Free Fatty Acid Delivery Research Articles

Soft drinks consumption and nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) is a common clinical condition which is associated with metabolic syndrome in 70% of cases. Inappropriate dietary fat intake, excessive intake of soft drinks, insulin resistance and increased oxidative stress combine to increase free fatty acid delivery to the liver, and increased hepatic triglyceride accumulation contributes to fatty liver. Regular soft drinks have high fructose corn syrup which contains basic sugar building blocks, fructose 55% and glucose 45%. Soft drinks are the leading source of added sugar worldwide, and have been linked to obesity, diabetes, and metabolic syndrome. The consumption of soft drinks can increase the prevalence of NAFLD independently of metabolic syndrome. During regular soft drinks consumption, fat accumulates in the liver by the primary effect of fructose which increases lipogenesis, and in the case of diet soft drinks, by the additional contribution of aspartame sweetener and caramel colorant which are rich in advanced glycation end products that potentially increase insulin resistance and inflammation. This review emphasizes some hard facts about soft drinks, reviews fructose metabolism, and explains how fructose contributes to the development of obesity, diabetes, metabolic syndrome, and NAFLD.

Pathogenesis and Pathophysiology of the Cardiometabolic Syndrome

The cardiometabolic syndrome represents a cluster of metabolic abnormalities that are risk factors for cardiovascular disease. The mechanism(s) responsible for developing the cardiometabolic syndrome is not known, but it is likely that multi-organ insulin resistance, which is a common feature of the cardiometabolic syndrome, is involved. Insulin resistance is an important risk factor for type 2 diabetes and can cause vasoconstriction and renal sodium reabsorption, leading to increased blood pressure. Alterations in adipose tissue fatty acid and adipokine metabolism are involved in the pathogenesis of insulin resistance. Excessive rates of fatty acid release into the bloodstream can impair the ability of insulin to stimulate muscle glucose uptake and suppress hepatic glucose production. Noninfectious systemic inflammation associated with adipocyte and adipose tissue macrophage cytokine production can also cause insulin resistance. In addition, increased free fatty acid delivery to the liver can stimulate hepatic very low-density lipoprotein triglyceride production, leading to dyslipidemia.

고밀도 지단백 콜레스테롤과 베타 3-아드레날린성 수용체 유전자 변이와의 관련성

The 3-adrenergic receptor (ADRB3) is expressed mainly in visceral adipose tissue and is thought to contribute to lipolysis and the delivery of free fatty acids to the portal vein. This study was aimed at evaluating the association between high-density lipoprotein cholesterol (HDL-C) and ADRB3 genetic polymophisms. A total of 991 healthy examinees who were examined in a university hospital, located in Busan City, between May and December 2006 were enrolled in this study. Height, weight, body mass index, waist circumference, and systolic and diastolic blood pressures of the subjects were examined. Intravenous concentrations of fasting blood glucose, total cholesterol, HDL-C, low-density lipoprotein cholesterol, and triglyceride were also measured. After extracting DNA from the subjects, mutations of the +188T>C (Trp64Arg) of exon 1 and +3893T>C of intron 2 on the ADRB3 gene were genotyped using the single base extension method. We have identified a novel mutation of ADRB3 that is located in intron 2. The frequency of its minor allele was 0.164. Both the +188T>C mutation of exon 1 and +3893T>C mutation of intron 2 were significantly associated with HDL-C. The mean concentration of serum HDL-C was significantly lower in the presence of their minor allele `C`. These results suggest that both mutations of +188T>C of exon 1 and +3895T>C of intron 2 have significant associations with HDL-C in the Korean population.

