Increased Plasma Free Fatty Acid Research Articles

Intraventricular 2-deoxyglucose, glucose, insulin, and free fatty acid mobilization.

The possibility of eliciting changes in the activity of lipomobilizing centers in the rat central nervous system was investigated by injecting glucose or substances that affect glucose metabolism directly into the cerebrospinal fluid of conscious, unrestrained rats. Intracerebroventricular administration of minute amounts of 2-deoxyglucose to fed rats induced a rapid increase in the concentration of plasma free fatty acids (FFA) without affecting plasma insulin levels. Furthermore, small amounts of either glucose or insulin injected intraventricularly reduced the increased plasma FFA levels of normal fasted rats without affecting the glycemia or plasma insulin levels in these animals. In diabetic rats, the increased levels of plasma FFA were not affected by intraventricular administration of glucose, but clearly decreased after intraventricular insulin. The results suggest that the lipomobilizing centers are insulin sensitive and that their activity is modulated by the rate of glucose uptake, rather than by external hexose concentration. The data are also consistent with our previous hypothesis of a direct control of the sympathetic tonus of adipose tissue by these centers.

D-Galactosamine hepatotoxicity : V. Role of free fatty acids in the pathogenesis of fatty liver

The role of free fatty acids (FFA) in the pathogenesis of fatty liver was investigated in female rats who received a single ip injection of d-galactosamine-HCl, (GalN), 750 mg/kg body weight. Groups of rats were either fasted for 14 hr prior to GalN injection and then fasted for the duration of the experiment or were fed ad libitum prior to and after GalN administration. Plasma FFA were determined in groups of fasting or fed rats sacrificed at intervals between 0 and 24 hr after GalN administration. The results revealed a progressive increase in plasma FFA in GalN-injected fasted rats (0 hr, 0.40 μmol/ml; 24 hr, 1.09 μmol/ml) whereas in fed animals only a modest increase in plasma FFA concentrations occurred. Hepatic triglyceride content was determined in groups of fasted and fed rats at 6 and 24 hr after GalN administration. Hepatic triglycerides, in fasted rats, were increased 7-fold at 6 hr (22.4 ± 8.5 mg/g) and were markedly increased at 24 hr (114.8 ± 18.4 mg/g). In contrast, feeding protected the rats from the development of fatty liver since hepatic triglycerides were only twice controls at 6 hr and 4-fold increased 24 hr after GalN. Ultrastructural studies were performed at 15, 24, and 48 hr after GalN in fed and fasted rats. Electron microscopy disclosed hepatocellular necrosis and profound fat accumulation in the fasted animals; however, feeding afforded marked protection against the development of fatty liver and hepatic injury. The results of these studies indicate that the GalN-induced fatty liver is associated with a sustained elevation of plasma FFA. The increase in plasma FFA can be prevented by feeding the animals prior to and after GalN administration suggesting that a stimulus for FFA elevation may be the alterations in carbohydrate metabolism known to be induced by GalN in rat liver.

Effects of prostaglandin‐E1 on ST segment elevation and regional myocardial blood flow during experimental myocardial ischaemia in dogs

Abstract. The effects of prostaglandin E1 (PGE1) on myocardial ischaemia (as measured by epicardial ST segment changes), myocardial flow and substrate exchange has been studied in dogs. Myocardial ischaemia was induced by intermittent external clipping of a branch of the left anterior descending coronary artery.During occlusion with a continuous intravenous infusion of isoprenaline, elevated epicardial ST segments (∑ST), were raised to 46 ± 6 mV (mean ± SEM). Pretreatment with PGE1 reduced ∑ST to 34 ± 6 mV (P<0.001), but had no effect on mean aortic blood pressure (AP¯) or on regional myocardial blood flow. Isoprenaline infusion increased plasma free fatty acids (FFA) to 1925 ± 150 μmol/l and this was reduced to 1320 ± 220 μmol/l by PGE1 (P<0.005).During occlusion without isoprenaline, PGE1 did not effect ∑ST or plasma FFA when infused intravenously or into the left atrium. Mean aortic blood pressure decreased from 131 ± 7 to 108 ± 10 (PGE1 i.v.) or 109 ± 8 mmHg (PGE1 i.a.) (P<0.001). This was associated with a decrease in regional myocardial blood flow, both in the ischaemic and non‐ischaemic myocardium. However, when blood pressure was maintained constant, intravenous PGE1 tended to decrease occlusion‐induced ST segment elevation.These results suggest that PGE1 can reduce isoprenaline‐stimulated myocardial ischaemia through its antilipolytic action but in the absence of catecholamine stimulation the main effect is to reduce blood pressure thereby counterbalancing any potentially beneficial effects on the ischaemic myocardium.

