Influence of blood flow on fatty acid mobilization from lipolytically active adipose tissue

Subcutaneous, ingvinal adipose tissue from dogs was perfused with blood to which had been added isoprenaline and theophyllamine in order to stimulate lipolysis. The supply of free fatty acid (FFA) carrier to the tissue was varied either by variations in the rate of blood flow or by changes in the albumin concentration of the perfusing blood at constant flow rate. The net production of FFA from the tissue was found to depend on the supply of carrier over a range from 0.1–12 moles of albumin × 100g tissue^–1 × min^–1. The corresponding molar ratios in adipose venous blood varied between 12.1 and 1.2. The changes in FFA production appeared to be due to varying degrees of reesterification rather than changes in the rate of lipolysis. The findings suggest that the increase in adipose tissue blood flow demonstrated during various lipolytic conditions is of physiological importance by facilitating the removal of FFA from adipose tissue. Equilibration experiments showed the FFA binding capacity of both dog serum and human plasma to be above that calculated from the association constants of purified human albumin, suggesting the binding of FFA to other plasma carriers than albumin.     

Vasoconstrictor effect of high FFA/albumin ratios in adipose tissue in vivo

Subcutaneous or perirenal adipose tissue blood flow was measured with the 133Xe-washout technique before and after intravenous injection or infusion of Intralipid in six anesthetized, otherwise intact mongrel dogs. In four anesthetized mongrel puppies adipose tissue blood flow was measured with the radioactive microsphere method in seven different adipose tissue depots before a bolus injection of Intralipid and at the time after the injection when the thermogenic effect of the Intralipid was maximal. The results showed that the vascular resistance increased in all the examined adipose depots in adult as well as in young dogs after this treatment. The administration of Intralipid did not per se induce the vasoconstriction. The vasoconstriction took place simultaneously with increasing FFA/albumin molar ratios. The results support our previous findings in perfused fat pads that high molar FFA/albumin ratios increase vascular resistance in adipose tissue and they give further support to our suggestion that this vasoconstriction may be a link in a negative-feedback mechanism regulating FFA-mobilization in relation to FFA utilization.     

Serum fatty acid/albumin molar ratio and the risk of diseases

Free fatty acids (FFA) in blood are carried by serum albumin. A hypothesis is offered that conditions giving a high molar ratio of FFA to albumin may lead to dysfunction of the cells which are directly exposed to the high FFA/albumin ratio, i.e. the red and white blood cells, and endothelial cells. The hypothesis is supported by observations of (1) hemolytic effect of FFA, and protection by albumin in vitro, (2) inhibition of white blood cells by FFA, (3) increased FFA/albumin ratio and erythrocyte susceptibility to hemolysis in pre-eclampsia, (4) increased incidence of eclampsia in undernutrition, (5) the paradox that famine suppresses and refeeding activates malaria, and (6) an inverse relationship between serum albumin level and mortality.     

Subcutaneous adipose tissue blood flow and triacylglycerol-mobilization during prolonged exercise in dogs

In 6 dogs concentration differences for glycerol and FFA were measured between the aorta and the external pudendal vein, a vein which mainly drains subcutaneous adipose tissue in dogs, during prolonged exercise. It was found that the a-v differences increased about 2-fold for both glycerol and FFA, however great interindividual differences were found. In 4 dogs adipose tissue blood flow, glycerol and FFA a-v differences were measured simultaneously, and the mobilizations of glycerol and FFA as well as the re-esterification of FFA were calculated. After 2 h of exercise the values were in the range of 1–7 mol/(100 g·min) for FFA and glycerol mobilizations while the FFA re-esterification was in the range of 2–14 mol/(100 g·min). It was found that the FFA/albumin ratio in adipose venous blood, on average 3.6, was at a level at which the FFA mobilization has been shown to depend on the adipose tissue blood flow in isolated fat pads. In 11 dogs subcutaneous adipose tissue blood flow rose 2-fold during exercise from about 5–10 ml/(100 g·min). It is concluded that the subcutaneous a dipose tissue blood flow response to exercise is equal in man and dog, that lipolysis, FFA mobilization and FFA re-esterification are increased in subcutaneous adipose tissue during exercise, and that the increase in blood flow is of importance for the enhanced FFA mobilization during exercise.     

