Increased Free Fatty Acids Concentrations Research Articles

Metabolic Effects of Brown Adipose Tissue Activity Due to Cold Exposure in Humans: A Systematic Review and Meta-Analysis of RCTs and Non-RCTs.

Brown adipose tissue (BAT), specialized in thermoregulation in mammals, has been linked to improved glucose and lipid homeostasis when activated by cold exposure (CE). This systematic review and meta-analysis assessed the metabolic effects of CE-induced BAT activation in healthy humans, examining changes in glucose and lipid metabolism compared to thermoneutrality (TN). A literature search was conducted, identifying relevant human studies, including randomized controlled trials (RCTs) and non-RCTs, based on predefined inclusion criteria. Seven studies (a total of 85 participants) fully met the criteria. Data on plasma glucose, insulin, triglycerides (TGs), and free fatty acids (FFAs) were extracted for meta-analysis. When comparing TN and CE under fasting conditions, there were no significant changes in glucose, insulin, or TG concentrations (all p > 0.36). In contrast, CE significantly increased FFA concentrations (p = 0.002; n = 38). Bias was absent for all parameters, but heterogeneity was observed for insulin (I2 = 74.8%). CE primarily affects FFA concentration, likely reflecting cold-induced BAT activity. This suggests that circulating FFAs, serving as the primary fuel for thermogenesis, could indicate BAT activation. However, understanding the effects of BAT activation on overall metabolism requires a broader approach beyond fasting glucose and lipid concentration measurements.

Rosiglitazone Prevents Free Fatty Acid-Induced Vascular Endothelial Dysfunction

Free fatty acids (FFAs) cause insulin resistance and vascular endothelial dysfunction. The peroxisome proliferator-activated receptor gamma agonist rosiglitazone acts as insulin sensitizer and could exert vasoprotective properties by preservation of endothelium-dependent vasodilation. We tested the effect of rosiglitazone on FFA-induced endothelial dysfunction of the forearm resistance vessels, insulin sensitivity, asymmetric dimethylarginine (ADMA), and high-sensitivity C-reactive protein concentrations in humans. We conducted a double-blind, randomized, placebo-controlled parallel-group study at a university hospital. Rosiglitazone 8 mg daily or placebo was administered to 16 healthy male subjects for 21 d. On the last day, triglycerides and heparin were infused iv to increase FFA plasma concentrations. Forearm blood flow responses to the endothelium-dependent vasodilator acetylcholine and the endothelium-independent vasodilator nitroglycerine were assessed using strain-gauge plethysmography at baseline, and on d 21 before and after 5 h of triglyceride/heparin infusion. Forearm blood flow reactivity was not affected by rosiglitazone or placebo. Infusion of triglyceride/heparin substantially increased FFA concentrations (P < 0.001) and reduced endothelium-dependent vasodilation by 38 +/- 17% (P = 0.024). In the face of lower FFA elevation (P = 0.047 vs. controls), endothelium-dependent vasodilation was preserved in subjects receiving rosiglitazone (P = 0.016 vs. placebo). Endothelium-independent vasodilation and C-reactive protein were unchanged, whereas insulin sensitivity and plasma ADMA similarly decreased in both study groups after FFA elevation (both P < 0.05 vs. baseline). Rosiglitazone mitigates the increase in FFA after infusion of triglyceride/heparin and prevents FFA-induced endothelial dysfunction. These effects are independent and possibly occur before any changes in insulin sensitivity and ADMA plasma concentrations in healthy subjects.

Time-Dependent Effects of Free Fatty Acids on Glucose Effectiveness in Type 2 Diabetes

