturated fatty acid in insulin resistance and type 2 diabetes
The molecular effects of PUFAs are such that these fatty acids may have an impact on the regulation of insulin sensitivity (Lombardo and Chicco, 2006). There are indeed indications that omega-3 PUFAs may have positive effects on glucose tolerance by reducing insulin resistance, as demonstrated in rodent models of obesity (Storlien et al., 2000). Rats fed a high-fat diet supplemented with a low ratio of omega-6 : omega-3 PUFA maintained normal insulin action, while rats fed a diet containing high levels of saturated and monounsaturated fats showed insulin resistance in several tissues (Storlien et al., 1991). Feeding fish oil to mice, providing 5-10% of the daily energy intake, accelerated glucose uptake and maintained glucose homeo-stasis during high-fat feeding (Storlien et al., 1997). The favourable effects of fish oil-derived PUFAs may be explained by suppression of hepatic fatty acids synthesis and increased fat oxidation. Another mechanism behind the positive effects of PUFAs on insulin sensitivity may occur through alteration in the plasma membrane composition of the cells. There is some evidence indicating that altered membrane structure may affect both insulin action and insulin binding to its receptor (Storlien et al., 1996). Another possible mechanism behind the effects of PUFAs in metabolism can be attributed to changes in protein acylation. Many membrane proteins are modified by fatty acid acylation with saturated fatty acids like palmitate or myristate. Whether this has any significant effects in insulin signalling, or whether PUFAs play a role, is unknown at the present time. In summary, the metabolic effects of omega-3 PUFAs promote the reduction of triglyceride in skeletal muscle and liver, which in turn is associated with improved insulin action and glucose tolerance thereby preventing development of insulin resistance.
13.3.5 Islet metabolism, insulin secretion and polyunsaturated fatty acid
Besides insulin resistance defective islet function is also of importance for the development of glucose intolerance and type 2 diabetes. In fact, a normal islet function with a normal compensation in insulin secretion is a prerequisite for maintaining normal glucose homeostasis in insulin resistance (Ahren and Pacini, 2005). Therefore, to improve glucose homeostasis, effects on islet function are required. Fatty acids are known to acutely stimulate insulin secretion via several possible pathways. First, it is believed that fatty acids are taken up into the P-cell, where they are converted to long-chain acyl-CoA (LC-CoA). Through glucose metabolism the uptake and oxidation of the fatty acids are blocked through the effect of malonyl-CoA, which accumulates in the cytosol when P-cells are exposed to high glucose concentrations (Corkey et al., 1989, Prentki et al., 1992). Malonyl-CoA is an effective inhibitor of CPT-1, inhibiting the transport of fatty acyl-CoA into the mitochondria, resulting in increased accumulation of LC-CoA in the cytosol. LC-CoA has been found to exert effects at several levels in the P-cell to promote second-phase insulin secretion: through binding to the KATP channels, affecting the exocytosis of insulin granulae, activation of protein kinases via acylation mechanism and thereby promoting insulin secretion (Corkey et al., 2000, Deeney et al., 2000, Yaney et al., 2000). Although this seems to be a common pathway for most of the fatty acids, saturated fats are more potent in stimulating glucose-induced insulin secretion than unsaturated ones, as was recently observed in isolated human islets (Gravena et al., 2002).
Another pathway for the fatty acids to stimulate insulin secretion is through the fatty acid binding protein GPR40 (Itoh et al., 2003; Salehi et al., 2005; Shapiro et al., 2005). This is a G-protein-coupled receptor that has fatty acids as substrate. Both saturated (C12-C16) and unsaturated (C18-C22) fatty acids have the potency to induce increased intracellular Ca2+ in Chinese hamster ovary (CHO) cells transfected with the GPR40 receptor (Itoh et al., 2003; Itoh and Hinuma, 2005). A third indirect pathway for fatty acids to stimulate insulin secretion is through phospholipase A2 (PLA2), which is activated during glucose stimulation (Simonsson and Ahren, 2000). PLA2 stimulates the formation of arachidonic acid and inhibition of PLA2 results in blunted arachidonic acid formation, which was accompanied by reduced glucose-stimulated insulin secretion. Fish oil has been found to induce insulin secretion through incorporation of the omega-3 PUFAs in the plasma membrane to compete with the production of arachidonic acid.
In a recent study, inclusion of 7% omega-3 PUFAs in a high-fat diet fed to rats resulted in lower glucose-stimulated insulin secretion from isolated islets, possibly through direct effects of the fatty acids on the islets, blocking the hyper-secretion induced by saturated fatty acids (Holness et al., 2003). In addition, in vivo, PUFA supplementation in rats fed a high-fat diet resulted in reversed insulin hyper-secretion, suggesting that PUFAs may have acute effects on islets resulting in reduced insulin secretion (Holness et al., 2004). Therefore, PUFAs seems to be protective at low doses in fatty acid-induced apoptosis and may have anti-apoptotic effects in islets in vivo. Furthermore, the normalising effect of omega-3 PUFAs on high-fat diet-induced hyperinsulinaemia in response to glucose may have long-term beneficial effects on insulin sensitivity.
It is now recognised that the adipocytes produce and actively secrete many hormones and cytokines into the circulation (Ahima and Flier, 2000). Many of these factors, collectively termed adipokines, are involved in inflammation and it has been suggested that inflammation is one important factor behind the development of obesity-related diseases (Havel, 2004; Berg and Scherer, 2005; Wellen and Hotamisligil, 2005).
The link between fatty acids and inflammation lies in the fact that the inflammatory mediators termed eicosanoids are generated from long-chain fatty acids. The role of PUFAs in inflammation has recently been thoroughly reviewed (Browning, 2003 ; Wu, 2004; Calder, 2005). Inflammatory cells contain high levels of the omega-6 PUFA arachidonic acid and low levels of the omega-3 PUFA EPA. The eicosanoids include prostaglandins, thromboxanes and leukotrienes, and these are typically produced from arachidonic acid. The eicosanoids in turn enhance the generation of reactive oxygen species and production of inflammatory cytokines like tumour necrosis factor-1a (TNF-1), interleukin-1 (IL-1) and IL-6 (Calder, 2005). Increased consumption of the omega-3 PUFAs EPA and DHA results in elevated levels of these fatty acids in the inflammatory cells, resulting in reduced production of eicosanoids with arachidonic acid as precursor. The eicosanoids produced from EPA are believed to be less potent in their inflammatory action compared with those formed from arachidonic acid. Thus, one positive effect of omega-3 PUFAs in inflammation is that less-potent eicosanoids are produced. Furthermore, EPA is precursor to a novel group of anti-inflammatory mediators (E-series resolvins) that may be of importance in the mechanism of action of PUFAs in inflammation (Serhan et al., 2002).
EPA and DHA have a number of other anti-inflammatory effects downstream of the eicosanoid production. For example in cell culture systems with endothelial cells, EPA and DHA inhibited the production of IL-6 and IL-8 (De Caterina et al., 1994). Dietary supplementation of fish oil in both rodents and humans has resulted in decreased production of TNF-1a, IL-1 and IL-6 (Endres et al., 1989; Yaqoob and Calder, 1995; Caughey et al., 1996).
Omega-3 PUFAs may also have a direct effect on inflammatory gene expression through activation of transcription factors such as nuclear factor (NF)-kB (Novak et al., 2003). Taken together, long-chain omega-3 PUFAs may function as anti-inflammatory agents in the prevention and/or treatment of obesity and its related diseases.
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