Hormones modulate adipocyte membrane potential ATP and lipolysis via free fatty acids

The hypothesis that lipolytic hormones reduce the mitochondrial electrical potential in rat white adipocytes via free fatty acids (FFA) was examined. Hormonal effects on plasma and mitochondrial membrane potentials were evaluated with [3H]triphenylmethylphosphonium (TPMP+) and 86Rb+. FFA generation was controlled by varying medium albumin concentrations. In 4.0% albumin buffer, adrenocorticotropin or l-epinephrine increased intracellular FFAs, produced cellular TPMP+ efflux, ATP depletion, release of FFAs and glycerol, and no change in 86Rb+ distribution. In 0.5% albumin buffer, greater intracellular FFA accumulation accompanied greater TPMP+ and ATP depletion, significant loss of cell-associated 86Rb+, and a concomitant inhibition of FFA and glycerol release. Exogenous addition of FFAs mimicked the effect of hormones on adipocyte TPMP+ distribution. TPMP+ and 86Rb+ uptake into adipocyte "ghosts" were unaffected by hormones. We suggest that mitochondrial membrane depolarization is a metabolic response to hormones via FFA accumulation by white adipocytes. The additional hormonal effects that were observed in 0.5% albumin buffer may be related to inhibition of lipolysis secondary to intracellular ATP depletion.     

Free fatty acids and albumin as mediators of thrombin-stimulated fibrinogen synthesis.

Mobilization of FFA in mice, triggered with an injection of thrombin, was followed within 24 h by a 2.5-fold increase in fibrinogen synthesis and a 30% increase in plasma fibrinogen concentration. In mouse liver slices, incubated in plasma, additions of palmitate or stearate in amounts similar to those expected in vivo in FFA mobilization stimulated fibrinogen synthesis 5.6- to 6.1-fold while unsaturated and short-chain FFA were less effective. Palmitate and linoleate also augmented albumin synthesis although not as stongly as fibrinogen synthesis. These observations raised the possibility that the greater effectiveness of saturated FFA in stimulating fibrinogen synthesis may reflect higher FFA/albumin ratios within hepatocytes in the presence of saturated FFA. Injection of exogenous defatted albumin into mice before thrombin injection prevented the FFA-associated rise in fibrinogen synthesis and plasma concentration. In incubated liver slices, defatted albumin abolished the FFA stimulation of fibrinogen synthesis when FFA/albumin ratios were maintained to the physiological range. These studies indicate that the FFA/ALBUMIN RATIO MAY PLAY A MAJOR ROLE IN THE REPLENISHMENT OF FIBRINOGEN AFTER PERIODS OF RAPID DEFIBRINOGENATION.     

Effect of glucose on lipolysis and on release of lipolytic products in isolated adipocytes.

Isolated adipocytes were prepared from epididymal adipose tissues removed from rats which had been fed or starved for 48 h (fed adipocytes or fasted adipocytes). These cells were incubated at 37 degrees C for 90 min in media containing 0, 3, or 30 mM glucose, with or without norepinephrine (1.0 mug/ml). Then the concentrations of free fatty acids (FFA) and free glycerol (FG) in the total mixture (medium plus cells) and in the medium alone were measured. Addition of glucose to the medium increased the total PG, presumably by increasing the basal lipolysis, and it decreased the intracellular retention ratio of FG (the ratio of intracellular FG to total FG). Addition of glucose did not change the total FFA, but decreased the FFA/FG ratio, presumably by increasing reesterification. The increase in FG and decrease in the FFA/FG ratio on addition of glucose were greater in fed than in fasted adipocytes. The intracellular retention ratio of FFA also decreased on addition of glucose. Glucose enhanced norepinephrine-induced lipolysis (release of free glycerol), and this effect of glucose was greater in fasted adipocytes. However, the increase in FFA in fasted adipocytes induced by norepinephrine was not altered by addition of glucose. In fed adipocytes norepinephrine decreased the total FFA in the presence of glucose. Reesterification of FFA following norepinephrine was increased by addition of glucose. Norepinephrine decreased the intracellular retention ratios of FG and FFA in the presence of glucose. These results suggest that the passage of the lipolytic products, FFA and FG, through the cell membranes may not occur by simple diffusion, but may require energy.     

