Fatty acid-induced atherogenic changes in extracellular matrix proteoglycans

PURPOSE OF REVIEW: Nonesterified fatty acids change the expression and properties of the extracellular matrix proteoglycans of arterial and hepatic cells. We review how this may contribute to arterial disease in insulin resistance and type 2 diabetes. RECENT FINDINGS: Elevated nonesterified fatty acids characterize the dyslipidemia of insulin resistance and type 2 diabetes. In hepatocytes high levels of fatty acids cause changes in proteoglycans leading to a matrix with decreased affinity for VLDL remnants. Furthermore, liver proteoglycans from insulin resistant hyperlipidemic Zucker rats showed alterations also associated with decreased remnant affinity. In arterial smooth muscle cells overexposure to fatty acids augmented expression of matrix proteoglycans for which LDL showed increased affinity. Fatty acids appeared to compromise insulin signaling by protein kinase C activation. The observed fatty acid-induced changes in matrix proteoglycans in liver and arteries can be an important component of the atherogenicity of the dyslipidemia of insulin resistance and type 2 diabetes. SUMMARY: Overexposure to fatty acids can contribute to generate a remnant-rich dyslipidemia and to precondition the arterial intima for lipoprotein deposition via changes in expression of matrix proteoglycans. Normalizing fatty acid should be a key target in treatment of the atherogenic dyslipidemia of insulin resistance.     

Dietary fatty acids modulate antigen presentation to hepatic NKT cells in nonalcoholic fatty liver disease

Dietary fatty acids are major contributors to the development and progression of insulin resistance and nonalcoholic fatty liver disease (NAFLD). Dietary fatty acids also alter hepatic NKT cells that are activated by antigens presented by CD1d. In the current study, we examine the mechanism of dietary fatty acid induced hepatic NKT cell deficiency and its causal relationship to insulin resistance and NAFLD. We discover that dietary saturated fatty acids (SFA) or monounsaturated fatty acids (MUFA), but not polyunsaturated fatty acids (PUFA), cause hepatic NKT cell depletion with increased apoptosis. Dietary SFA or MUFA also impair hepatocyte presentation of endogenous, but not exogenous, antigen to NKT cells, indicating alterations of the endogenous antigen processing or presenting pathway. In vitro treatment of normal hepatocytes with fatty acids also demonstrates impaired ability of CD1d to present endogenous antigen by dietary fatty acids. Furthermore, dietary SFA and MUFA activate the NFκB signaling pathway and lead to insulin resistance and hepatic steatosis. In conclusion, both dietary SFA and MUFA alter endogenous antigen presentation to hepatic NKT cells and contribute to NKT cell depletion, leading to further activation of inflammatory signaling, insulin resistance, and hepatic steatosis.     

Adipocyte dysfunctions linking obesity to insulin resistance and type 2 diabetes

Acquired resistance to the action of insulin to stimulate glucose transport in skeletal muscle is associated with obesity and promotes the development of type 2 diabetes. In skeletal muscle, insulin resistance can result from high levels of circulating fatty acids that disrupt insulin signalling pathways. However, the severity of insulin resistance varies greatly among obese people. Here we postulate that this variability might reflect differences in levels of lipid-droplet proteins that promote the sequestration of fatty acids within adipocytes in the form of triglycerides, thereby lowering exposure of skeletal muscle to the inhibitory effects of fatty acids.     

Relationship between fatty acids and the endocrine system

Significant interactions exist between fatty acids and the endocrine system. Hormones affect the metabolism of fatty acids and the fatty acid composition of tissue lipids. The principal hormones involved in lipid metabolism are insulin, glucagon, catecholamines, cortisol and growth hormone. The concentrations of these hormones are altered in chronic degenerative conditions such as diabetes and cardiovascular disease, which in turn lead to alterations in tissue lipids. Lipogenesis and lipolysis, which modulate fatty acid concentrations in plasma and tissues, are under hormonal control. Neuropeptides are involved in lipid metabolism in brain and other tissues. Polyunsaturated fatty acids (PUFA) are also precursors for eicosanoids including prostaglandins, leukotrienes, and thromboxanes, which have hormone-like activities. Fatty acids in turn alter both hormone and neuropeptide concentrations and their receptors. Saturated and trans fatty acids (TFA) decrease insulin concentration leading to insulin resistance. In contrast, PUFA increase plasma insulin concentration and decrease insulin resistance. In humans, omega-3 PUFA alter the levels of opioid peptides in plasma.     

