Elevated Free Fatty Acid Concentrations Research Articles

Influence of Free Fatty Acid Concentrations and Weight Loss on Adipose Tissue Direct Free Fatty Acid Storage Rates.

The factors that determine the recycling of free fatty acids (FFA) back into different adipose tissue depots via the direct storage pathway are not completely understood. To assess the interactions between adipocyte factors and plasma FFA concentrations that determine regional FFA storage rates. We measured direct adipose tissue FFA storage rates before and after weight loss under high FFA (intravenous somatostatin and epinephrine) and low (intravenous insulin and glucose) FFA concentrations. Mayo Clinic Clinical Research Unit. Sixteen premenopausal women, body mass index 30 to 37 kg/m2. Comprehensive lifestyle weight loss program. Direct FFA storage rates in upper and lower body subcutaneous fat. Over the entire range of FFA and under isolated conditions of elevated FFA concentrations, the storage rates of FFA into upper and lower body subcutaneous fat per unit lipid were associated with concentrations, not adipocyte fatty acid storage factors. Under low FFA conditions, direct FFA storage rates were related to adipocyte CD36 content, not tissue level content of fatty acid storage factors. Weight loss did not change these relationships. The regulation of direct FFA storage under low FFA concentration conditions appears to be at the level of the cell/adipocyte content of CD36, whereas under high FFA concentration conditions, direct FFA storage at the tissue level is predicted by plasma FFA concentrations, independent of adipocyte size or fatty acid storage factors. These observations offer novel insights into how adipose tissue regulates direct FFA storage in humans.

Impaired Very-Low-Density Lipoprotein catabolism links hypoglycemia to hypertriglyceridemia in Glycogen Storage Disease typeIa.

Prevention of hypertriglyceridemia is one of the biomedical targets in Glycogen Storage Disease type Ia (GSD Ia) patients, yet it is unclear how hypoglycemia links to plasma triglyceride (TG) levels. We analyzed whole‐body TG metabolism in normoglycemic (fed) and hypoglycemic (fasted) hepatocyte‐specific glucose‐6‐phosphatase deficient (L‐G6pc −/−) mice. De novo fatty acid synthesis contributed substantially to hepatic TG accumulation in normoglycemic L‐G6pc −/− mice. In hypoglycemic conditions, enhanced adipose tissue lipolysis was the main driver of liver steatosis, supported by elevated free fatty acid concentrations in GSD Ia mice and GSD Ia patients. Plasma very‐low‐density lipoprotein (VLDL) levels were increased in GSD Ia patients and in normoglycemic L‐G6pc −/− mice, and further elevated in hypoglycemic L‐G6pc −/− mice. VLDL‐TG secretion rates were doubled in normo‐ and hypoglycemic L‐G6pc −/− mice, while VLDL‐TG catabolism was selectively inhibited in hypoglycemic L‐G6pc −/− mice. In conclusion, fasting‐induced hypoglycemia in L‐G6pc −/− mice promotes adipose tissue lipolysis and arrests VLDL catabolism. This mechanism likely contributes to aggravated liver steatosis and dyslipidemia in GSD Ia patients with poor glycemic control and may explain clinical heterogeneity in hypertriglyceridemia between GSD Ia patients.

Elevated free fatty acids affect bovine granulosa cell function: a molecular cue for compromised reproduction during negative energy balance.