Impaired effectiveness of glucose to suppress endogenous glucose production (EGP) is an important cause of worsening hyperglycemia in type 2 diabetes. Elevated free fatty acids (FFAs) may impair glucose effectiveness via several mechanisms, including rapid changes in metabolic fluxes and/or more gradual changes in gene expression of key enzymes or other proteins. Thus, we examined the magnitude and time course of effects of FFAs on glucose effectiveness in type 2 diabetes and whether glucose effectiveness can be restored by lowering FFAs. Glucose fluxes ([3-(3)H]-glucose) were measured during 6-h pancreatic clamp studies, at euglycemia (5 mmol/l glucose, t=0-240 min), and hyperglycemia (10 mmol/l, t=240-360 min). We studied 19 poorly controlled subjects with type 2 diabetes (HbA(1c) 10.9 +/- 0.4%, age 50 +/- 3 years, BMI 30 +/- 2 kg/m(2)) on at least two occasions with saline (NA- group) or nicotinic acid (NA group) infusions for 3, 6, or 16 h (NA3h, NA6h, and NA16h groups, respectively) to lower FFAs to nondiabetic levels. As a reference group, glucose effectiveness was also assessed in 15 nondiabetic subjects. There was rapid improvement in hepatic glucose effectiveness following only 3 h of NA infusion (NA3h = 31 +/- 6% suppression of EGP with hyperglycemia vs. NA- = 8 +/- 7%; P<0.01) and complete restoration of glucose effectiveness after 6 h of NA (NA6h = 41 +/- 8% suppression of EGP; P = NS vs. nondiabetic subjects). Importantly, the loss of hepatic glucose effectiveness in type 2 diabetes is completely reversible upon correcting the increased FFA concentrations. A longer duration of FFA lowering may be required to overcome the chronic effects of increased FFAs on hepatic glucose effectiveness.

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 …

Milk harvesting and cow factors influencing seasonal variation in the levels of free fatty acids in milk from Waikato dairy herds

Free fatty acids (FFA) occur naturally in milk and, under certain on‐farm conditions, concentrations increase, affecting the flavour, processing efficiency, and shelf‐life of dairy products. To obtain some understanding of these, FFA concentration was determined in silo milk samples collected from seasonal supply dairy farms in Waikato, New Zealand during the 1997/98 and 1998/99 dairying seasons. Selected farms represented the major dairy systems: 25 farms had continuous (rotary) milking systems and 25 farms had batch (herringbone) milking systems. Four of the herringbone dairies had milk‐harvesting systems that eliminated the air‐milk interface (Ruakura Milk Harvester; RMH). FFA concentrations were assessed every 2 weeks in bulk milk samples collected from the farm silo. Concentrations of FFA were lowest in spring (early‐lactation) and highest in summer and autumn (mid‐late lactation). The type of dairy design (herringbone versus rotary) had no association with FFA concentrations, but the four herds milked by the RMH system tended to produce milk with lower (P < 0.10) FFA concentrations during summer and autumn 1998/99. A number of factors were associated with increased FFA concentrations: type of milking system, milk yield, somatic cell count (SCC), milk composition, and stage of lactation. Bacterial infection as identified by SCC and the elimination of the air‐milk interface during milk harvesting (RMH) had possibly major influences on FFA concentrations.

The Potential Therapeutic Role of Insulin in Acute Myocardial Infarction in Patients Admitted to Intensive Care and in Those With Unspecified Hyperglycemia

While acute myocardial infarction and patients admitted to intensive care units carry a serious risk of mortality and morbidity, the concomitant occurrence of hyperglycemia enhances this risk. This has been established through various studies over the past decade (1–3). More recently, it has been shown that the treatment of these conditions with intravenous infusions of insulin results in marked improvements in clinical outcomes (3–5). While the normalization of blood glucose concentration may be one factor in the improvement of these outcomes, insulin may exert benefits of its own, independently of the plasma glucose concentrations. Both septicemia and acute myocardial infarction are inflammatory states with markedly enhanced catabolism. There may be hyperglycemia and an increase in plasma free fatty acid (FFA) concentrations in both of these conditions. Increased FFA concentrations are known to be associated with a deterioration of clinical outcomes and may have toxic effects of their own on vascular reactivity and on the myocardium (6–9). FFAs may have effects on endothelial nitric oxide (NO) production (6), prostacyclin production (10), and the stability of prostacyclin in plasma (11). FFAs may also induce a state of insulin resistance through the induction of protein kinase C and inflammation through the suppression of inhibitor κB (IκB) in the skeletal muscle (12). Proinflammatory changes are also induced in the mononuclear cells by FFAs as reflected in an increase in nuclear factor-κB (NF-κB), the major proinflammatory transcription factor, an increase in reactive oxygen species (ROS) generation, and an increase in p47 phox (13). Thus, the normalization of FFA concentrations by insulin may produce a benefit. Similarly, it can be argued that insulin administration may facilitate the uptake of glucose by insulin-responsive organs, including the myocardium, thus providing for their metabolic needs. These mechanisms are based on our understanding of …

Prolonged exposure to free fatty acids has cytostatic and pro-apoptotic effects on human pancreatic islets: evidence that beta-cell death is caspase mediated, partially dependent on ceramide pathway, and Bcl-2 regulated.