Comparative Physiology of Metabolic Responses to Neurohypophysial Hormones in Vertebrates

The neurohypophysial (NHP) hormones in mammals are arginine vasopressin (AVP) (lysine vasopressin (LVP) in Suiformes) and oxytocin. Since these hormones have been implicated in the regulation of water balance and oxytocic functions in the body, metabolic responses to their action have to be considered in relation to problems associated with adaptive radiation and physiological evolution of vertebrates. Studies on species from different classes of vertebrates have shown that water deprivation, salt-loading and thermal stress could lead to the release of neurosecretory material (NSM) from the hypothalamo-neurohypophysial system (HNPS). Salt-loading has been shown to produce in rats significant decrease in both vasopressin and oxytocin in HNPS and also cause a fall in plasma free fatty acid (FFA) and a rise in plasma glucose. Injections of exogenous AVP and LVP decrease plasma FFA level in most of the mammals studied. AVP, LVP and oxytocin produce hyperglycemia in the mammals, birds and amphibians hitherto investigated. Arginine vasotocin (AVT) is shown to increase plasma FFA and glucose levels in the bird, fish and cyclostome. Possibly growth hormone (GH) is at least one of the extraneurohypophysial hormones through which the metabolic effects of AVT may be mediated. Thermal stress and dehydration in pigeons cause the release of NSM granules from the neurohypophysis and a rise in plasma levels of GH, cAMP and FFA with no significant change in glucose. Prostaglandin E, is found to increase plasma GH and FFA with a tendency toward hyperglycemia in the pigeon. Under heat stress, some reptiles, birds and mammals pant causing increased activity of the respiratory muscles. Increased activity can also cause rise in body temperature. Whether with exercise or increased body temperature the metabolic responses are indicated by increased mobilization and utilization of lipid which yields more energy and metabolic water than carbohydrate, thus sparing glucose for glycogen build-up in the muscles. In short-term muscular activity carbohydrate is the main fuel, whereas in long-term, fat becomes the preferred source of energy. In most mammals at least in in vivo experiments, AVP and LVP cause decrease in plasma FFA but increase in plasma glucose unlike AVT in birds as far as plasma FFA is concerned. This difference may be attributed to the presence of sweat glands in mammals which are thermoregulatory in function. The NHP hormones seem to have a regulatory role in bird migration. In certain birds there is found to be a build-up of NSM in HNPS towards migration and it is released before migration thereby possibly triggering a chain of regulatory and metabolic events. Melatonin which is known to release AVT has been shown to increase plasma levels of GH, FFA and glucose in the pigeon. The influence of environmental factors such as temperature and photoperiod in bird migration may be mediated through NHP and the pineal hormones.

The effects of prolonged fasting on plasma triglyceride kinetics in man

Studies were undertaken to examine triglyceride turnover in obese humans on isocaloric balanced diets and during prolonged (3–5 wk) fasting. The data were related to plasma concentrations of insulin (IRI), glucagon (IRG), and free fatty acids (FFA) and to blood ketone concentrations. The triglyceride turnover rates were also related to the plasma triglyceride concentration. This relationship was the same in the obese on isocaloric balanced diets as that we have previously observed in lean humans on similar diets. The relationship between triglyceride turnover and concentration changed during prolonged fasting in a way that suggested that triglyceride removal was impaired. This viewpoint is consistent with the known effects of fasting on adipose tissue lipoprotein lipase activity. In another group of fasted obese, refed with a hypocaloric diet, the relationship returned toward normal. In addition to the impaired triglyceride removal, prolonged fasting resulted in a decrease in triglyceride production. This decrease occurred despite an increase in plasma FFA. After 3–5 wk of fasting the IRI was about 50% of the initial value, while the IRG was the same as the initial value. While triglyceride production fell during fasting, the blood ketone concentration rose. Others have seen similar changes in ketones and triglycerides in livers perfused with medium in which the ratio of insulin to glucagon fell. The rate of triglyceride production was not related to body weight. However, regardless of nutritional state, it was positively related to the basal plasma insulin levels. These data indicate that, in man as in animal preparations, insulin may regulate hepatic triglyceride production.