Role of fatty acid uptake and fatty acid β-oxidation in mediating insulin resistance in heart and skeletal muscle

Fatty acids are a major fuel source used to sustain contractile function in heart and oxidative skeletal muscle. To meet the energy demands of these muscles, the uptake and β-oxidation of fatty acids must be coordinately regulated in order to ensure an adequate, but not excessive, supply for mitochondrial β-oxidation. However, imbalance between fatty acid uptake and β-oxidation has the potential to contribute to muscle insulin resistance. The action of insulin is initiated by binding to its receptor and activation of the intrinsic protein tyrosine kinase activity of the receptor, resulting in the initiation of an intracellular signaling cascade that eventually leads to insulin-mediated alterations in a number of cellular processes, including an increase in glucose transport. Accumulation of fatty acids and lipid metabolites (such as long chain acyl CoA, diacylglycerol, triacylglycerol, and/or ceramide) can lead to alterations in this insulin signaling pathway. An imbalance between fatty acid uptake and oxidation is believed to be responsible for this lipid accumulation, and is thought to be a major cause of insulin resistance in obesity and diabetes, due to lipid accumulation and inhibition of one or more steps in the insulin-signaling cascade. As a result, decreasing muscle fatty acid uptake can improve insulin sensitivity. However, the potential role of increasing fatty acid β-oxidation in the heart or skeletal muscle in order to prevent cytoplasmic lipid accumulation and decrease insulin resistance is controversial. While increased fatty acid β-oxidation may lower cytoplasmic lipid accumulation, increasing fatty acid β-oxidation can decrease muscle glucose metabolism, and incomplete fatty acid oxidation has the potential to also contribute to insulin resistance. In this review, we discuss the proposed mechanisms by which alterations in fatty acid uptake and oxidation contribute to insulin resistance, and how targeting fatty acid uptake and oxidation is a potential therapeutic approach to treat insulin resistance.     

Free fatty acids and skeletal muscle insulin resistance

PURPOSE OF REVIEW: Acute exposure to fatty acids causes insulin resistance in muscle, and excess dietary lipid and obesity are also strongly associated with muscle insulin resistance. Relevant mechanisms, however, are still not fully elucidated. Here we examine the latest evidence as to why lipids might accumulate in muscle and the possible mechanisms for lipid-induced insulin resistance. RECENT FINDINGS: Muscle lipid metabolites such as long chain fatty acid coenzyme As, diacylglycerol and ceramides may impair insulin signalling directly. Crosstalk between inflammatory signalling pathways and insulin signalling pathways, mitochondrial dysfunction and oxidative stress have also been put forward as major contributors to the development or maintenance of lipid-induced insulin resistance in muscle. Several animal models with gene deletions in pathways of fatty acid synthesis and storage also show increased metabolic rate, reduced intramuscular lipid storage and improved insulin action when challenged with a high lipid load. SUMMARY: Studies in genetic and dietary obese animal models, genetically modified animals and humans with obesity or type 2 diabetes suggest plausible mechanisms for effects of fatty acids, lipid metabolites, inflammatory pathways and mitochondrial dysfunction on insulin action in muscle. Many of these mechanisms, however, have been demonstrated in situations in which lipid accumulation (obesity) already exists. Whether the initial events leading to muscle insulin resistance are direct effects of fatty acids in muscle or are secondary to lipid accumulation in adipose tissue or liver remains to be clarified.     

Fatty acid transport proteins and insulin resistance

PURPOSE OF REVIEW: Disturbed fatty acid metabolism and homeostasis is associated with insulin resistance. The aim of this review, therefore, is to summarize recent developments relating to the relevance and importance of the fatty acid transport proteins (FATPs) in the aetiology of insulin resistance. In particular, the potential differences between the six members of the FATP family will be considered. RECENT FINDINGS: FATP1 knockout mice failed to develop insulin resistance associated with lipid infusion or a high-fat diet, as wild-type mice did. FATP1-mediated fatty acid uptake may cause intramuscular lipid accumulation leading to insulin resistance in muscle if the fatty acids are not oxidized. While mouse models demonstrated an absolute requirement for FATP4 for survival, they provided no direct evidence for a role of FATP4 in insulin resistance. However, expression of FATP4 in human adipose tissue was increased in obesity (independent of genetic factors). While other members of the FATP family have important roles in fatty acid metabolism, they have not been clearly linked to insulin resistance. FATP-mediated fatty acid uptake may be driven by intrinsic acyl-CoA synthase activity. SUMMARY: Any role in the development of insulin resistance is likely to be different for each member of the FATP family. So far, both FATP1 and FATP4 have been associated with parameters related to insulin resistance. Whether increased FATP-mediated fatty acid uptake is beneficial or detrimental may be dependent on the tissue in question and on the subsequent fate of the fatty acids. These issues remain to be resolved.     

