Free Fatty Acid Mobilization Research Articles

Metabolic correlates of the circadian pattern of suckling-associated arousal in young rabbits.

Young rabbits (Oryctolagus cuniculus) are only nursed for 3-5 min every 24 h. They show a circadian increase in activity in anticipation of this, which is entrained by suckling. Our aim was to determine whether serum and liver metabolites show diurnal fluctuations which could act to regulate this circadian pattern. Stomach weight, liver glycogen and serum metabolites were measured every 3 h in 7- to 8-day-old pups when normally nursed (up to 24 h after suckling) and fasted (up to 48 h after suckling). The results suggest: 1. Energy balance between feeds was maintained by a cascade in the use of fuels, first glucose from the milk, then glycogen stores and gluconeogenesis from circulating products of proteins and triglycerides, and finally, in late-fasted animals, the mobilization of free fatty acids. 2. The empty stomach and depletion of glycogen 23-24 h after the last feed could act to trigger anticipatory arousal in normally nursed pups, and the release of free fatty acids 45 48 h after the last feed could trigger this in fasted pups. 3. Unmasking of rhythmicity by fasting in serum levels of glucose and proteins suggests their regulation by endogenous oscillators, which may also be the case for the mobilization of free fatty acids.

Neuroendocrine perturbations as a cause of insulin resistance.

Insulin resistance is followed by several prevalent diseases. The most common condition with insulin resistance is obesity, particularly when localized to abdominal, visceral regions. A summary of recent reviews on the pathogenesis of systemic insulin resistance indicates that major factors are decreased insulin effects on muscular glycogen synthase or preceding steps in the insulin signalling cascade, on endogenous glucose production and on circulating free fatty acids (FFA) from adipose tissue lipolysis. Contributions of morphologic changes in muscle and other factors are considered more uncertain. Newly developed methodology has made it possible to determine more precisely the neuroendocrine abnormalities in abdominal obesity including increased cortisol and adrenal androgen secretions. This is probably due to a hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, amplified by inefficient feedback inhibition by central glucocorticoid receptors, associated with molecular genetic defects. Secondly, secretion of gender-specific sex steroid hormones becomes inhibited and the sympathetic nervous system activated. At this stage the HPA axis shows signs of a 'burned-out' condition, and cortisol secretion is no longer elevated. Cortisol counteracts the insulin activation of glycogen synthase in muscle, the insulin inhibition of hepatic glucose production and the insulin inhibition of lipolysis in adipose tissue, leading to the well-established systemic insulin resistance caused by excess cortisol. This is exaggerated by increased free fatty acid mobilization, particularly with a concomitant elevation of the activity of the sympathetic nervous system. Furthermore, capillarization and fiber composition in muscle are changed. These are the identical perturbations responsible for insulin resistance in recent reviews. The diminished sex steroid secretion in abdominal obesity has the same consequences. It is thus clear that insulin resistance may be induced by neuroendocrine abnormalities, such as those seen in abdominal obesity. These endocrine perturbations also direct excess fat to visceral fat depots via mechanisms that are largely known, indicating why abdominal obesity is commonly associated with insulin resistance. This possible background to the most prevalent condition of insulin resistance has been revealed by development of methodology that allows sufficiently sensitive measurements of HPA axis activity. These findings demonstrate the power of neuroendocrine regulations for somatic health.

Enhanced thermogenesis in rats by a composite Indian herbal preparation-I and its mechanism of action.

A composite Indian herbal preparation-I (CIHP-I) containing ingredients derived from 7 different plants and asphalt was tested for its adaptogenic activity and its mechanism of action was investigated. CIHP-I was tested using the cold-hypoxia-restraint (C-H-R) animal model in which the restrained rats were exposed to 5 degrees C at 428 mm Hg atmospheric pressure. Rectal temperature (Trec) of the rats was continuously monitored during the exposure and the recovery periods. The time for fall of Trec to 23 degrees C and its recovery to 37 degrees C were used as indices of endurance and the adaptogenic activity. Carbohydrate and lipid parameters were investigated to find out the nature of fuel being used during thermogenesis. After 12 weeks of administration of an oral dose of 7.5 mg/kg(-1)/day(-1), CIHP-I was found to possess significant adaptogenic activity. CIHP-I helped improve resistance to C-H-R induced hypothermia (Trec 23 degrees C) in animals by increased mobilization of free fatty acids (FFA) from adipose tissue. Blood glucose and muscle glycogen levels were maintained. CIHP-I treatment restricted the release of creatine phosphokinase (CPK) into the circulation during C-H-R exposure. The results suggested that CIHP-I is a strong adaptogen. It improved cold resistance during C-H-R exposure and enhanced recovery from hypothermia. The energy-dependent cell membrane permeability was maintained. Stored lipids were mobilised and possibly used for thermogenesis in preference to carbohydrates.