High-yielding dairy cows postpartum face the challenge of negative energy balance leading to elevated free fatty acids levels in the serum and follicular fluid thus affecting the ovarian function. Here, we investigated effects of physiological concentrations of palmitic acid (PA), stearic acid (SA) and oleic acid (OA) on the viability, steroid production and gene expression in a bovine granulosa cell (GC) culture model. Treatment with individual and combined fatty acids increased the CD36 gene expression, while no significant apoptotic effects were observed. Both PA and SA significantly upregulated the expression of FSHR, LHCGR, CYP19A1, HSD3B1, CCND2 and increased 17β-estradiol (E2) production, while OA downregulated the expression of these genes and reduced E2. Interestingly, STAR was equally downregulated by all fatty acids and combination treatment. E2 was significantly reduced after combination treatment. To validate the effects of OA, in vivo growing dominant follicles (10–19 mm) were injected with bovine serum albumin (BSA) with/without conjugated OA. The follicular fluid was recovered 48 h post injection. As in our in vitro model, OA significantly reduced intrafollicular E2 concentrations. In addition, expression of CD36 was significantly up- and that of CYP19A1 and STAR significantly downregulated in antral GC recovered from aspirated follicles. The ovulation rates of OA-injected follicles tended to be reduced. Our results indicate that elevated free fatty acid concentrations specifically target functional key genes in GC both in vitro and in vivo. Suggestively, this could be a possible mechanism through which elevated free fatty acids affect folliculogenesis in dairy cows postpartum.

Elevated free fatty acid level is a risk factor for early postoperative hypoxemia after on-pump coronary artery bypass grafting: association with endothelial activation

BackgroundWe aimed to investigate the relationship between increased free fatty acid (FFA) level and early postoperative hypoxemia after coronary artery bypass grafting (CABG) with cardiopulmonary bypass (CPB).MethodsNinety-eight consecutive patients undergoing CABG were enrolled. Early postoperative hypoxemia was defined as the lowest of the ratio of arterial oxygen tension (PaO2) to inspired oxygen fraction (FiO2) ≤ 200 mm Hg within 24 h without pleural effusion and pneumothorax. The 26 perioperative factors, serum levels of FFA and inflammatory cytokines between the hypoxemia and non-hypoxemia groups were recorded or detected using autoanalyzer and enzyme-linked immunosorbent assay, respectively. Additionally, the risk factors for early postoperative hypoxemia were evaluated using multiple logistic regression analysis.ResultsThe incidence rate of early postoperative hypoxemia was 37.8 %. Serum FFA levels were significantly higher in the hypoxemia group than in the non-hypoxemia group (P < 0.001). Further, postoperative serum FFA levels were inversely related to the lowest of the ratio of PaO2/FiO2 at 24 h after CABG (r = − 0.367, P < 0.001). Multiple logistic regression analysis confirmed that age, body mass index and postoperative serum FFA concentrations were independently associated with early postoperative hypoxemia. Notably, patients with hypoxemia had markedly higher serum intercellular adhesion molecule-1 (ICAM-1) levels than those without (P < 0.001). Moreover, serum FFA levels at 2 h after CABG correlated positively with ICAM-1 concentrations (r = 0.492, P < 0.001).ConclusionsElevated FFA concentration is a risk factor for early postoperative hypoxemia after on-pump CABG, which may be closely associated with endothelial activation.

High free fatty acid level is associated with recurrent stroke in cardioembolic stroke patients

To determine whether the plasma level of free fatty acid (FFA) could be associated with recurrent stroke in cardioembolic (CE) stroke patients. We analyzed data from 669 acute ischemic stroke patients and examined the association between FFA concentration and recurrent stroke in CE stroke patients compared with non-CE stroke patients. The baseline plasma FFA concentration (mEq/L) was approximately 1.5-fold higher in CE stroke patients (1.01 ± 0.63) than in non-CE stroke patients (0.72 ± 0.51). Multivariate logistic analysis showed that an increased level of FFA was significantly associated with CE stroke (hazard ratio [HR] 2.124, confidence interval [CI] 1.492-3.024). During the mean follow-up period of 25.4 months, a total of 56 (8.4%) patients experienced a stroke recurrence. The recurrence rate did not differ between patients with CE (10.5%) and non-CE (8.0%) stroke (p = 0.396). In CE stroke patients, an elevated baseline FFA concentration was independently associated with stroke recurrence (HR 2.711, CI 1.056-6.959). However, there was no association between FFA and stroke recurrence in non-CE stroke patients. In this retrospective registry-based observational study, CE stroke seemed to be associated with elevated plasma level of FFA. In addition, the present study suggested that an elevated FFA concentration could be a useful indicator for predicting recurrent stroke in CE stroke patients.