Inosine causing insulin release and increased myocardial uptake of carbohydrates relative to free fatty acids in dogs

The aim of the present study was to determine the effect of i.v. inosine on myocardial substrate uptake and function in the in situ dog heart. Inosine was infused i.v. at a rate of 5 mg kg min-1 in eight closed-chest pentobarbital anaesthetized dogs. Inosine caused a 46% decrease (P less than 0.01) in plasma free fatty acids (FFA), a 15% decrease (P less than 0.05) in plasma glycerol, an 18% decrease (P less than 0.05) in plasma glucose and a 46% increase (P less than 0.01) in blood lactate. This was associated with a 55% decrease (P less than 0.01) in myocardial FFA uptake and a 72% increase in lactate uptake, while glucose uptake remained unchanged. These metabolic changes were associated with a five-fold increase (P less than 0.05) in arterial insulin. Inosine caused an 18% increase (P less than 0.01) in myocardial blood flow without changing MVO2. There was a 33% increase (P less than 0.01) in LV dP/dtmax, a decrease in LVEDP from 4.9 +/- 0.9 (mean +/- SEM) to 0.9 +/- 0.3 mmHg (P less than 0.05) and a 24% decrease (P less than 0.01) in systemic vascular resistance. Inosine caused a transient 38% increase (P less than 0.05) in pulmonary vascular resistance. In conclusion, in addition to a positive inotropic effect and vascular effects inosine was found to cause release of insulin and to shift myocardial metabolism towards increased uptake of carbohydrates relative to FFA.     

The Effect of Lactate in Canine Subcutaneous Adipose Tissue in Situ1

Fredholm , B. B. The effect of lactate in canine subcutaneous adipose tissue in situ. Acta physiol. scand. 1971. 81. 110–123. Na-L(+)-lactate and Na-pyruvate were administered by intraarterial infusion in canine subcutaneous adipose tissue, perfused with the dogs own blood either at a constant rate from a reservoir or by autoperfusion. The glucose uptake was found to be dependent upon the arterial glucose concentration. Similarly the uptake of lactate and pyruvate increased with increasing arterial concentrations, the latter more rapidly than the former. Infusion of Na-L(+)-lactate below 5 mM and Na-D(—)-lactate (10–11 mM) had no effect on the release of FFA and glycerol upon nerve stimulation (4 cps for 5 to 10 min). On the other hand Na-L(+)-lactate above 10 mM caused a 70 per cent inhibition of the release of FFA without significantly affecting the glycerol release. Na-pyruvate (5 mM) decreased the glycerol output significantly, but increased the FFA release. Neither of the anions had any significant effect on the glucose uptake. Na-lactate was not vasoactive, whereas Na-pyruvate was slightly vasodilator. It is concluded that lactate in concentrations occurring a.g. during muscular exercise and shock is capable of significantly depressing the rate of FFA release upon nerve stimulation by increasing the rate of re-esterification. The finding that lactate and pyruvate had opposite effects on esterification indicates a role of the cytoplasmatic NADH/NAD ratio in determining the rate of esterification.     

Direct antilipolytic effect of acidosis in isolated rat adipocytes.

The possibility that acidosis inhibits lipolysis indirectly by causing ionic shifts or by favouring the accumulation of an inhibitor has been tested in isolated fat cells. Lipolysis induced by 3 muM noradrenaline (NA) was inhibited by 40-60% and that induced by 1 mM theophylline (THEO) by about 75% when the pH was reduced to 6.6. Lipolysis induced by NA + THEO was inhibited by 20-30%. Changing the concentration of Ca++ or Mg++ did not alter the degree of inhibition. Reducing the K+-ion concentration enhanced the inhibitory effect of low pH on lipolysis induced by NA or NA + THEO, whereas cyclic AMP accumulation was uninfluenced. Omitting glucose from the incubation medium caused a slight enhancement of pH-induced inhibition of lipolysis (from 60 to 70%, p less than 0.01). Reducing the concentration of albumin, which binds inhibitory substances such as FFA, reduced lipolysis more at normal than at reduced pH. At high FFA/albumin ratios (5 or above) lipolysis was similar at normal and reduced pH. The antilipolytic effect of decreased pH was equally pronounced in perifused fat cells, where inhibitory substances are not allowed to accumulate. Our results suggest that the antilipolytic effect of acidosis is mainly a direct effect of the increase in H+ ion concentration. The inhibitory effect of acidosis on various responses to beta-adrenoceptor stimulation may be caused by a decreased formation of cyclic AMP in turn caused directly by the decrease in pH.     