The medial preoptic area modulates the increase in plasma glucose and free fatty acid mobilization induced by acute cold exposure

The effect of cold exposure (0°C, 1 h) on free fatty acid (FFA) mobilization and plasma glucose was studied in freely moving male rats injected with adrenergic blockers (phentolamine or propranolol) into the medial preoptic area (MPOA). The rats were implanted with chronic jugular catheters for blood sampling and with unilateral intracerebral cannulas placed just above the MPOA. Blood samples were taken 2 min before and 10, 20, 40 and 60 min after cold exposure. After cold exposure plasma glucose and plasma FFA levels rose rapidly, reaching a peak at 20 min post-stimulus. Previous administration of phentolamine (50 nmol), but not propranolol (100 nmol), into the MPOA blocked the glycemic response to cold exposure. On the other hand, previous administration of propranolol, but not phentolamine, into the MPOA blocked the increased FFA mobilization in response to cold exposure. On the basis of these results, we propose that MPOA α-adrenergic synapses relay impulses activating the sympathetic outflow expressed by neurally mediated hyperglycemia, and β-adrenergic synapses relay impulses activating the sympathetic outflow to the adipose tissue, increasing FFA acid mobilization.

Interaction of rat hormone-sensitive lipase with adipocyte lipid-binding protein.

Hormone-sensitive lipase (HSL) is a cytosolic neutral lipase that functions as the rate-limiting enzyme for the mobilization of free fatty acids in adipose tissue. By using the yeast two-hybrid system to examine the potential interaction of HSL with other cellular proteins, evidence is provided to demonstrate a direct interaction of HSL with adipocyte lipid-binding protein (ALBP), a member of the family of intracellular lipid-binding proteins that binds fatty acids, retinoids, and other hydrophobic ligands. The interaction was demonstrated in vitro by the binding of ALBP to HSL translated in vitro, to HSL in extracts of HSL overexpressing Chinese hamster ovary (CHO) cells, and to HSL in extracts of rat adipose tissue. Finally, the presence of ALBP was documented in immune complexes from rat adipose tissue immunoprecipitated with anti-HSL antibodies. The HSL-ALBP interaction was mapped to an N-terminal 300-aa region of HSL that is distinct from the C-terminal catalytic domain. These results suggest that HSL-derived fatty acids are bound by ALBP to facilitate intracellular trafficking of hydrophobic lipids.

Lipid metabolism during exercise.

Fat is an extremely important substrate for muscle contraction, both at rest and during exercise. Triglycerides (TGs), stored in adipose tissue and within muscle fibres, are considered to be the main source of the free fatty acids (FFAs) oxidised during exercise. It is still unclear, however, how the use of these substrates is regulated during exercise. The regulation seems to be multifactorial and includes: (i) dietary and nutritional status; (ii) hormonal milieu; (iii) exercise mode, intensity and duration; and (iv) training status. On the other hand, the mechanism for FFA transport from its storage as triglycerides in adipose tissue and muscle to its place of utilisation in heart, skeletal muscle, kidney and liver is more clearly understood. It has been determined that the plasma FFA turnover rate is sufficiently rapid to account for most of the fat metabolised during low intensity exercise (25 to 40% VO2max). However, an exercise intensity of 65% VO2max results in a slight decrease in the amount of plasma FFA uptake by muscle tissue. Other studies have found that during prolonged exercise, muscle TGs become the predominant source of energy obtained from fat. Furthermore, it is widely documented that endurance activities increase the energy utilisation from fat while sparing carbohydrate sources. For example, during exercise on a cycle ergometer, nonplasma FFAs and plasma FFAs contribute 40%, and carbohydrates 60%, of the total calculated amount of energy expenditure before exercise and vice versa after exercise (60% nonplasma and plasma FFAs and 40% carbohydrates). Although it was many years before it was fully demonstrated, fat is now known to be transported in the blood as FFA bound to the protein carrier albumin. The mobilisation of FFA is primarily a function of sympathetic nervous activity directed towards the adipocytes, or the 'fat pad'. This nervous activity can be direct or may be an effect of circulating catecholamines such as adrenaline (epinephrine). This article summarises the role of fat metabolism during exercise.