Olive oil consumption and non-alcoholic fatty liver disease

The clinical implications of non-alcoholic fatty liver diseases (NAFLD) derive from their potential to progress to fibrosis and cirrhosis. Inappropriate dietary fat intake, excessive intake of soft drinks, insulin resistance and increased oxidative stress results in increased free fatty acid delivery to the liver and increased hepatic triglyceride (TG) accumulation. An olive oil-rich diet decreases accumulation of TGs in the liver, improves postprandial TGs, glucose and glucagon-like peptide-1 responses in insulin-resistant subjects, and upregulates glucose transporter-2 expression in the liver. The principal mechanisms include: decreased nuclear factor-kappaB activation, decreased low-density lipoprotein oxidation, and improved insulin resistance by reduced production of inflammatory cytokines (tumor necrosis factor, interleukin-6) and improvement of jun N-terminal kinase-mediated phosphorylation of insulin receptor substrate-1. The beneficial effect of the Mediterranean diet is derived from monounsaturated fatty acids, mainly from olive oil. In this review, we describe the dietary sources of the monounsaturated fatty acids, the composition of olive oil, dietary fats and their relationship to insulin resistance and postprandial lipid and glucose responses in non-alcoholic steatohepatitis, clinical and experimental studies that assess the relationship between olive oil and NAFLD, and the mechanism by which olive oil ameliorates fatty liver, and we discuss future perspectives.

Hepatic triglyceride synthesis and nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease is a spectrum of diseases ranging from simple steatosis to cirrhosis. The hallmark of nonalcoholic fatty liver disease is hepatocyte accumulation of triglycerides. We will review the role of triglyceride synthesis in nonalcoholic fatty liver disease progression and summarize recent findings about triglyceride synthesis inhibition and prevention of progressive disease. Attempts to inhibit triglyceride synthesis in animal models have resulted in improvement in hepatic steatosis. Studies in animal models of nonalcoholic fatty liver disease demonstrate that inhibition of acyl-coenzyme A:diacylglycerol acyltransferase, the enzyme that catalyzes the final step in triglyceride synthesis, results in improvement in hepatic steatosis and insulin sensitivity. We recently confirmed that hepatic specific inhibition of acyl-coenzyme A:diacylglycerol acyltransferase with antisense oligonucleotides improves hepatic steatosis in obese, diabetic mice but, unexpectedly, exacerbated injury and fibrosis in that model of progressive nonalcoholic fatty liver disease. When hepatocyte triglyceride synthesis was inhibited, free fatty acids accumulated in the liver, leading to induction of fatty acid oxidizing systems that increased hepatic oxidative stress and liver damage. These findings suggest that the ability to synthesize triglycerides may, in fact, be protective in obesity. Nonalcoholic fatty liver disease is strongly associated with obesity and peripheral insulin resistance. Peripheral insulin resistance increases lipolysis in adipose depots, promoting increased free fatty acid delivery to the liver. In states of energy excess, such as obesity, the latter normally triggers hepatic triglyceride synthesis. When hepatic triglyceride synthesis is unable to accommodate increased hepatocyte free fatty acid accumulation, however, lipotoxicity results. Thus, rather than being hepatotoxic, liver triglyceride accumulation is actually hepato-protective in obese, insulin-resistant individuals.

The lowering of hepatic fatty acid uptake improves liver function and insulin sensitivity without affecting hepatic fat content in humans

Lipolysis may regulate liver free fatty acid (FFA) uptake and triglyceride accumulation; both are potential causes of insulin resistance and liver damage. We evaluated whether 1) systemic FFA release is the major determinant of liver FFA uptake in fasting humans in vivo and 2) the beneficial metabolic effects of FFA lowering can be explained by a reduction in liver triglyceride content. Sixteen healthy subjects were subdivided in two groups of similar characteristics to undergo positron emission tomography with [(11)C]acetate and [(11)C]palmitate to quantify liver FFA metabolism (n = 8), or magnetic resonance spectroscopy (MRS) to measure hepatic fat content (n = 8), before and after the acute lowering of circulating FFAs by using the antilipolytic agent acipimox. MRS was again repeated after a 1-wk treatment period. Acipimox suppressed FFA levels while stimulating hepatic fractional extraction of FFAs (P < 0.05). As a result, fasting liver FFA uptake was decreased by 79% (P = 0.0002) in tight association with lipolysis (r = 0.996, P < 0.0001). The 1-wk treatment induced a significant improvement in systemic (+30%) and liver (+70%) insulin sensitivity (P < 0.05) and decreased circulating triglycerides (-20%, P = 0.06) and liver enzymes (ALT -20%, P = 0.03). No change in liver fat content was observed after either acute or sustained FFA suppression. We conclude that acute and sustained inhibitions of lipolysis and liver FFA uptake fail to deplete liver fat in healthy human subjects. Liver FFA uptake was decreased in proportion to FFA delivery. As a consequence, liver and systemic insulin sensitivity were improved, together with liver function, independently of changes in hepatic triglyceride accumulation.