Direct Antilipolytic Effect of Acidosis in Isolated Rat Adipocytes

The possibility that acidosis inhibits lipolysis indirectly by causing ionic shifts or by favouring the accumulation of an inhibitor has been tested in isolated fat cells. Lipolysis induced by 3 μM noradrenaline (NA) was inhibited by 40–60% and that induced by 1 mM theophylline (THEO) by about 75% when the pH was reduced to 6.6. Lipolysis induced by NA+THEO was inhibited by 20–30%. Changing the concentration of Ca⁺⁺or Mg⁺⁺did not alter the degree of inhibition. Reducing the K⁺-ion concentration enhanced the inhibitory effect of low pH on lipolysis induced by NA or NA + THEO, whereas cyclic AMP accumulation was uninfluenced. Omitting glucose from the incubation medium caused a slight enhancement of pH-induced inhibition of lipolysis (from 60 to 70%, p<0.01). Reducing the concentration of albumin, which binds inhibitory substances such as FFA, reduced lipolysis more at normal than at reduced pH. At high FFA/albumin ratios (5 or above) lipolysis was similar at normal and reduced pH. The antilipolytic effect of decreased pH was equally pronounced in perifused fat cells, where inhibitory substances are not allowed to accumulate. Our results suggest that the antilipolytic effect of acidosis is mainly a direct effect of the increase in H⁺ion concentration. The inhibitory effect of acidosis on various responses to β-adrenoceptor stimulation may be caused by a decreased formation of cyclic AMP in turn caused directly by the decrease in pH.     

Effect of ACTH on lipolysis in adipose tissue of normal and adrenalectomized rats in vivo.

Parametrial fat-pads of fed rats were perfused in vivo. Rates of release of glycerol and free fatty acids (FFA) were determined from venous-arterial difference and plasma flow. Adrenalectomy lowered basal release of FFA and glycerol, but not reesterification of FFA within the fat-pad. ACTH (5 mug iv) in normal rats increased release of FFA and glycerol (mumol-g-1-h-1) from basal values of 0.90 and 0.48 to 3.2 and 1.3, respectively, and in adrenalectomized rats from 0.41 and 0.33 to 1.5 and 3.1, respectively. Thus in normal rats ACTH increased the molar ratio of FFA to glycerol released from 1.9 to 2.5, whereas in adrenalectomized rats the ratio fell from 1.3 to 0.5. After stimulation of lipolysis in normal rats 85% of the FFA formed were released but only 20% in adrenalectomized rats; the remainder was reesterified to triglyceride. It is concluded that adipose tissue of adrenalectomized rats is sensitive to the lipolytic activity of ACTH, but increased glucose utilization by adipocytes in the absence of glucocorticoid enhances reesterification and reduces release of FFA by the tissue.     

Ionized calcium influences gastrin stimulated histamine release and acid secretion, but not histamine stimulated acid output in the totally isolated vascularly perfused rat stomach

When changing from bovine serum albumin to dextran T70 as colloid without adjusting the total calcium concentration in the vascular perfusate of the totally isolated vascularly perfused rat stomach, we noticed a drastic fall in gastrin-stimulated acid secretion. In the present study the effect of the two colloids on ionized calcium in the vascular perfusate as well as the effect on acid secretion and vascular histamine release were studied. There was no difference in gastrin-stimulated acid secretion or vascular histamine release between the two colloids after adjusting the total calcium concentrations so that ionized calcium was similar. Whereas baseline acid secretion showed no marked dependency of ionized calcium within the range tested (0.73-1.54 mmol l-1, gastrin-stimulated acid secretion was highly dependent on ionized calcium being reduced at the higher concentration of Ca2+. Histamine stimulated acid secretion, on the other hand, was virtually unaffected by the concentration of ionized calcium in the same range. Like gastrin-stimulated acid secretion, gastrin-stimulated histamine release was inhibited at higher Ca2+ concentrations. Thus, elevated Ca2+ concentrations seemed to reduce gastrin-stimulated acid secretion by inhibiting vascular histamine release.     

Some metabolic consequences of the anaphylactic reaction in the rabbit.