Key role for ceramides in mediating insulin resistance in human muscle cells

Elevated non-esterified fatty acids, triglyceride, diacylglycerol, and ceramide have all been associated with insulin resistance in muscle. We set out to investigate the role of intramyocellular lipid metabolites in the induction of insulin resistance in human primary myoblast cultures. Muscle cells were subjected to adenovirus-mediated expression of perilipin or incubated with fatty acids for 18 h, prior to insulin stimulation and measurement of lipid metabolites and rates of glycogen synthesis. Adenovirus-driven perilipin expression lead to significant accumulation of triacylglycerol in myoblasts, without any detectable effect on insulin sensitivity, as judged by the ability of insulin to stimulate glycogen synthesis. Similarly, incubation of cells with the monounsaturated fatty acid oleate resulted in triacylglycerol accumulation without inhibiting insulin action. By contrast, the saturated fatty acid palmitate induced insulin resistance. Palmitate treatment caused less accumulation of triacylglycerol than did oleate but also induced significant accumulation of both diacylglycerol and ceramide. Insulin resistance was also caused by cell-permeable analogues of ceramide, and palmitate-induced resistance was blocked in the presence of inhibitors of de novo ceramide synthesis. Oleate co-incubation completely prevented the insulin resistance induced by palmitate. Our data are consistent with ceramide being the agent responsible for insulin resistance caused by palmitate exposure. Furthermore, the triacylglycerol derived from oleate was able to exert a protective role in sequestering palmitate, thus preventing its conversion to ceramide.     

不同类型脂肪酸对SD大鼠血清脂肪酸及胰岛素抵抗的影响

目的分析中链饱和脂肪酸（MC-SFA,MCF组）、长链饱和脂肪酸（LC-SFA,LCF组）、n-6多不饱和脂肪酸（n-6 PUFA,SUF组）和n-3多不饱和脂肪酸（n-3 PUFA,TUF组）四种脂肪酸对大鼠血清脂肪酸及胰岛素抵抗的影响。方法雄性SD大鼠40只随机分为5组,对照组给予普通日粮,高脂组给予脂肪热量比相同的高脂日粮。喂养10周,每18 d测定空腹血糖（GLU）、血清脂肪酸、血清胰岛素水平,根据胰岛素敏感性指数（ISI）=ln1/（FPG×FINS）评定大鼠的胰岛素敏感性。结果10周后,LCF组和SUF组大鼠体重显著高于对照组和其它高脂组;LCF组血清胰岛素显著高于对照组（P﹤0.05）;LCF组、TUF组ISI显著低于对照组（P﹤0.05）;各组间血糖无明显差异（P〉0.05）。SUF组、TUF组血清LC-SFA浓度显著低于LCF组（P﹤0.05）;TUF组血清（n-3 PUFA）显著高于对照组和其它高脂组（P﹤0.05）。结论不同类型脂肪酸的高脂饲料对SD大鼠的血清脂肪酸组成和含量有显著的影响,SD大鼠脂肪沉积及胰岛素抵抗程度随血清脂肪酸代谢作用的不同而变化。     

Thematic review series: patient-oriented research. Nutritional determinants of insulin resistance

Interpreting the literature relating to the nutritional determinants of insulin resistance is complicated by the wide range of methods used to determine insulin sensitivity. Excess adiposity is unquestionably the most important determinant of insulin resistance, although the effect may be tempered by a relatively high proportion of lean body mass. Weight loss is associated with improved insulin sensitivity. Thus, diet-related factors that promote excessive energy intake may be regarded as promoters of insulin resistance. In the context of energy balance, diets characterized by high intakes of saturated fat and low intakes of dietary fiber are associated with reduced insulin sensitivity. Total fat intakes greater than the usually consumed range appear to promote insulin resistance, although the relative proportions of total fat and carbohydrate within the usual range appear unimportant. Monounsaturated fatty acids with a cis configuration and fiber-rich carbohydrate foods appear to be appropriate substitutes for saturated fatty acids and rapidly digested glycemic carbohydrates. In animal studies, n-3 unsaturated fatty acids have been shown to enhance insulin sensitivity and fructose and sucrose to increase insulin resistance. However, human data are limited. Large prospective studies currently being conducted should confirm the most appropriate macronutrient composition of diets for preventing and treating insulin resistance as well as establishing whether a range of candidate genes explains the variation in response to dietary change.     