Abstract W P354: Effect of Free Fatty Acid on Recurrent Stroke in Stroke Patients With Atrial Fibrillation

Background: Although free fatty acid (FFA) has been considered to have a link with atherosclerosis, recently, an association between FFA and atrial fibrillation was reported. In this study, we tried to determine whether FFA could be associated with recurrent stroke in stroke patients with atrial fibrillation. Methods: Retrospective analyses of 279 stroke patients who had atrial fibrillation from multicenter hospital-based stroke registry. We examined the effect of FFA on recurrent stroke using survival analysis. Results: Twenty-two patients had recurrent stroke (7.9%) during the study periods (mean follow-up duration 16.7 months). The baseline plasma FFA concentration was significantly higher in patients with recurrent stroke (1.54 ± 0.81 mEq/L 1.54 ± 0.81 mEq/L) than those without recurrent stroke (1.09 ± 0.76 mEq/L). In Cox’s survival analysis, plasma FFA concentration (mEq/L) was significantly associated with recurrent stroke in univariate model (HR 1.521, 95% CI 1.094 - 2.114) and model after adjustment for CHADS2 score (HR 1.509, 95% CI 1.056 - 2.156). Conclusion: The present study suggested that elevated FFA concentration could be indicator for recurrent stroke in stroke patients with atrial fibrillation.

24-h Urinary Vanillylmandelic Acid (VMA) is not a Sensitive Pa-rameter to Identify Acute or Chronic Stress Generated by High Intensity Exercise in Animal Model

Vanillylmandelic acid (VMA) is the main urinary end-stage metabolite of epinephrine and norepinephrine. Its con- centration can be elevated in some cases of cancer, but also after other stress stimuli. The aim of the study was to investigate the effect of high intensity physical training (HIPT) and acute exercise on urinary VMA concentration and metabolic aspects related to glucose metabolism in animal model. Wistar rats underwent four sets of 10 jumps/day supporting a load equivalent to 50% of body weight, in a water tank for six weeks. A control group was kept in sedentary condition during the same period of time. After six weeks, sedentary and trained animals underwent an exercise session with the same characteristics of HIPT. Acute high intensity effort did not change 24-hour urinary VMA concentration in both trained and untrained rats. Both groups increased glycaemia and lactacidaemia while serum insulin reduced. Acute exercise elevated free fatty acid concentration and decreased gastrocnemius muscle glycogen content in sedentary animals. It was concluded that high intensity physical training and acute exercise interfere on glucose metabolism profile without change 24-h VMA.

Bovine Cumulus Cells Protect Maturing Oocytes from Increased Fatty Acid Levels by Massive Intracellular Lipid Storage

Metabolic conditions characterized by elevated free fatty acid concentrations in blood and follicular fluid are often associated with impaired female fertility. Especially elevated saturated fatty acid levels can be lipotoxic for several somatic cell types. The aim of this study was to determine the impact of elevated free fatty acid concentrations in follicular fluid on neutral lipids (fatty acids stored in lipid droplets) inside cumulus cells and oocytes and their developmental competence. To this end, cows were exposed to a short-term fasting period during final oocyte maturation. This resulted in elevated, but distinct, free fatty acid concentrations in blood and follicular fluid and a rise in the concentrations of in particular fatty acids with a chain length of 14-18 carbon atoms. Interestingly, elevated free fatty acid concentrations in follicular fluid resulted in a massive increase in the level of neutral lipids in cumulus cells, whereas the level of neutral lipid in oocytes was hardly affected. Furthermore, competence of oocytes to develop to the blastocyst stage after fertilization and culture of cumulus-oocyte-complexes of the experimental and control group was not different. In conclusion these data suggest that short-term elevated free fatty acid concentrations in follicular fluid do not harm oocyte developmental competence. We propose that the involvement of high levels of mobilized oleic acid in follicular fluid in combination with the induced lipid storage in cumulus cells serves to prevent harmful saturated fatty acid exposure to the oocyte.