Recent advances in nonalcholic fatty liver disease

The purpose of this review is to summarize recent advances in defining the clinical features, pathophysiology, natural history, and treatment of nonalcoholic fatty liver disease. Nonalcoholic fatty liver disease is present in approximately 30% of the US population. A histologic grading and staging system has been developed and validated. Nonalcoholic fatty liver disease increases the risk of developing the metabolic syndrome. The presence and severity of nonalcoholic fatty liver disease correlates with the severity of obesity, fat distribution, age, and presence of other features of the metabolic syndrome. Fifteen to 20% of subjects with nonalcoholic steatohepatitis develop cirrhosis. Hepatic steatosis is associated with an increase in both free fatty acid delivery to the liver for re-esterification and increased de-novo lipogenesis. Several mechanisms of hepatocyte injury and death including free fatty acid toxicity, increased free cholesterol, cytokine-mediated injury and activation of the unfolded protein response have been defined. While many therapeutic targets have been identified and pilot studies performed, a definitive treatment for nonalcoholic steatohepatitis remains to be established. Nonalcoholic fatty liver disease is a widely prevalent disease that is critically linked to insulin resistance and the metabolic syndrome. While much new information on the pathogenesis and natural history of nonalcoholic steatohepatitis is available, an effective therapy remains to be established.

Free fatty acids sensitize hepatocytes to bile acid-induced apoptosis

Delivery of free fatty acids to the liver in nonalcoholic fatty liver disease (NAFLD) may render hepatocytes more vulnerable to glycochenodeoxycholic acid (GCDCA)-induced apoptosis. Fat overloading was induced in HepG2-Ntcp cells and primary rat hepatocytes by incubation with palmitic or oleic acid. Apoptosis was quantified by measuring caspase 3/7 activity and transcription of interleukin (IL) 8 and IL-22 by quantitative real-time PCR. Oleic acid (500 μM) alone did not induce apoptosis, while palmitic acid (500 μM) increased apoptosis 5-fold. GCDCA did not induce significant apoptosis at low micromolar concentrations (5–30 μM) in non-steatotic cells. However, at the same concentrations, GCDCA increased apoptosis 3-fold in oleic acid-pretreated HepG2-Ntcp cells and 3.5-fold in primary rat hepatocytes. Pretreatment with oleic acid increased GCDCA-induced gene transcription of the proinflammatory cytokines IL-8 and IL-22 5-fold and 19-fold, respectively. Thus, low levels of cholestasis normally not considered harmful could advance liver injury in patients with NAFLD.

Visceral adipose tissue specific persistence of Mycobacterium tuberculosis may be reason for the metabolic syndrome