Saturated, but not n-6 polyunsaturated, fatty acids induce insulin resistance: role of intramuscular accumulation of lipid metabolites.

Consumption of a Western diet rich in saturated fats is associated with obesity and insulin resistance. In some insulin-resistant phenotypes this is associated with accumulation of skeletal muscle fatty acids. We examined the effects of diets high in saturated fatty acids (Sat) or n-6 polyunsaturated fatty acids (PUFA) on skeletal muscle fatty acid metabolite accumulation and whole-body insulin sensitivity. Male Sprague-Dawley rats were fed a chow diet (16% calories from fat, Con) or a diet high (53%) in Sat or PUFA for 8 wk. Insulin sensitivity was assessed by fasting plasma glucose and insulin and glucose tolerance via an oral glucose tolerance test. Muscle ceramide and diacylglycerol (DAG) levels and triacylglycerol (TAG) fatty acids were also measured. Both high-fat diets increased plasma free fatty acid levels by 30%. Compared with Con, Sat-fed rats were insulin resistant, whereas PUFA-treated rats showed improved insulin sensitivity. Sat caused a 125% increase in muscle DAG and a small increase in TAG. Although PUFA also resulted in a small increase in DAG, the excess fatty acids were primarily directed toward TAG storage (105% above Con). Ceramide content was unaffected by either high-fat diet. To examine the effects of fatty acids on cellular lipid storage and glucose uptake in vitro, rat L6 myotubes were incubated for 5 h with saturated and polyunsaturated fatty acids. After treatment of L6 myotubes with palmitate (C16:0), the ceramide and DAG content were increased by two- and fivefold, respectively, concomitant with reduced insulin-stimulated glucose uptake. In contrast, treatment of these cells with linoleate (C18:2) did not alter DAG, ceramide levels, and glucose uptake compared with controls (no added fatty acids). Both 16:0 and 18:2 treatments increased myotube TAG levels (C18:2 vs. C16:0, P < 0.05). These results indicate that increasing dietary Sat induces insulin resistance with concomitant increases in muscle DAG. Diets rich in n-6 PUFA appear to prevent insulin resistance by directing fat into TAG, rather than other lipid metabolites.     

Improved n-3 fatty acid status does not modulate insulin resistance in fa/fa Zucker rats

The objective was to examine the effect of polyunsaturated fatty acid type (plant vs fish oil-derived n-3, compared to n-6 fatty acids in the presence of constant proportions of saturated, monounsaturated and polyunsaturated fatty acids) on obesity, insulin resistance and tissue fatty acid composition in genetically obese rats. Six-week-old fa/fa and lean Zucker rats were fed with a 10% (w/w) mixed fat diet containing predominantly flax-seed, menhaden or safflower oils for 9 weeks. There was no effect of dietary lipid on obesity, oral glucose tolerance (except t=60 min insulin), pancreatic function or molecular markers related to insulin, glucose and lipid metabolism, despite increased n-3 fatty acids in muscle and adipose tissue. The menhaden oil diet reduced fasting serum free fatty acids in both fa/fa and lean rats. These data suggest that n-3 composition does not alter obesity and insulin resistance in the fa/fa Zucker rat model when dietary lipid classes are balanced.     

Diets Rich in Saturated and Polyunsaturated Fatty Acids Induce Morphological Alterations in the Rat Ventral Prostate

Aim

To evaluate the influence of dietary lipid quality on the body mass, carbohydrate metabolism and morphology of the rat ventral prostate.

Materials and Methods

Wistar rats were divided into four groups: SC (standard chow), HF-S (high-fat diet rich in saturated fatty acids), HF-P (high-fat diet rich in polyunsaturated fatty acids) and HF-SP (high-fat diet rich in saturated and polyunsaturated fatty acids). We analyzed body mass, fat mass deposits, plasma blood, insulin resistance and the ventral prostate structure.