1 CUMULUS CELLS PROTECT OOCYTES AGAINST POTENTIAL LIPOTOXICITY FROM ELEVATED FREE FATTY ACID CONCENTRATIONS IN FOLLICULAR FLUID

Metabolic conditions characterized by elevated free fatty acid levels in the blood are often associated with reduced fertility performance. Increased concentrations of saturated free fatty acids can induce lipotoxicity in cumulus–oocyte-complexes in vitro, while unsaturated fatty acids like oleic acid are mostly harmless and able to counteract the impact of saturated fatty acids (Aardema et al. 2011 Biol. Reprod. 85, 62–69). This study investigates the impact of elevated free fatty acids in the blood on the follicular fluid and the lipid of cumulus and oocytes derived from these follicles. Furthermore, in vitro maturing oocytes were exposed to free fatty acid concentrations measured in follicles of control and metabolically stressed animals from this study to determine the impact on oocyte developmental competence. Cyclic heifers (n = 12) were synchronized (7 days CIDR®) and superstimulated from Day 10 of the synchronized cycle [4 days of Folltropin-V® (Bioniche Animal Health Inc., Belleville, ON, Canada) in decreasing doses; in total 200 mg]. Heifers received ad libitum grass silage, apart from the experimental group (n = 6), which was metabolically stressed during the period of superstimulation. Ovaries were collected by ovariectomy at final maturation, 22 h after the induced LH peak. Follicular fluids and cumulus–oocyte complexes (COC) were collected from follicles of ≥8 mm. To determine the free fatty acid and lipid composition, blood, follicular fluid, cumulus cells, and oocytes were analyzed with mass spectrometry. The COC (4 runs, 400 per group) derived from slaughterhouse ovaries were in vitro matured in a standard medium without or with the dominating free fatty acids, saturated palmitic and stearic and unsaturated oleic acid, in concentrations measured in follicular fluid of control (80, 70, and 100 µM) and experimental heifers (150, 100, and 200 µM) and fertilized and cultured until the blastocyst stage. Culture data were analyzed by one-way ANOVA and lipid data by two-sample t-test (P ≤ 0.05 considered significant). Procedures were approved by the Institutional Animal Care and Use Committee. Metabolic stress resulted in elevated free fatty acid levels in blood (from 430 ± 70 to 1048 ± 190 µM) and follicular fluid (from 357 ± 72 to 670 ± 133 µM), with relatively high oleic acid concentrations in follicular fluid (+10%). The increased levels of free fatty acids in follicular fluid resulted in a massive increase of fatty acids in the cumulus cells, but oocytes did only show marginal changes. In line with this, maturation in the presence of elevated palmitic, stearic, and oleic acid did not impair oocyte developmental competence and resulted in comparable blastocyst rates for the standard medium and the free fatty acid control and metabolic stress medium (31 ± 8.7, 34 ± 7.8, and 28 ± 1.7%). Thus, cumulus cells appear to protect oocytes against potential lipotoxicity from elevated free fatty acid concentrations by the accumulation of these fatty acids. This work was funded by Pfizer Animal Health.

Fatty Acid-Induced Production of Plasminogen Activator Inhibitor-1 by Adipose Macrophages Is Greater in Middle-Aged Versus Younger Adult Participants

Human aging is associated with heightened risk of diabetes and cardiovascular disease. Increased fat mass may contribute to age-related diseases by harboring inflammatory macrophages that produce metabolically important proteins such as plasminogen activator inhibitor-1 (PAI-1). Elevated PAI-1 concentrations have been implicated in the pathogenesis of such aging-related conditions as insulin resistance, obesity, and atherosclerosis. We have previously reported that increased plasma free fatty acid (FFA) concentrations augment both circulating PAI-1 concentrations and PAI-1 production by adipose tissue macrophages (ATMs). Because increasing age is associated with increased infiltration and reactivity of adipose macrophages, we performed euglycemic-hyperinsulinemic clamp studies and adipose tissue biopsies with and without elevated FFA concentrations in 31 nondiabetic participants stratified by age, to determine whether middle-aged individuals manifest heightened insulin resistance and PAI-1 production by ATMs in response to elevated nutrient signals relative to their young adult peers. We observed that elevating FFA concentrations under euglycemic-hyperinsulinemic clamp conditions induced the same degree of insulin resistance in both middle-aged and younger body mass index-matched adults, whereas systemic PAI-1 concentrations were significantly increased in the middle-aged group. Likewise, elevated FFA and insulin concentrations induced larger increases in PAI-1 gene expression in the whole fat and ATMs of middle-aged compared with younger adult participants. These studies reveal a heightened adipose inflammatory response to increased FFA and insulin availability in middle-aged individuals relative to younger adults, suggesting that increased susceptibility to the effects of fatty acid excess may contribute to the pathogenesis of age-related diseases.