The administration of egg albumin to rabbits sensitized to this antigen caused marked increases in the arterial concentration of lactate, glucose and glycerol, but no change in the arterial FFA level. Antigen administration had no effect in non-sensitized rabbits. Phentolamine (3 mg/kg) or propranolol (1 mg/kg) did not significantly alter the responses to egg albumin in sensitized rabbits. Noradrenaline or sympathetic nerve stimulation decreased blood flow but caused no significant change in lipolysis in rabbit epigastric adipose tissue in situ. It is therefore questionable if catecholamines are the major cause of the observed metabolic consequences of the anaphylactic reaction in the rabbit. These metabolic events, i.e. increased lactate levels, lipolysis, and reesterification of fatty acids, are similar to those reported during hemorrhagic or endotoxin shock in dogs, in spite of specied-differences and the difference in the genesis of the shock.     

Effects of sodium salicylate on plasma insulin concentration and fatty acid turnover in dogs

The effects of intravenous sodium salicylate administration on plasma concentrations of insulin, free fatty acids (FFA) and glucose were studied in intact, anaesthetized dogs both during basal and isoprenaline stimulated lipolysis. In both situations sodium salicylate reduced the plasma concentrations of insulin. The reduction was associated with decreased plasma FFA concentrations and FFA turnover rate, while plasma glucose concentrations remained unaltered. The reduced plasma insulin concentrations effected by sodium salicylate is most likely secondary to the concomitant fall in plasma FFA concentrations due to inhibition of FFA mobilization from adipose tissue.     

Both protein and blood cells reduce coronary microvascular permeability to macromolecules

A number of studies report that isolated Krebs-perfused hearts deteriorate with time, develop edema, and demonstrate a progressive increase in coronary vascular resistance. However, hearts perfused with filtered blood are more stable with regard to cardiac function and coronary resistance. The changes observed in the Krebs hearts may be due to a "permeability"-type edema. The purpose of this study was to systematically determine whether adding protein and blood cells to a Krebs perfusate affected coronary microvascular permeability to macromolecules. The rat heart preparation employed allowed direct visualization and quantification of transcoronary macromolecular leakage. We observed severe transcoronary leakage of fluorescent albumin (FITC-BSA) when FITC-BSA was later added after 20 min of perfusion with Krebs. Leakage was decreased by including 2 g/100 ml albumin (BSA) in the initial perfusate but was not further reduced by increasing the BSA concentration to 5 g/100 ml. However, adding washed blood cells to the initial perfusate did further reduce FITC-BSA leakage. The index of FITC-BSA exchange, the O/I ratio, was 0.70 +/- 0.02 (+/- SE) for Krebs perfusate, 0.55 +/- 0.03 for Krebs-BSA, and 0.45 +/- 0.02 for Krebs-BSA-blood cells, indicating significant effects for both protein and blood cells (P less than 0.05). The results suggest that both protein and blood cells are necessary to maintain the semipermeable characteristics of the coronary exchange vessels.     

Metabolic effects of blood flow restriction in adipose tissue

The metabolic effects of blood flow restriction were studied in isolated blood-perfused canine subcutaneous adipose tissue. Blood flow restriction (on the average to 20 per cent of control flow) was caused by either mechanical clamping of the arterial inflow or by i.a. injections of methoxamine or angiotensin. Glucose uptake in the adipose tissue was reduced during blood flow restriction. This was partially compensated for by a period of increased glucose uptake following restoration of flow. Blood flow restriction also caused an increase in the venous lactate/pyruvate ratio. The basal lipolytic rate was decreased during blood flow restriction. Lipolysis induced by brief (5 min) sympathetic nerve stimulation (4 Hz) was not inhibited by blood flow restriction as the total amount of glycerol released from the tissue was unaffected. The outflow rate was reduced during blood flow restriction, but glycerol trapped within the tissue was apparently not reutilized by the fat cells as it was released upon flow restoration. FFA outflow following nerve stimulation was, however, inhibited suggesting increased reutilization of FFA within the tissue. This increased reutiliza-tion may ultimately be caused by the observed change in red./ox.-balance and/or by the limited carrier capacity (albumin) available during blood flow restriction. Three main conclusions may be drawn from the present results. Firstly, plasma levels of glycerol and FFA do not necessarily reflect adipose tissue lipolysis at a given moment. Secondly, the decreased adipose tissue blood flow seems to be a major cause of the lowered FFA-levels during hemorrhage. Thirdly, in contrast to hemorrhage, even severe reduction of adipose tissue blood flow is insufficient to cause irreversible ischemic damage.     