The influence of polychlorinated biphenyl 126 on tilapia (Oreochromis mossambicus) liver

Tilapia ( Oreochromis mossambicus) of both sexes were fed a diet containing polychlorinated biphenyl (PCB) 126 (50 μg kg −1 fish day −1) for 5 days to investigate whether a short-term exposure influences liver histology or lipid and glucose metabolism. Semiquantiative electron microscopical analysis confirmed gender-related differences in hepatocyte ultrastructure in sham-treated tilapia as described previously for other fish species. In hepatocytes from males, the amount of glycogen deposits was much larger than in females, as was the number of lipid droplets. Hepatocytes of females had larger amounts of perinuclear rough and smooth endoplasmic reticulum and larger lipid droplets. The treatment led to PCB accumulation in livers of exposed fish to levels previously reported for livers of fish caught from polluted areas. Concurrently, the amount of rough and smooth endoplasmic reticulum and the number of lysosomes increased in the livers of tilapia of both sexes. The cytoplasm became more diffuse and the glycogen space was reduced. In female tilapia lipid droplets increased in number but became smaller in size, while lipid droplets in hepatocytes of males were unaffected. Quantitative light microscopical morphometric analysis of liver sections revealed an increase in cell area after PCB treatment in females only. In males and females a decrease in nuclear area was observed. Because (a) the histological changes observed were moderate and not of an overt pathologic nature, and (b) no changes in basal plasma glucose and free fatty acid levels were observed, it is concluded that the stress-free administration of PCB led to a new equilibrium between mobilisation and tissue uptake of glucose and free fatty acids.

Clinical Relevance of Pharmacokinetic Differences Between Beta Blockers

Fundamental differences in the pharmacodynamic and pharmacokinetic profiles of β-adrenergic blocking agents must be considered in optimizing their efficacy and determining the appropriate selection of these drugs in different patients. Beta blockers are contraindicated in patients with asthma and should be used cautiously in heart failure. Clinically important distinctions are related to whether a β blocker is β 1-selective or nonselective. Most adverse effects of β-blocker use are related to interference with β 2-mediated functions including bronchodilation, vasodilation, and mobilization of free fatty acids. To achieve the potential benefits of β 1 blockade (decreased heart rate, blood pressure, cardiac workload, and excitability), a low plasma concentration of a β 1-selective drug is required. Adverse effects of β blockers can be further decreased by selecting a sustained-release β 1-selective drug. Beta blockers are further differentiated on the basis of lipophilicity or hydrophilicity. Lipophilic β blockers cross the blood-brain barrier, whereas hydrophilic agents do not enter the central nervous system. Some lipophilic agents (metroprolol, timolol, and propanolol) have been shown to decrease mortality in coronary heart disease, particularly sudden cardiac death.

Sex differences in visceral fat lipolysis and metabolic complications of obesity.