The effect of continuous heparin infusion for one year on serum cholesterol and triglyceride concentrations in the dog

Fourteen normal dogs received continuous infusions of intravenous heparin for one year by means of an implantable infusion pump. Heparin was admistered at an overall mean rate of 666 units/kg/day, a dose sufficient to prolong the Lee-White clotting time to greater than twice normal. Eight control, animals, under the same dietary and activity regimen, received continuous infusions of bacteriostatic water for one year by means of implanted pumps. Serum cholesterol concentrations rose to 50% above control values after one month of heparin infusion, and remained significantly ( P < 0.05) elevated at this level for the remaining 11 months. Serum triglyceride levels were unchanged. A possible mechanism for this elevation resides in the known effect of heparin to increase plasma free fatty acid concentrations by its activation of lipoprotein lipase. These results may have implications for the long-term use of heparin anticoagulation in the treatment of atherosclerotic states in man.

Mechanism of action of phenethylbiguanide (phenformin) in man. III. Interrelationship between ethanol and phenethylbiguanide (PBG) in normal and diabetic subjects

A standard 4-hr ethanol infusion (236 mg/min) after a 3-day fast with and without phenformin (25 mg q.i.d.), with blood drawn every hour for 8 hr, was performed on five normal subjects, eight obese nondiabetics, seven obese chemical diabetics, and four nonobese diabetics. Control infusion induced in all subjects a decline in blood sugar levels during and/or after the alcohol challenge, with a parallel decrease in basal plasma insulin. Hypoglycemia and the decrease in insulin secretion were associated with increased plasma free fatty acid concentration. Addition of phenethylbiguanide (PBG) to the preparatory 3-day fast resulted in a greater drop in the blood glucose levels of the normal control subjects, obese and nonobese diabetics; in the obese nondiabetics, however, a significantly lower degree of blood glucose decrease than control was elicited. Furthermore, obese nondiabetics altered their blood glucose-insulin interaction with apparent increased responsivess of the B cells to PBG. The results suggest that effects of phenformin on blood glucose levels are more dependent on the metabolic state of the patient than on a property of the drug itself.

A sparing effect of increased plasma fatty acids on muscle and liver glycogen content in the exercising rat

Increasing plasma free fatty acids decreased the degree of glycogen depletion, and increased the citrate concentration, in slow-red (soleus) and fast-red (deep portion of vastus lateralis) muscle during exercise (approx. 50% depletion of glycogen, as against 75% in control animals). There was no effect in fast-white muscle (superficial portion of vastus lateralis). Glycogen concentration in the liver decreased by 83% in controls, but only by 23% in animals with increased free fatty acids during exercise. The decreased glycogen depletion may be partly explained by the findings that (a) plasma-insulin concentration was two- to three-fold higher in animals with increased plasma free fatty acids and (b) the exercise-induced increase in plasma glucagon was lessened by increased free fatty acids. Blood glucose was higher in the animals with increased free fatty acids after the exercise. The rats with increased plasma free fatty acids utilized approx. 50% as much carbohydrate as did the controls during the exercise.