Results

Groups that received high-fat diets were heavier and presented larger fat deposits than SC group. The HF-S and HF-SP groups had higher glucose, insulin and total cholesterol serum levels and insulin resistance compared with the SC. The acinar area, epithelium height and area density of the lumen were higher in the HF-SP than in the other groups. The epithelium area density and epithelial cell proliferation were greater in the HF-P and HF-SP than in the SC group. All of the groups that received high-fat diets had greater area density of the stroma, area density of smooth muscle cells and stromal cell proliferation compared with the SC group.

Conclusion

Diets rich in saturated and/or polyunsaturated fatty acids induced overweight. Independently of insulin resistance, polyunsaturated fatty acids increased prostate stromal and epithelial cell proliferation. Saturated fatty acids influenced only stromal cellular proliferation. These structural and morphometric alterations may be considered risk factors for the development of adverse remodeling process in the rat ventral prostate.     

Contribution of free fatty acids to impairment of insulin secretion and action: mechanism of beta-cell lipotoxicity

Type 2 diabetes is characterized by two major defects: a dysregulation of pancreatic hormone secretion (quantitative and qualitative--early phase, pulsatility--decrease of insulin secretion, increase in glucagon secretion), and a decrease in insulin action on target tissues (insulin resistance). The defects in insulin action on target tissues are characterized by a decreased in muscle glucose uptake and by an increased hepatic glucose production. These abnomalities are linked to several defects in insulin signaling mechanisms and in several steps regulating glucose metabolism (transport, key enzymes of glycogen synthesis or of mitochondrial oxidation). These postreceptors defects are amplified by the presence of high circulating concentrations of free fatty acids. The mechanisms involved in the of long-chain fatty acids are reviewed in this paper. Indeed, elevated plasma free fatty acids contribute to decrease muscle glucose uptake (mainly by reducing insulin signaling) and to increase hepatic glucose production (stimulation of gluconeogenesis by providing cofactors such as acetyl-CoA, ATP and NADH). Chronic exposure to high levels of plasma free fatty acids induces accumulation of long-chain acyl-CoA into pancreatic beta-cells and to the death of 50 % of beta-cell by apoptosis (lipotoxicity).     

Characterizing the effects of saturated fatty acids on insulin signaling and ceramide and diacylglycerol accumulation in 3T3-L1 adipocytes and C2C12 myotubes

A strong correlation between intramyocellular lipid concentrations and the severity of insulin resistance has fueled speculation that lipid oversupply to skeletal muscle, fat, or liver may desensitize these tissues to the anabolic effects of insulin. To identify free fatty acids (FFAs) capable of inhibiting insulin action, we treated 3T3-L1 adipocytes or C2C12 myotubes with either the saturated FFA palmitate (C16:0) or the monounsaturated FFA oleate (C18:1), which were shown previously to be the most prevalent FFAs in rat soleus and gastrocnemius muscles. In C2C12 myotubes, palmitate, but not oleate, inhibited insulin-stimulation of glycogen synthesis, as well as its activation of Akt/Protein Kinase B (PKB), an obligate intermediate in the regulation of anabolic metabolism. Palmitate also induced the accrual of ceramide and diacylglycerol (DAG), two lipid metabolites that have been shown to inhibit insulin signaling in cultured cells and to accumulate in insulin resistant tissues. Interestingly, in 3T3-L1 adipocytes, neither palmitate nor oleate inhibited glycogen synthesis or Akt/PKB activation, nor did they induce ceramide or DAG synthesis. Using myotubes, we also tested whether other saturated fatty acids blocked insulin signaling while promoting ceramide and DAG accumulation. The long-chain fatty acids stearate (18:0), arachidate (20:0), and lignocerate (24:0) reproduced palmitate's effects on these events, while saturated fatty acids with shorter hydrocarbon chains [i.e., laurate (12:0) and myristate (14:0)] failed to induce ceramide accumulation or inhibit Akt/PKB activation. Collectively these findings implicate excess delivery of long-chain fatty acids in the development of insulin resistance resulting from lipid oversupply to skeletal muscle.     

Acyl-CoA synthesis,lipid metabolism and lipotoxicity

Although the underlying causes of insulin resistance have not been completely delineated, in most analyses, a recurring theme is dysfunctional metabolism of fatty acids. Because the conversion of fatty acids to activated acyl-CoAs is the first and essential step in the metabolism of long-chain fatty acid metabolism, interest has grown in the synthesis of acyl-CoAs, their contribution to the formation of signaling molecules like ceramide and diacylglycerol, and their direct effects on cell function. In this review, we cover the evidence for the involvement of acyl-CoAs in what has been termed lipotoxicity, the regulation of the acyl-CoA synthetases, and the emerging functional roles of acyl-CoAs in the major tissues that contribute to insulin resistance and lipotoxicity, adipose, liver, heart and pancreas.     