Adiponectin improves endothelial dysfunction caused by elevated FFAs levels, partially through cAMP-dependent pathway

AimsTo determine whether adiponectin can attenuate endothelial dysfunction caused by elevated free fatty acids (FFAs) concentration, and if so, to explore the underlying mechanism. MethodsMale Sprague-Dawley rat thoracic aortas were isolated then cut into four vascular rings, incubated in organ bath containing Krebs–Henseleit buffer with different agents separately: 800μmol/L Palmic acid (FFA, n=14), 800μmol/L Palmic acid+2μg/mL adiponectin (FFA+gAd, n=14), 800μmol/L Palmic acid+2μg/mL adiponectin+200μmol/L adenylate cyclase inhibitor dideoxyadenosine (FFA+gAd+ddAdo, n=7), blank control (NC, n=10). The endothelial dependent vasodilatation (EDV) and endothelial independent vasodilatation (EIV) were assessed by acetylcholine (Ach) induced contraction of the aortas. Nuclear transcription factor kappa B (NF-κB) expression in rat aortic section was evaluated immunohistochemically. ResultsAch caused a concentration dependent vascular relaxation in all pre-constricted aortic rings. PA treatment impaired the Ach induced EDV which was significantly attenuated by pretreatment with adiponectin. Dideoxyadenosine partly abolished the vascular protective effect of adiponectin. Sodium nitroprusside (SNP) had no significant effect on the vasodilatation among four groups. Increased NF-κB expression was noted in FFA group. Pretreatment with adiponectin partly decreased NF-κB expression when compared with FFA group. ConclusionAdiponectin may independently mitigate endothelial dysfunction caused by elevated FFAs concentration through the cross talk between cAMP and NF-κB signaling pathway.

Fatty acids trigger mitochondrion-dependent necrosis

Obesity is characterized by lipid accumulation in non-adipose tissues, leading to organ degeneration and a wide range of diseases, including diabetes, heart attack, and liver cirrhosis. Free fatty acids (FFA) are believed to be the principal toxic triggers mediating the adverse cellular effects of lipids. Here, we show that various cooking oils used in human nutrition cause cell death in yeast in the presence of a triacylglycerol lipase, mimicking the physiological microenvironment of the small intestine. Combining genetic and cell death assays, we demonstrate that elevated FFA concentrations lead to necrotic cell death, as evidenced by loss of membrane integrity and release of nuclear HMGB1. FFA-mediated necrosis depends on functional mitochondria and leads to the accumulation of reactive oxygen species. We conclude that lipotoxicity is executed via a mitochondrial necrotic pathway, challenging the dogma that the adverse effects of lipid stress are exclusively apoptotic.

Metabolic Effects of Free Fatty Acids During Endotoxaemia in a Porcine Model – Free Fatty Acid Inhibition of Growth Hormone Secretion as a Potential Catabolic Feedback Mechanism