On the lipolytic action of parathyroid hormone in man

An investigation was carried out to determine whether bovine PTH stimulates lipolysis in human fat tissue, whether this action is mediated by cyclic adenosine 3′,5′-monophosphate and whether the N-terminal 1–34 peptide of bovine PTH is responsible for the lipolytic effect. Studies were also performed to determine if parathyroid extract (PTE) produces lipolysis in normal subjects and in patients with pseudohypoparathyroidism in whom there is a defect in the adenylate system in response to PTH in the renal cortex and presumably in the skeletal system as well. It was found that highly purified bovine PTH in the concentration range between 10 −9, M and 10 −5, M stimulated lipolysis in vitro by human fat in a dose-dependent manner. Significant increases in glycerol production were observed at concentrations of PTH as low as 10 −9, M and maximal increases were seen at 10 −6, M. The hormone significantly increased the concentration of cyclic adenosine 3′,5′-monophosphate in fat tissue. The synthetic N-terminal 1–34 peptide of bovine PTH was as effective as the native hormone in stimulating glycerol production at a concentration of 10 −9, M – 10 −6, M. PTE, 100 mU per kg per min for 30 min given intravenously, produced transient increases in the concentration of plasma free fatty acid in each of eight normal subjects, three patients with hypoparathyroidism and eight patients with pseudohypoparathy-roidism. Purified bovine PTH also increased plasma free fatty acid in each of two normal subjects. It is concluded that PTH stimulates lipolysis in human subcutaneous fat, that this action of the hormone is mediated through cyclic adenosine 3′,5′-monophosphate and that the N-terminal 1–34 peptide portion of the hormone is responsible for this lipolytic action. Further, PTE stimulates lipolysis in vivo in man. There appears to be no defect in the adenylate cyclase system in the fat cell in response to PTH in patients with pseudohypoparathyroidism.

Effect of thyroid hormone on metabolic adaptation to fasting

The acute effect of triiodothyronine (T 3) on mobilization of fat and protein energy stores has been measured in five fasting, normal men. Fasting subjects were chosen for this study to amplify catabolic effects occurring during brief thyroid hormone treatment. Subjects were fasted for 72 hr on two occasions with administration of T 3, 150 μg every 12 hr, for 72 hr before and during the second fast. Plasma beta hydroxybutyrate, acetoacetate, and free fatty acid levels as well as ketone, creatine, and urea excretion were measured during control and T 3 fasts. T 3 enhances catabolism of protein stores as indicated by the doubling of urea excretion during the T 3 fasts. Likewise, creatine excretion is increased six to ninefold during the T 3 fasts. Catabolism of fat stores is enhanced during the T 3 fasts as shown by increased plasma free fatty acid and ketone levels, and increased ketone excretion. Brief T 3 treatment for 3 days augments the expected protein and fat catabolism of starvation without causing subjective changes of hyperthyroidism. Much of the catabolic expression of hyperthyroidism may simply reflect inadequate caloric intake to fuel energy requiring processes stimulated by thyroid hormone such as cell membrane sodium pumping and protein synthesis.

Lipid Biosynthesis in the Chick. A Consideration of Site of Synthesis, Influence of Diet and Possible Regulatory Mechanisms

Studies in vitro and with intact chicks support the view that liver is the major site of lipid biosynthesis in the chicken. Adipose tissue is relatively unimportant as a site of fatty acid biosynthesis in this species although it does have the ability to esterify fatty acids to triglycerides. The available evidence, therefore, suggests that in the chicken, and presumably other avian species, fatty acids are synthesized in liver and are transported as triglycerides in the plasma low-density lipoproteins to the adipose tissue for storage.Fasting, even for short periods of time, markedly depresses the capacity for hepatic lipogenesis in the chick. Food restriction for 2 hr. depresses hepatic lipogenesis by about 90% and refeeding for 1 hr.|or|the intravenous administration of glucose or fructose restores the lipogenic capacity. Feeding diets high in fat or protein to chicks also reduces the capacity for hepatic lipogenesis. The effects of dietary fat and protein cannot be adequately explained on the basis of the reduction of dietary carbohydrate which accompanies increased dietary protein or fat levels. Dietary fat and protein appear to exert their effects on hepatic lipid synthesis by different mechanisms.The depression in hepatic fatty acid synthesis brought about by fasting or fat-feeding is accompanied, and probably preceded, by an increased plasma free fatty acid level. Under these conditions hepatic fatty-acyl CoA levels increase while free CoA levels are reduced. Long-chain acyl CoA derivatives are capable of inhibiting acetyl CoA carboxylase activity as well as citrate transport. The reduced availability of free CoA may limit the citrate cleavage reaction.Dietary alterations influence the hepatic lactate-pyruvate ratio of chicks, however the changes observed are not always consistent with the changes observed in rat liver. Chicks fed high-protein diets have a decreased hepatic lactate/pyruvate ratio indicative of a more oxidized cytoplasmic environment. This change in redox state may be associated with control of fatty acid synthesis in chicks fed high-protein diets.Thyroxine and glucagon affect hepatic fatty acid synthesis in the chick, however insulin appears to play a lesser role.