Mycobacterium tuberculosis (Mtb) is highly successful intracellular pathogen. Infection is maintained in spite of acquired immunity and resists eradication by antimicrobials. Following bacillaemia, small numbers of bacteria are disseminated to the extrapulmonary organs most likely including visceral adipose tissue by a mechanism that may involve the migration of M. tuberculosis within dendritic cells. In this lipid rich environment, Mtb can metabolize the fatty acids in a glyoxylate cycle dependent manner, and a state of chronic persistence may ensue. The persistent bacilli primarily use fatty acids as their carbon source. Expression of isocitrate lyase (ICL), gating enzyme of glyoxylate cycle, is upregulated during infection. ICL is important for survival during the persistent phase of infection. Expression of adipokines, particularly monocyte chemoattractant protein-1 (MCP-1), which is a potent proinflammatory cytokine, may be increased. MCP-1 contributes both to the recruitment of macrophages to adipose tissue and to the development of insulin resistance in humans. In addition, prolonged low level immune stimulation induces local adipolipogenesis, increasing visceral fat. Increased delivery of free fatty acid to the liver may stimulate the glyoxylate cycle-induced gluconeogenesis, raising hepatic glucose output. Hence, inhibition of the triggering enzyme ICL, which initiates all the pathologies related to persistent Mtb infection, may block the growth of the bacteria and may resolve the systemic metabolic complications.

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

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. 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. 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.

Postburn trauma insulin resistance and fat metabolism

Hyperglycemia and insulin resistance have long been recognized in severe burn patients. More recently, it has been observed that controlling hyperglycemia, or alleviating insulin resistance, is associated with improved outcomes. This has led to a renewed interest in the etiology of insulin resistance in this population. The postinjury hyperglycemic response appears to be associated with multiple metabolic abnormalities, such as elevated basal energy expenditure, increased protein catabolism, and, notably, significant alterations in fat metabolism. The synergy of all of the responses is not understood, although many studies have been conducted. In this article we will review the present understanding of the relationship between fat metabolism and insulin resistance posttrauma, and discuss some of the recent discoveries and potential therapeutic measures. We propose that the insulin resistance is likely related to the development of "ectopic" fat stores, i.e., triglyceride (TG) storage in sites such as the liver and muscle cells. Deposition of TG in ectopic sites is due to an increase in free fatty acid delivery secondary to catecholamine-induced lipolysis, in conjunction with decreased beta-oxidation within muscle and decreased hepatic secretion of fats. The resultant increases in intracellular TG or related lipid products may in turn contribute to alterations in insulin signaling.

Deficiency in monocyte chemoattractant protein-1 modifies lipid and glucose metabolism

We describe the effect of MCP-1 deficiency in mice rendered hyperlipemic by the concomitant ablation of the LDL receptor. The MCP-1 −/−LDLr −/− mice in comparison with LDLr −/− mice showed a decreased lipoprotein clearance, derangements in free fatty acids delivery and less glucose tolerance when fed a regular chow, and they showed a partial resistance to alterations in glucose and lipid metabolism induced by dietary fat and cholesterol. They also were less prone to the development of diet-induced obesity. Our results suggest that the role of MCP-1 in metabolism is relevant and that, although new hidden complexities are evident, the function of MCP-1/CCL2 extends far beyond the monocyte chemoattractant effect. Therefore, the regulatory mechanisms influenced by MCP-1 should be fully ascertained to understand the metabolic consequences of inflammation and before considering MCP-1 as a therapeutic target.

Effect of maternal triglycerides and free fatty acids on placental LPL in cultured primary trophoblast cells and in a case of maternal LPL deficiency

Maternal hypertriglyceridemia is a normal condition in late gestation and is an adaptation to ensure an adequate nutrient supply to the fetus. Placental lipoprotein lipase (LPL) is involved in the initial step in transplacental fatty acid transport as it hydrolyzes maternal triglycerides (TG) to release free fatty acids (FFA). We investigated LPL activity and protein (Western blot) and mRNA expression (real-time RT-PCR) in the placenta of an LPL-deficient mother with marked hypertriglyceridemia. The LPL activity was fourfold lower, LPL protein expression 50% lower, and mRNA expression threefold higher than that of normal, healthy placentas at term (n = 4-7). To further investigate the role of maternal lipids in placental LPL regulation, we isolated placental cytotrophoblasts from term placentas and studied LPL activity and protein and mRNA expression after incubation in Intralipid (as a source of TG) and oleic, linoleic, and a combination of oleic, linoleic, and arachidonic acids as well as insulin. Intralipid (40 and 400 mg/dl) decreased LPL activity by approximately 30% (n = 10-14, P < 0.05) and 400 microM linoleic and linoleic-oleic-arachidonic acid (n = 10) decreased LPL activity by 37 and 34%, respectively. No major changes were observed in LPL protein or mRNA expression. We found no effect of insulin on LPL activity or protein expression in the cultured trophoblasts. To conclude, the activity of placental LPL is reduced by high levels of maternal TG and/or FFA. This regulatory mechanism may serve to counteract an excessive delivery of FFA to the fetus in conditions where maternal TG levels are markedly increased.