In an effort to better understand the phenomenon of lipotoxicity in human beta-cells, we evaluated the effects of 48-h preculture with 1.0 or 2.0 mmol/l free fatty acid (FFA) (2:1 oleate to palmitate) on the function and survival of isolated human islets and investigated some of the possible mechanisms. Compared with control islets, triglyceride content was significantly increased and insulin content and glucose-stimulated insulin release were significantly reduced in islets precultured with increased FFA concentrations. These changes were accompanied by a significant reduction of glucose utilization and oxidation. By cell death detection techniques, it was observed that exposure to FFAs induced a significant increase of the amount of dead cells. Electron microscopy showed the involvement of beta-cells, with morphological appearance compatible with the presence of apoptotic phenomena. FFA-induced islet cell death was blocked by inhibition of upstream caspases and partially prevented by inhibiton of ceramide synthesis or serine protease activity, whereas inhibition of nitric oxide synthesis had no effect. RT-PCR studies revealed no major change of iNOS and Bax mRNA expression and a marked decrease of Bcl-2 mRNA expression in the islets cultured with FFA. Thus, prolonged exposure to FFAs has cytostatic and pro-apoptotic effects on human pancreatic beta-cells. The cytostatic action is likely to be due to the FFA-induced reduction of intraislet glucose metabolism, and the proapoptotic effects are mostly caspase mediated, partially dependent on ceramide pathway, and possibly Bcl-2 regulated.

20-Hour Physiological Responses to a Single Weight-Training Session

This study compared trained and untrained subjects' responses to a single bout of weight-training exercise of the same relative intensity. Young men (N = 21) were divided into three similar groups based on their 1-RM dead-stop squat. Group 1 (n = 8) was made up of well-trained weightlifters (TWL). Group 2 (n = 7) were untrained subjects who took part in the exercise session (UTWL). Group 3 (n = 6) served as untrained controls (C). Food and drink were controlled and measured. Heart rate, profile-of-moods states, and blood samples were taken three times before and five times after exercise. Blood was analyzed for hematocrit (Hct), lactate (HLa), blood glucose (glu), free fatty acids (FFA), insulin (I), glucagon (G), cortisol (Cort), growth hormone (hGH), epinephrine (E), and norepinephrine (NE) using standard methods. Data were analyzed using ANOVA with a repeated-measures design. The alpha level was p≤0.05. The single exercise session elicited significantly higher HR, HLa, glu, FFA, hGH, E, and NE values in the TWL and UTWL 5 min postexercise than in the C group. UTWL Cort values were significantly higher than the TWL or C groups at 5 min postexercise. At 1-1/2 hrs postexercise the UTWL had significantly higher values for HR, HLa, and Cort than the other groups. The UTWL had significantly higher FFA concentrations compared to the Controls at 20 hrs postexercise. Shifts in plasma volume did not adequately account for the observed changes in HLa, glu, or hormones. These data suggest that the magnitude of the response to weight-training exercise is related to the subject's trained state. Additionally, these data indicate that weight training can stimulate increased FFA concentrations at various times during recovery.

Metabolic response during impending myocardial infarction. I. Relevance of studies of glucose and fatty acid metabolism in animals.

Both glucose and free fatty acids (FFA) are major fuels for the normally oxygenated heart with the dominant contribution being derived from glucose in the resting, fed state and FFA in the resting, fasted state. In anoxia, all energy must be produced anaerobically from glycogen or glucose. Anoxia by itself accelerates glycolysis, but further increases may follow an increased circulating glucose concentration and the addition of insulin. Even maximal rates of anaerobic glycolysis, achieved at high coronary flow rates, can only sustain the energy needs of the K + -arrested heart but not of the working heart. FFA cannot be utilized for energy in anoxia and may accumulate intracellularly as triglyceride or FFA. From these and other animal data have grown the concepts that glucose is "good" for the survival of the ischemic heart, and that FFA is "bad." However, glucose-fatty acid interaction has not been well studied in the infarcting, ischemic myocardium. While a "toxic" effect of FFA has been shown in many experimental models, there are other reports of increased FFA concentrations having no harmful effect or even a beneficial effect on the infarcting myocardium. The possible benefits of administration of glucose (with insulin) to patients with acute myocardial infarction could only be assessed by a controlled therapeutic trial.