Influence of a Fat-Mobilizing Substance from Geese Urine on Geese and Chickens

A fat-mobilizing substance (FMS) was extracted from the urine of fasting, ad-libitum-fed or over-fed colostomized geese. Injection of these materials into geese and cockerels caused increases in plasma-free fatty acids (FFA).A marked anorexigenic effect was obtained in cockerels only, by the FMS obtained from ad-libitum-fed geese. The daily amount of FMS excreted in the urine was proportional to the amount of feed consumed.

Carbohydrate metabolism in the chronically uremic rat: II. In vivo glucose utilization

The sub-totally nephrectomized chronically uremic rat has been found to have significantly increased hepatic glucose-6-phosphate dehydrogenase activity and increased lipogenesis and glycoportein synthesis. Increased conversion of 14-C-D-glucose to 14-CO2, and increased plasma free fatty acid levels were also observed. The metabolic significance of these findings has been discussed, particularly with respect to the importance of the pentose shunt in this model. The influence of reduced diet intake, resulting from uremic anorexia, has been considered in light of changes observed. It is concluded that decreased food intake alone is unlikely to be responsible for the altered glucose utilization evident in this model.

Plasma Triglyceride Secretion in Squirrel Monkeys: Effects of Nicotine

The acute effects of intravenous nicotine on the appearance of plasma triglycerides have been studied in anaesthetised squirrel monkeys given Triton-WR 1339. At both dose levels studied, 4 and 10 mug/kg/30 sec, nicotine caused a stimulation in the rate of accumulation of plasma glycerides, the larger dose producing the greater effect. Nicotine caused a transient elevation in plasma free fatty acids (FFA), also in proportion to the dose given. It is suggested the changes in plasma glycerides are due to enhanced hepatic secretion secondary to increased plasma FFA. The administration of Triton-WR 1339 caused a rapid and sustained fall in plasma cholesterol concentrations. This fall was similar to that observed in plasma Triton and evidence is presented to suggest that Triton and cholesterol are removed from the circulation by a similar mechanism. There was no effect of nicotine on plasma cholesterol. The implications of the effects of nicotine of plasma triglycerides in relation to coronary heart disease are discussed briefly.

Effect of cortisol on insulin sensitivity of the marsupial brush-tailed opossum, Trichosurus vulpecula (Kerr).

SUMMARY An investigation was made of the interactions between insulin and cortisol on carbohydrate, fat and protein metabolism in the marsupial brush-tailed opossum Trichosurus vulpecula (Kerr). Intravenous injection of 0·15 i.u. regular insulin/kg caused a prompt fall in plasma glucose concentration to 33–54% of the control value, in the first 30 min, with complete recovery within 4 h. This was associated with a slow fall in plasma amino acid concentration and a moderate rise in plasma free fatty acid (FFA) concentration. Plasma cortisol concentration was increased 1·5 h after insulin injection to maximum values of 1·24–4·44 μg/100 ml, which were approximately proportional to the degree of hypoglycaemia. Pretreatment with five daily i.m. injections of 1 mg cortisol acetate/kg caused a marked reduction in insulin sensitivity of three out of four opossums, and increasing the dose to 5 mg/kg caused a similar reduction in insulin sensitivity of the remaining opossum. Cortisol pretreatment raised the control plasma amino acid and FFA concentrations and enhanced the effect of insulin injection on these variables. There was a linear relationship between the control plasma cortisol concentration, within the physiological range, and sensitivity to insulin. It is concluded that, in contrast to the red kangaroo, the interactions between insulin and glucocorticoids in Trichosurus resemble those reported for eutherian mammals. However, the unusual increase in plasma FFA after insulin injection is unexplained.

Effect of somatostatin on blood glucose, plasma growth hormone, insulin, and free fatty acids in normal subjects and acromegalic patients

Synthetic growth-hormone-release inhibitory hormone (GRIH, somatostatin) infused in seven acromegalics significantly lowered plasma growth hormone (GH) and immunoreactive insulin (IRI) levels, did not have any effect on blood glucose, and significantly increased plasma free fatty acids (FFA). Somatostatin, when infused in three normal subjects during an arginine test, inhibited plasma GH and IRI responses. Hypoglycemia-induced GH release was also blocked by somatostatin in two normal subjects thus tested.