Metabolic liver disease of obesity and role of adipose tissue in the pathogenesis of nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) is an increasingly recognized cause of liver-related morbidity and mortality. It can develop secondary to numerous causes but a great majority of NAFLD cases occur in patients who are obese or present with other components of metabolic syndrome (hypertension, dyslipidemia, diabetes). This is called primary NAFLD and insulin resistance plays a key role in its pathogenesis. Obesity is characterized by expanded adipose tissue, which is under a state of chronic inflammation. This disturbs the normal storage and endocrine functions of adipose tissue. In obesity, the secretome (adipokines, cytokines, free fatty acids and other lipid moieties) of fatty tissue is amplified, which through its autocrine, paracrine actions in fat tissue and systemic effects especially in the liver leads to an altered metabolic state with insulin resistance (IR). IR leads to hyperglycemia and reactive hyperinsulinemia, which stimulates lipid-accumulating processes and impairs hepatic lipid metabolism. IR enhances free fatty acid delivery to liver from the adipose tissue storage due to uninhibited lipolysis. These changes result in hepatic abnormal fat accumulation, which may initiate the hepatic IR and further aggravate the altered metabolic state of whole body. Hepatic steatosis can also be explained by the fact that there is enhanced dietary fat delivery and physical inactivity. IR and NAFLD are also seen in various lipodystrophic states in contrary to popular belief that these problems only occur due to excessive adiposity in obesity. Hence, altered physiology of adipose tissue is central to development of IR, metabolic syndrome and NAFLD.

The Role of Insulin Resistance in Nonalcoholic Fatty Liver Disease

Insulin resistance is an almost universal finding in nonalcoholic fatty liver disease (NAFLD). This review outlines the evidence linking insulin resistance and NAFLD, explores whether liver fat is a cause or consequence of insulin resistance, and reviews the current evidence for treatment of NAFLD. Evidence from epidemiological, experimental, and clinical research studies investigating NAFLD and insulin resistance was reviewed. Insulin resistance in NAFLD is characterized by reductions in whole-body, hepatic, and adipose tissue insulin sensitivity. The mechanisms underlying the accumulation of fat in the liver may include excess dietary fat, increased delivery of free fatty acids to the liver, inadequate fatty acid oxidation, and increased de novo lipogenesis. Insulin resistance may enhance hepatic fat accumulation by increasing free fatty acid delivery and by the effect of hyperinsulinemia to stimulate anabolic processes. The impact of weight loss, metformin, and thiazolidinediones, all treatments aimed at improving insulin sensitivity, as well as other agents such as vitamin E, have been evaluated in patients with NAFLD and have shown some benefit. However, most intervention studies have been small and uncontrolled. Insulin resistance is a major feature of NAFLD that, in some patients, can progress to steatohepatitis. Treatments aimed at reducing insulin resistance have had some success, but larger placebo-controlled studies are needed to fully establish the efficacy of these interventions and possibly others in reducing the deleterious effects of fat accumulation in the liver.

Why do omega-3 fatty acids lower serum triglycerides?