Metabolic effects of blood flow restriction in adipose tissue.

The metabolic effects of blood flow restriction were studied in isolated blood-perfused canine subcutaneous adipose tissue. Blood flow restriction (on the average to 20 per cent of control flow) was caused by either mechanical clamping of the arterial inflow or by i.a. injections of methoxamine or angiotensin. Glucose uptake in the adipose tissue was reduced during blood flow restriction. This was partially compensated for by a period of increased glucose uptake following restoration of flow. Blood flow restriction also caused an increase in the venous lactate/pyruvate ratio. The basal lipolytic rate was decreased during blood flow restriction. Lipolysis induced by brief (5 min) sympathetic nerve stimulation (4 Hz) was not inhibited by blood flow restriction as the total amount of glycerol released from the tissue was unaffected. The outflow rate was reduced during blood flow restriction, but glycerol trapped within the tissue was apparently not reutilized by the fat cells as it was released upon flow restroation. FFA outflow following nerve stimulation was, however, inhibited suggesting increased reutilization of FFA within the tissue. This increased reutilization may ultimately be caused by the observed change in red./ox.-balance and/or by the limited carrier capacity (albumin) available during blood flow restriction. Three main conclusions may be drawn from the present results. Firstly, plasma levels of glycerol and FFA do not necessarily reflect adipose tissue lipolysis at a given moment. Secondly, the decreased adipose tissue blood flow seems to be a major cause of the lowered FFA-levels during hemorrhage. Thirdly, in contrast to hemorrhage, even severe reduction of adipose tissue blood flow is insufficient to cause irreversible ischemic damage.     

Some Metabolic Consequences of the Anaphylactic Reaction in the Rabbit

The administration of egg albumin to rabbits sensitized to this antigen caused marked increases in the arterial concentration of lactate, glucose and glycerol, but no change in the arterial FFA level. Antigen administration had no effect in non-sensitized rabbits. Phentolamine (3 mg/kg) or propranolol (1 mg/kg) did not significantly alter the responses to egg albumin in sensitized rabbits. Noradrenaline or sympathetic nerve stimulation decreased blood flow but caused no significant change in lipolysis in rabbit epigastric adipose tissue in situ. It is therefore questionable if catecholamines are the major cause of the observed metabolic consequences of the anaphylactic reaction in the rabbit. These metabolic events, i.e. increased lactate levels, lipolysis, and reesterification of fatty acids, are similar to those reported during hemorrhagic or endotoxin shock in dogs, in spite of species-differences and the difference in the genesis of the shock.     

Time‐course effects of physiological free fatty acid surges on insulin sensitivity in humans

Aim: Physiological elevations of free fatty acids (FFAs) occur in bell‐shaped surges lasting some hours, observed nocturnally, during exercise and inflammation. The time‐course effects of such FFA surges on insulin sensitivity are unknown. We therefore aimed to define the effects of a graded 4‐h FFA elevation intended to mimick physiological excursions. Methods: Eight lean, healthy men were studied on two occasions: (1) control (saline) and (2) 4 h graded infusion of intralipid (20%)/heparin. Insulin sensitivity was continuously assessed by isotope dilution (3H‐glucose) during an 8 h hyperinsulinemic‐euglycaemic clamp (0.5 mU kg^?1 min^?1). Phosphorylation of Akt and ERK1/2 was measured in muscle biopsies taken at 0 and 120 min. Inflammatory cytokines were assessed with a Luminex Suspension Array System. Results: Infusion of intralipid caused a bell‐shaped increase in FFA levels reaching peak levels ～1.9 mmol L^?1 and markedly impairing insulin sensitivity. Impairment of insulin sensitivity was apparent (P > 0.05) 120 min after initiation of FFA infusion, significant after 270 min (P < 0.001) and peaked after 360 min. FFA induced insulin resistance prevailed 210 min after cessation of FFA infusion. No effect was observed on Akt and ERK1/2 phosphorylation. Conclusions: (1) Physiological FFA elevations require at least 120 min to induce insulin resistance, (2) that insulin resistance peaks 360 min after initiation of FFA exposure and (3) ceases 210 min after termination of the FFA infusion. These observations add to our understanding of FFA induced insulin resistance in relation to circadian variations, exercise, generalized inflammation and exposure to stress hormones such as growth hormone.