Operation of the “Glucose‐Fatty Acid Cycle” during Experimental Elevations of Plasma Free Fatty Acid Levels in Man

Abstract. In order to determine whether increased plasma free fatty acid (FFA) levels inhibit glucose utilization in man, glucose metabolism was studied in 8 normal subjects both under basal conditions and during experimental elevations of plasma FFA concentrations induced by the administration of high fat meals and heparin. A primed constant infusion of 1‐14C‐glucose was used to measure the rate of turnover, the fractional removal rate and the rate of oxidation of plasma glucose under both experimental conditions. Elevations of FFA levels (+117%) were accompanied by a 9% reduction in both the fractional removal rate of glucose and the hepatic glucose production so that glycaemia remained unchanged. The % glucose converted to CO2, and the % CO2 derived from plasma glucose decreased respectively by 13.5% and 21.7%, while unlabelled CO2 production remained unchanged. This reduction in glucose utilization occurred despite a significant rise in insulin concentration indicating that high FFA levels reduce sensitivity to insulin. The tissue implicated in the inhibitory effect of FFA on overall glucose utilization cannot be determined from these experiments but it is suggested that muscle participated in these metabolic changes. These data provide further arguments supporting the view that plasma FFA participate in the regulation of glucose metabolism in man.

Lactate inhibition of lipolysis in exercising man

The role of rising lactate levels on substrate mobilization in exercising man is unclear. To define the role of increasing lactate levels, D,L-sodium lactate, 6 meq/kg, was infused into six exercising normal males. A mild work load was chosen that increased arterial free fatty acids (FFA) and glycerol, but did not increase lactate significantly. Infused sodium bicarbonate and sodium chloride of equal volume and osmolality served as controls. The marked rise in arterial lactate and pyruvate to 8.8 ± 0.31 μM/ml and 0.328 ± 0.023 μM/ml (mean ± SEM), respectively, resulted in a significant inhibition of the increase of plasma FFA and glycerol, which occurred during the control studies. The decreased release of these constituents could not be attributed to an “insulin effect”, since the concentration of arterial insulin decreased during exercise and was similar during each infusion period. It appears that an increase in plasma lactate or pyruvate, or both, results in a direct inhibition of exercise-mediated lipolysis in man.

Operation of the "glucose-fatty acid cycle" during experimental elevations of plasma free fatty acid levels in man.

Abstract. In order to determine whether increased plasma free fatty acid (FFA) levels inhibit glucose utilization in man, glucose metabolism was studied in 8 normal subjects both under basal conditions and during experimental elevations of plasma FFA concentrations induced by the administration of high fat meals and heparin. A primed constant infusion of 1‐14C‐glucose was used to measure the rate of turnover, the fractional removal rate and the rate of oxidation of plasma glucose under both experimental conditions. Elevations of FFA levels (+117%) were accompanied by a 9% reduction in both the fractional removal rate of glucose and the hepatic glucose production so that glycaemia remained unchanged. The % glucose converted to CO2 and the % CO2 derived from plasma glucose decreased respectively by 13.5% and 21.7%, while unlabelled CO2 production remained unchanged. This reduction in glucose utilization occurred despite a significant rise in insulin concentration indicating that high FFA levels reduce sensitivity to insulin. The tissue implicated in the inhibitory effect of FFA on overall glucose utilization cannot be determined from these experiments but it is suggested that muscle participated in these metabolic changes. These data provide further arguments supporting the view that plasma FFA participate in the regulation of glucose metabolism in man.

Influence of glucagon and neurohypophysial hormones on plasma free fatty acid levels in the pigeon

1. 1. The effect of intravenous injections of vasopressin, oxytocin, vasotocin and glucagon on the plasma free fatty acid (FFA) level was studied in the pigeon. 2. 2. The plasma FFA level in pigeons during winter was found to be higher than that in the fall. 3. 3. Vasopressin caused a decline and oxytocin a slight increase in plasma FFA at 15 min post-injection. Vasotocin brought about a highly significant increase at 30 min. Glucagon produced a marked increase in 5 min and when followed by vasotocin, a further increase was obtained. 4. 4. The possible significance of the lipolytic action and lipid mobilization, of oxytocin and vasotocin in bird migration, is discussed in the light of the release of the neurohypophysial neurosecretory material prior to migration reported earlier in two passerine migrants.