Fish oils rich in n-3 fatty acids reduce serum triglyceride levels. This well known effect has been shown to be caused by decreased very low-density lipoprotein triglyceride secretion rates in kinetic studies in humans. Animal studies have explored the biochemical mechanisms underlying this effect. Triglyceride synthesis could be reduced by n-3 fatty acids in three general ways: reduced substrate (i.e. fatty acids) availability, which could be secondary to increase in beta-oxidation, decreased free fatty acids delivery to the liver, decreased hepatic fatty acids synthesis; increased phospholipid synthesis; or decreased activity of triglyceride-synthesizing enzymes (diacylgylcerol acyltranferase or phosphatidic acid phosphohydrolase). Rarely were experimental conditions used in rat studies physiologically relevant to the human situation in which 1.2% energy as n-3 fatty acids lowers serum triglyceride levels. Nevertheless, the most consistent effect of n-3 fatty acids feeding in rats is to decrease lipogenesis. Increased beta-oxidation was frequently, but not consistently, reported with similar numbers of studies reporting increased mitochondrial compared with peroxisomal oxidation. Inhibition of triglyceride-synthesizing enzymes was only occasionally noted. As the vast majority of studies fed unphysiologically high doses of n-3 fatty acids, these findings in rats must be considered tentative, and the mechanism by which n-3 fatty acids reduce triglyceride levels in humans remains speculative.

Effects of portal free fatty acid elevation on insulin clearance and hepatic glucose flux

We tested the hypothesis that, due to greater hepatic free fatty acid (FFA) load, portal delivery of FFAs, as in visceral obesity, induces hyperinsulinemia and increases endogenous glucose production to a greater extent than peripheral FFA delivery. For 5 h, 10 microeq.kg(-1).min(-1) portal oleate (n = 6), equidose peripheral oleate (n = 5), or saline (n = 6) were given intravenously to conscious dogs infused with a combination of portal and peripheral insulin to enable calculation of hepatic insulin clearance during a pancreatic euglycemic clamp. Peripheral FFAs were similar with both oleate treatments and were threefold greater than in controls. Portal FFAs were 1.5- to 2-fold greater with portal than with peripheral oleate. Peripheral insulin concentrations were greatest with portal oleate, intermediate with peripheral oleate (P < 0.001 vs. portal oleate or controls), and lowest in controls, consistent with corresponding reductions in plasma insulin clearance and hepatic insulin clearance. Although endogenous glucose production did not differ between the two routes of oleate delivery, total glucose output (endogenous glucose production plus glucose cycling) was greater with portal than with peripheral oleate (P < 0.001) despite the higher insulin levels. In conclusion, during euglycemic clamps in dogs, the main effect of short-term elevation in portal FFA is to generate peripheral hyperinsulinemia. This may, in the long term, contribute to the metabolic and cardiovascular risk of visceral obesity.

Glucose‐dependent Insulin Modulation of Oscillatory Lipolysis in Perifused Rat Adipocytes

We showed glucose-dependent lipolytic oscillations in adipocytes that are modulated by free fatty acids (FFAs). We hypothesized that the oscillations are driven by oscillatory glucose metabolism that leads to oscillatory formation of alpha-glycerophosphate (alpha-GP), oscillatory removal of long-chain coenzyme A (LC-CoA) by alpha-GP to form triglycerides, and oscillatory relief of LC-CoA inhibition of triglyceride lipases. This study examined the effect of insulin on this hypothesis. Samples were collected every minute from perifused rat adipocytes during the basal state followed by insulin (+/-glucose) or isoproterenol (+/-insulin; n = 4 each). Insulin caused a significant increase in glycerol release (18%), with a concomitant significant decrease in FFA release (38%). Without glucose, insulin had no effect on glycerol release while still decreasing FFA release (35%). Insulin (5 microU/mL) attenuated the response of lipolysis to isoproterenol (approximately 3-fold increase with isoproterenol vs. 2-fold increase with insulin + isoproterenol). However, 1 mU/mL insulin amplified the lipolytic response ( approximately 5-fold increase in glycerol release with insulin + isoproterenol), with a concomitant increase in FFA reesterification (no increase in FFA release compared with isoproterenol alone). We interpret these results to be due to insulin's ability to increase glucose uptake and conversion to alpha-GP, thus removing LC-CoA inhibition of triglyceride lipases. While the physiological importance of lipolytic oscillations remains to be determined, we hypothesize that such an oscillation may play an important role in the delivery of FFAs to the liver, beta cells, and other tissues.