Critical illness and severe inflammation are catabolic states characterised by breakdown of tissue and protein stores, by increased levels of free fatty acids, and by insulin resistance. These metabolic features contribute to morbidity and mortality. Growth hormone and insulin are the two major anabolic hormones. The present study was designed to test whether increased levels of free fatty acids (i) inhibit growth hormone secretion and (ii) induce insulin resistance during acute endotoxin exposure in a porcine model of critical illness. We studied 20 pigs for 6 h during combined anaesthesia and endotoxin infusion and a hyperinsulinaemic glucose clamp to control glucose, insulin, and free fatty acid concentrations. Pigs were randomised to two different continuous infusion rates of Intralipid resulting in different, sustained, and elevated free fatty acid concentrations (1.63 mmol l(-1) vs. 0.58 mmol l(-1), p=0.0002). Concomitantly, we observed reduced growth hormone concentrations in the group with high free fatty acid concentrations (3.5 ng ml(-1) vs. 6.6 ng ml(-1), p<0.003). No difference in insulin sensitivity, measured as the glucose infusion rate necessary to maintain euglycaemia, was observed. We conclude that high levels of free fatty acids reduce circulating growth hormone concentrations in porcine endotoxaemia; this probably constitutes a negative feedback mechanism whereby growth hormone induced-stimulation of free fatty acids release inhibit growth hormone secretion. This mechanism may further contribute to protein loss in critical illness. We found no evidence that the increment of plasma free fatty acids between groups contribute to insulin resistance in critical illness.

Direct Effect of Glucocorticoids on Lipolysis in Adipocytes

Hypercortisolemia and glucocorticoid treatment cause elevated level of circulating free fatty acids (FFAs). The basis of this phenomenon has long been linked to the effect of glucocorticoids permitting and enhancing the adipose lipolysis response to various hormones. In this study, we demonstrate that glucocorticoids directly stimulate lipolysis in rat primary adipocytes in a dose- and time-responsive manner; this lipolytic action was attenuated by treatment with the glucocorticoid antagonist RU486. Dexamethasone down-regulates mRNA and protein levels of cyclic-nucleotide phosphodiesterase 3B, thereby elevating cellular cAMP production and activating protein kinase A (PKA). On inhibition of PKA but not other kinases, the lipolysis response ceases. Furthermore, dexamethasone induces phosphorylation and down-regulation of perilipin, a lipid droplet-associating protein that modulates lipolysis; this effect is restored by RU486 or PKA inhibitor H89. Dexamethasone up-regulates mRNA and protein levels of hormone-sensitive lipase (HSL) and adipose triglyceride lipase; these effects, parallel to increased lipolysis, are attenuated by RU486 or actinomycin D. Phosphorylation at Ser-563 and Ser-660 residues of HSL and activity of cellular lipases are elevated on dexamethasone stimulation but abrogated by the coaddition of H89. However, dexamethasone does not induce HSL translocation to the lipid droplet surface in differentiated adipocytes. We show that elevated FFA concentration in plasma is associated with increased lipase activity and lipolysis in vivo in adipose tissues of dexamethasone-treated rats. Therefore, the lipolytic action of glucocorticoids liberates FFA efflux from adipocytes to the bloodstream, which could be a cellular basis of systemic FFA elevation in response to glucocorticoid challenge.

Direct effect of glucocorticoids on lipolysis in adipocytes.

Hypercortisolemia and glucocorticoid treatment cause elevated level of circulating free fatty acids (FFAs). The basis of this phenomenon has long been linked to the effect of glucocorticoids permitting and enhancing the adipose lipolysis response to various hormones. In this study, we demonstrate that glucocorticoids directly stimulate lipolysis in rat primary adipocytes in a dose- and time-responsive manner; this lipolytic action was attenuated by treatment with the glucocorticoid antagonist RU486. Dexamethasone down-regulates mRNA and protein levels of cyclic-nucleotide phosphodiesterase 3B, thereby elevating cellular cAMP production and activating protein kinase A (PKA). On inhibition of PKA but not other kinases, the lipolysis response ceases. Furthermore, dexamethasone induces phosphorylation and down-regulation of perilipin, a lipid droplet-associating protein that modulates lipolysis; this effect is restored by RU486 or PKA inhibitor H89. Dexamethasone up-regulates mRNA and protein levels of hormone-sensitive lipase (HSL) and adipose triglyceride lipase; these effects, parallel to increased lipolysis, are attenuated by RU486 or actinomycin D. Phosphorylation at Ser-563 and Ser-660 residues of HSL and activity of cellular lipases are elevated on dexamethasone stimulation but abrogated by the coaddition of H89. However, dexamethasone does not induce HSL translocation to the lipid droplet surface in differentiated adipocytes. We show that elevated FFA concentration in plasma is associated with increased lipase activity and lipolysis in vivo in adipose tissues of dexamethasone-treated rats. Therefore, the lipolytic action of glucocorticoids liberates FFA efflux from adipocytes to the bloodstream, which could be a cellular basis of systemic FFA elevation in response to glucocorticoid challenge.