Lipid-Overloaded Enlarged Adipocytes Provoke Insulin Resistance Independent of Inflammation

In obesity, adipocyte hypertrophy and proinflammatory responses are closely associated with the development of insulin resistance in adipose tissue. However, it is largely unknown whether adipocyte hypertrophy per se might be sufficient to provoke insulin resistance in obese adipose tissue. Here, we demonstrate that lipid-overloaded hypertrophic adipocytes are insulin resistant independent of adipocyte inflammation. Treatment with saturated or monounsaturated fatty acids resulted in adipocyte hypertrophy, but proinflammatory responses were observed only in adipocytes treated with saturated fatty acids. Regardless of adipocyte inflammation, hypertrophic adipocytes with large and unilocular lipid droplets exhibited impaired insulin-dependent glucose uptake, associated with defects in GLUT4 trafficking to the plasma membrane. Moreover, Toll-like receptor 4 mutant mice (C3H/HeJ) with high-fat-diet-induced obesity were not protected against insulin resistance, although they were resistant to adipose tissue inflammation. Together, our in vitro and in vivo data suggest that adipocyte hypertrophy alone may be crucial in causing insulin resistance in obesity.     

Impaired non-esterified fatty acid suppression is associated with endothelial dysfunction in insulin resistant subjects.

In a recent study, we found a significant association between insulin resistance (IR) and disturbed flow-associated (endothelial-dependent) vasodilation in first-degree relatives of subjects with type 2 diabetes. However, the mechanisms linking insulin resistance and endothelial dysfunction (ED) have not been fully elucidated. Experimental data have pointed out that non-esterified fatty acids (NEFA) have a modulating effect on NO-synthase activity, and therefore on endothelial function. The aim of our study was to evaluate whether insulin resistance associated impaired NEFA suppression is present in subjects with ED. We examined 53 first-degree relatives (FDR) of patients with type 2 diabetes (32f, 21 m, mean age 35 years). Endothelial function was measured as flow-associated vasodilation (FAD%) of the brachial artery. Insulin sensitivity was evaluated with a standard hyperinsulinemic glucose clamp (insulin infusion rate of 1 mU/kg/min). While under fasting conditions, NEFA did not differ between groups with high or low FAD (0.415+/-0.033 vs. 0.394 +/- 0.040 mmol/l; p = n. s.), reduced FAD% was significantly associated with higher non-esterified fatty acids concentrations during steady state of the glucose clamp (0.072+/-0.022 vs. 0.039+/-0.016mmol/l; p=0.04). This association was independent of insulin levels under fasting conditions and during the glucose clamp. In conclusion, our results reveal a significant association between endothelial dysfunction and impaired non-esterified fatty acid suppression in insulin resistant subjects. As insulin resistance of lipolysis is a feature of the insulin resistance syndrome, these results suggest that elevated NEFA concentrations could play a role linking endothelial dysfunction and insulin resistance in vivo.     

Fructose consumption: potential mechanisms for its effects to increase visceral adiposity and induce dyslipidemia and insulin resistance

PURPOSE OF REVIEW: Based on interim results from an ongoing study, we have reported that consumption of a high-fructose diet, but not a high-glucose diet, promotes the development of three of the pathological characteristics associated with metabolic syndrome: visceral adiposity, dyslipidemia, and insulin resistance. From these results and a review of the current literature, we present two potential sequences of events by which fructose consumption may contribute to metabolic syndrome. RECENT FINDINGS: The earliest metabolic perturbation resulting from fructose consumption is postprandial hypertriglyceridemia, which may increase visceral adipose deposition. Visceral adiposity contributes to hepatic triglyceride accumulation, novel protein kinase C activation, and hepatic insulin resistance by increasing the portal delivery of free fatty acids to the liver. With insulin resistance, VLDL production is upregulated and this, along with systemic free fatty acids, increase lipid delivery to muscle. It is also possible that fructose initiates hepatic insulin resistance independently of visceral adiposity and free fatty acid delivery. By providing substrate for hepatic lipogenesis, fructose may result in a direct lipid overload that leads to triglyceride accumulation, novel protein kinase C activation, and hepatic insulin resistance. SUMMARY: Our investigation and future studies of the effects of fructose consumption may help to clarify the sequence of events leading to development of metabolic syndrome.