Counterpoint: Visceral Adiposity Is Not Causally Related to Insulin Resistance

It has been known for over half a century that accumulation of fat in the upper body is associated with metabolic complications of obesity. The mechanism responsible for this association is widely believed to be insulin resistance, which is frequently present in individuals with upper-body obesity (1) and is associated with increased cardiovascular risk (2). The upper-body obesity phenotype is accompanied by increased free fatty acid (FFA) flux and concentration, whereas individuals with predominantly lower-body obesity tend to have normal FFA kinetics (3). Increased FFA concentrations, in turn, are thought to be a major mediator of insulin resistance (4) and have been shown to cause endothelial dysfunction (5), impair pancreatic β-cell function (6), and acutely raise blood pressure (7). Increased delivery of FFA to skeletal muscle can result in insulin resistance in that tissue, either directly or via accumulation of increased intramyocellular triglyceride stores (8). Similarly, increased delivery of FFA to the liver may be responsible for hepatic insulin resistance (9), accumulation of intrahepatocellular triglyceride (10), and increased synthesis and secretion of VLDL (11). Hormone-sensitive lipase in adipocytes is exquisitely sensitive to the antilipolytic effect of insulin in lean healthy individuals (12). However, impaired insulin suppression of adipose tissue lipolysis is a feature of, and may even be the primary cause of, insulin resistance (13). To our knowledge, insulin resistance has not been reported in individuals with normal sensitivity to the antilipolytic effects of insulin. The degree of upper-body obesity can be estimated by measurement of waist circumference, which is predictive of cardiovascular risk (14). However, nonobese individuals exhibit considerable variability in insulin sensitivity (15) that is not necessarily explained by differences in waist circumference (16). It is possible that differences in the distribution of upper-body fat could explain variability in insulin sensitivity at a given BMI and a given …

In VivoEvidence of Impaired Peripheral Fatty Acid Trapping in Patients with Human Immunodeficiency Virus-Associated Lipodystrophy

The use of antiretroviral combination therapy in HIV has been associated with lipodystrophy and several metabolic risk factors. We postulated that patients with HIV-lipodystrophy have impaired adipose tissue free fatty acid (FFA) trapping and, consequently, increased hepatic FFA delivery. We investigated FFA, hydroxybutyric acid (HBA; reflecting hepatic FFA oxidation), and triglyceride (TG) changes after a high fat meal in HIV-infected males with (LIPO; n = 26) and without (NONLIPO; n = 12) lipodystrophy and in healthy males (n = 35). Because defective peripheral FFA trapping has been associated with impaired action of complement component 3 (C3), we also determined postprandial C3 concentrations. The LIPO group had higher homeostasis model assessment scores compared with the other groups. Areas under the curve (AUCs) for FFA, HBA, and TG were higher in the LIPO group than in the NONLIPO group or the controls. No differences in TG-AUC, FFA-AUC, and HBA-AUC were observed between the NONLIPO group and controls. In HIV-infected patients, FFA-AUC and HBA-AUC were inversely related to sc adipose tissue area. Plasma C3 showed a postprandial increase in healthy controls, but not in the HIV-infected groups. C3 was not related to body fat distribution, postprandial FFA, or HBA. The present data suggest disturbed postprandial FFA metabolism in patients with HIV-lipodystrophy, most likely due to inadequate incorporation of FFA into TG in sc adipose tissue, but do not support a major role for C3 in these patients. The higher postprandial HBA levels reflect increased hepatic FFA delivery and may aggravate insulin resistance and dyslipidemia, leading to increased cardiovascular risk.