Does the human heart fatigue subsequent to prolonged exercise?

A reduction in left ventricular systolic and diastolic function subsequent to prolonged exercise in healthy humans, often called exercise-induced cardiac fatigue (EICF), has recently been reported in the literature. However, our current understanding of the exact nature and magnitude of EICF is limited. To date, there is no consensus as to the clinical relevance of such findings and whether such alterations in function are likely to impact upon performance. Much of the existing literature has employed field-based competitions. Whilst ecologically valid, this approach has made it difficult to control many factors such as the duration and intensity of effort, fitness and training status of subjects and environmental conditions. The impact of such variables on EICF has not been fully evaluated and is worthy of further research. To date, most EICF studies have been descriptive, with limited success in elucidating mechanisms. To this end, the assessment of humoral markers of cardiac myocyte or membrane disruption has produced contradictory findings partially due to controversy over the validity of specific assays. It is, therefore, important that future research utilises reliable and valid biochemical techniques to address these aetiological factors as well as develop work on other potential contributors to EICF such as elevated free fatty acid concentrations, free radicals and beta-adrenoceptor down-regulation. In summary, whilst some descriptive evidence of EICF is available, there are large gaps in our knowledge of what specific factors related to exercise might facilitate functional changes. These topics present interesting but complex challenges to future research in this field.

Free fatty acids in obesity and type 2 diabetes: defining their role in the development of insulin resistance and beta-cell dysfunction.

Plasma free fatty acids (FFA) play important physiological roles in skeletal muscle, heart, liver and pancreas. However, chronically elevated plasma FFA appear to have pathophysiological consequences. Elevated FFA concentrations are linked with the onset of peripheral and hepatic insulin resistance and, while the precise action in the liver remains unclear, a model to explain the role of raised FFA in the development of skeletal muscle insulin resistance has recently been put forward. Over 30 years ago, Randle proposed that FFA compete with glucose as the major energy substrate in cardiac muscle, leading to decreased glucose oxidation when FFA are elevated. Recent data indicate that high plasma FFA also have a significant role in contributing to insulin resistance. Elevated FFA and intracellular lipid appear to inhibit insulin signalling, leading to a reduction in insulin-stimulated muscle glucose transport that may be mediated by a decrease in GLUT-4 translocation. The resulting suppression of muscle glucose transport leads to reduced muscle glycogen synthesis and glycolysis. In the liver, elevated FFA may contribute to hyperglycaemia by antagonizing the effects of insulin on endogenous glucose production. FFA also affect insulin secretion, although the nature of this relationship remains a subject for debate. Finally, evidence is discussed that FFA represent a crucial link between insulin resistance and beta-cell dysfunction and, as such, a reduction in elevated plasma FFA should be an important therapeutic target in obesity and type 2 diabetes.

Association of the Pro90Ser CD36 mutation with elevated free fatty acid concentrations but not with insulin resistance syndrome in Japanese