Cardiovascular complications of obesity are more common in men than women. Sex differences in visceral fat lipolysis may be of importance in this respect, since increased release of free fatty acids (FFAs) from visceral fat to the liver by the portal venous system has been thought to cause several metabolic complications due to obesity, such as hypertension, hyperlipidemia, and glucose intolerance. The aim of this study was to investigate sex differences in clinical characteristics and visceral fat mobilization in obesity. Obese subjects (22 male and 23 female) undergoing elective surgery were matched for body mass index and age. The males had both higher waist-to-hip ratio (WHR), sagittal diameter, blood pressure, fat-cell volume, plasma insulin, glucose, and triglyceride and lower HDL cholesterol levels than the females. The rate of norepinephrine-induced FFA and glycerol release was twofold higher in men (P = .02). No significant reutilization of FFA was observed. The difference in maximum norepinephrine-induced rate of lipolysis between men and women was independent of both WHR and sagittal diameter and was an independent regressor for levels of plasma glucose and plasma HDL cholesterol. Fat-cell volume was an independent regressor for plasma triglycerides and blood pressure. No sex differences in the lipolytic sensitivity to beta 1- or beta 2-adrenoceptor-specific agonists or in the antilipolytic effect of insulin were observed. However, the lipolytic beta 3-adrenoceptor sensitivity was 12 times higher (P = .004) and the antilipolytic alpha 2-adrenoceptor sensitivity 17 times lower (P = .003) in men. Furthermore, lipolysis induced by agents acting at the adenylate cyclase and protein kinase A levels were almost twofold enhanced in men. However, no sex difference in maximum hormone-sensitive lipase activity was observed. In conclusion, in obesity, catecholamine-induced rate of FFA mobilization from visceral fat to the portal venous system is higher in men than women. This phenomenon is partly due to a larger fat-cell volume but also to a decrease in the function of alpha 2-adrenoceptors, an increase in the function of beta 3-adrenoceptors, and an increased ability of cyclic AMP to activate hormone-sensitive lipase. These factors may contribute to gender-specific differences in metabolic and cardiovascular disturbances accompanied by obesity.

Biological Changes Induced by Physical Activity in Individuals with Down’s Syndrome

The effects of exercise and of a physical conditioning program on 11 subjects (7 males, 4 females, aged 15 to 20) with Down’s syndrome (DS) were analyzed. Metabolic responses were evaluated before and after two ergometric cycle exercise tests: an incremental exercise to symptom limited VO2 max. and an endurance test performed at 60% of maximal aerobic power. Plasma substrates, electrolytes, catecholamines, lipoprotein lipid profiles, and superoxide dismutase were assayed immediately before and after these tests. The results indicated (a) a low blood lactate level for peak exercise, (b) slow free fatty acid mobilization at the start of exercise, (c) a low level of cholesterol HDL and a high level of pre-beta VLDL at rest, (d) adjustment to nearly normal lipid profiles with endurance activity, and (e) differences between before and after training for superoxide dismutase levels in subjects with DS. These results suggest that endurance training could have long-term effects on the pathophysiological consequences of DS.

The effect of substrate utilization, manipulated by nicotinic acid, on excess postexercise oxygen consumption.

Increased fat oxidation during the recovery period from exercise is thought to be a contributing factor for excess postexercise oxygen consumption (EPOC). In an attempt to study the effect of serum free fatty acid (FFA) availability during exercise and recovery on the EPOC, nicotinic acid, a potent inhibitor of FFA mobilization from adipose tissue, was administered to five trained male cyclists prior to, during, and after a bout of cycling at 65% VO2max. In the nicotinic acid trial, a 500 mg dose of nicotinic acid was ingested prior to exercise, and 100 mg doses were ingested at 15, 30, and 45 min exercise, and 30 min recovery. The cyclists also completed a trial under control conditions. Serum FFA, serum glycerol, RER and VO2 were monitored during rest, exercise, and recovery, each of which was 1-h in duration. Nicotinic acid ingestion prevented the increase in serum FFA that occurred during exercise in the control trial. FFA levels during the nicotinic acid trial were significantly lower than control values during both exercise and recovery. Serum glycerol levels were also significantly lower during exercise in the nicotinic acid trial, indicative of a reduction in lipolysis. RER was not significantly different at rest or during exercise; however, RER values were significantly lower during recovery in the control trial, indicative of greater fat oxidation. For both treatments, postexercise VO2 remained elevated above resting levels at the completion of the 1-h recovery period. However, the magnitude of EPOC was significantly reduced after FFA blockade with nicotinic acid (3.4 +/- 0.61 vs 5.5 +/- 0.71). These results support the hypothesis that increased FFA metabolism during exercise and recovery is an important contributing factor to the magnitude of EPOC.