Background: CD36 deficiency is reportedly an underlying factor about insulin resistance, defective fatty acid metabolism and hypertriglyceridemia in spontaneously hypertensive rat (SHR), and may be involved in the pathogenesis of insulin resistance and hyperlipidemia in humans. Methods: We examined 831 adults undergoing health screening. The majority (780) was Pro90 homozygous for the CD36 gene product, but 51 displayed a CD36 mutation (2 homozygous and 49 heterozygous for Ser90). This is the major mutation site involved in CD36 deficiency in Japanese. Results: Among parameters related to insulin resistance, there were no differences in body mass index (BMI), HDL cholesterol, total cholesterol, triglycerides, insulin and insulin resistance index (HOMA IR), or blood pressure between 91 normal subjects (45 male and 46 female) randomly selected from the 780 Pro90 homozygotes and the 51 (29 male and 22 females) CD36-deficient subjects (Ser90 homozygote and Pro90Ser heterozygote). Free fatty acid concentrations, however, were higher in Ser90 CD36 subjects than in Pro90 control subjects. Conclusions: The CD36Pro90Ser mutation is not necessarily related to the insulin resistance syndrome, but is associated with high free fatty acid concentrations in Japanese.

Hyperlipidemia with Hypoglycemia Reduces Myocardial Oxygen Utilization Efficiency but not Contractile Function During Coronary Hypoperfusion

This study was designed to determine changes in myocardial contractile function and fuel selection during moderate coronary hypoperfusion in the presence of elevated plasma free fatty acid (FFA) at normal and reduced blood glucose concentrations. Coronary perfusion pressure (CPP) was sequentially lowered from 100 to 60, 50, and 40 mmHg in the left anterior descending coronary artery (LAD) of anesthetized, open-chest dogs. Regional glucose uptake (GU), fatty acid uptake (FAU), percentage segment shortening (%SS), and oxygen consumption (MV O2) were determined with normal arterial plasma FFA concentrations (Group 1) or with elevated FFA concentrations (Groups 2 and 3). In Group 3, glucose in the coronary perfusate blood was reduced from 3.53±0.36 to 0.15±0.03 m M by hemodialysis. In Group 1, FAU fell by 85% as CPP was lowered to 60 mmHg and remained depressed as CPP was reduced further; GU did not fall significantly. Hyperlipidemia in Group 2 did not alter GU at any CPP, but maintained FAU at baseline levels until CPP was lowered to 40 mmHg. At 40 mmHg CPP, myocardial function and metabolic variables were similar in Groups 1 and 2. In Group 3 at 40 mmHg, FAU increased four-fold and MV O2doubled v Groups 1 and 2, and GU fell to zero. Despite these metabolic changes, %SS in Group 3 was unchanged relative to Group 2. Addition of glucose to the dialysate prevented the effects of dialysis on FAU, GU, and MV O2. Thus, preferential glucose oxidation sustains myocardial oxygen utilization efficiency [(heart rate × %SS × maximum left ventricular pressure)/MV O2] during hypoperfusion. Blocking preferential glucose oxidation by combined hyperlipidemia and hypoglycemia lowers oxygen utilization efficiency, but does not compromise myocardial contractile function.

Elevation of plasma fatty acids by ten-hour intralipid infusion has no effect on basal or glucose-stimulated insulin secretion in normal man

There is controversy over the effect of free fatty acids (FFAs) on insulin secretion. Previous studies have shown opposite effects of short- and long-term exposure to elevated concentrations of FFAs. We studied 8 normal subjects (mean age, 30 years; mean body mass index, 23.4 kg/m2) on 2 occasions. Each had a 10-hour overnight infusion of Intralipid 20% (Pharmacia, Milton Keynes, UK) with simultaneous infusion of heparin (0.4 U/kg body weight/min) or a control infusion of saline (150 mmol/L). Insulin secretion was assessed immediately after completion of the 10-hour infusion by an intravenous glucose tolerance test. Results were analyzed using paired ttests. Intralipid infusion caused an increase in plasma FFAs of more than 9-fold (P < .01), with a simultaneous increase in glycerol (P < .01) and hydroxybutyrate (P < .01). There was no difference in blood glucose concentrations during the infusion or intravenous glucose tolerance test. Similarly, insulin secretion was not significantly different during Intralipid infusion or in the intravenous glucose tolerance test (peak insulin achieved in glucose tolerance test, P = .51; total insulin secretion during intravenous glucose tolerance test, P = .27). In conclusion, after increasing plasma FFA concentrations over 9-fold during a 10-hour infusion of Intralipid and heparin, we found no difference in basal or glucose-stimulated insulin secretion.