Blood ketone bodies in congestive heart failure

Objectives. The present study was designed to assess whether blood ketone bodies are elevated in congestive heart failure (CHF) and whether ketonemia is related to the hemodynamic and neurohumoral abnormalities of CHF.Background. In CHF, consumption of the body's fat stores may become abnormally high, contributing to the development of cardiac cachexia. Increased mobilization of free fatty acids could, in theory, augment ketogenesis, but whether patients with CHF are prone to ketosis remains unknown.Methods. Forty-five patients with chronic CHF (mean age [±SD] 57 ± 13 years) and 14 control subjects free of CHF (mean age 53 ± 13 years) underwent invasive and noninvasive cardiac studies and determination of blood ketone bodies (acetoacetate plus beta-hydroxybutyrate), circulating free fatty acids, glucose, lactate, insulin, glucagon, growth hormone, cortisol, norepinephrine, N-terminal proatrial natriuretic peptide, tumor necrosis factor-alpha and interleukin-6 after an overnight fast.Results. Patients with CHF had elevated blood ketone bodies (median 267 μmol/liter, range 44 to 952) compared with control subjects (median 150 μmol/liter, range 31 to 299, p < 0.05). In the total study group, blood ketone bodies were related to pulmonary artery wedge pressure (rs = 0.45, p < 0.001), left ventricular ejection fraction (rs = −0.37, p < 0.01), right atrial pressure (rs = 0.36, p < 0.01) and circulating concentrations of free fatty acids (rs = 0.52, p < 0.001), glucose (rs = −0.39, p < 0.01), norepinephrine (rs = 0.45, p < 0.001), growth hormone (rs = 0.30, p < 0.05) and interleukin-6 (rs = 0.27, p < 0.05). In multivariate analysis, left ventricular ejection fraction, serum free fatty acids and serum glucose were independent predictors of ketonemia.Conclusions. Blood ketone bodies are elevated in CHF in proportion to the severity of cardiac dysfunction and neurohormonal activation. This may be at least partly attributable to increased free fatty acid mobilization in response to augmented neurohormonal stimulation. Additional studies are needed to identify the detailed mechanisms and clinical implications of CHF ketosis.

Participation of the autonomic nervous system in lipolysis induced by intraventricular injection of carbachol in the pigeon

The possible involvement of central cholinergic neurotransmission in lipomobilization in avian species was investigated by injecting carbachol into the brain lateral ventricle (ICV) of conscious pigeons (N = 9 per experimental group). ICV injections of carbachol (27 nmol in 1 μl) induced an intense increase (nearly 91% above baseline levels) in the concentration of plasma free fatty acids (FFA). Previous intraperitoneal administration of hexamethonium (10 mg/kg) completely blocked the lipomobilizing effect of ICV injections of carbachol. These results suggest that cholinergic neurons may be involved in central mechanisms controlling FFA mobilization in pigeons, and that this response is mainly mediated by activation of autonomic nervous system.

The nervous system and the endocrine pancreas: A 35-year odyssey

While training in 1989 with Richard Have1 in San Francisco, I became interested in his studies of the role of the sympathetic nervous system in the regulation of free fatty acid (FFA) mobilization from adipose tissue.’ Therefore, when I arrived at the laboratory of Robert H. Williams as a postdoctoral endocrine fellow in 1963, I chose to study the effects of catecholamines on carbohydrate and lipid metabolism. To evaluate these effects, Alan Graber and I gave prolonged infusion of epinephrine to a male subject. We found that FAA levels rose and then returned to basal values despite continued administration of the amine. Since hyperglycemia and tachycardia persisted, we concluded that reesterification of FFA in adipose tissue or inhibition of lipolysis by insulin might be involved. To determine which mechanism was most likely, we asked Takashi Kuzuya (now at Jichi Medical School, Japan), another postdoctoral fellow, to assay the plasma samples from our catecholamine infusions for insulin using the newly developed radioimmunoassay. To our surprise, insulin levels did not change during the epinephrine infusions but rose dramatically upon their termina

Relationship between fatty acid delivery and fatty acid oxidation during strenuous exercise.

To evaluate the extent to which decreased plasma free fatty acid (FFA) concentration contributes to the relatively low rates of fat oxidation during high-intensity exercise, we studied FFA metabolism in six endurance-trained cyclists during 20-30 min of exercise [85% of maximal O2 uptake (VO2max)]. They were studied on two occasions: once during a control trial when plasma FFA concentration is normally low and again when plasma FFA concentration was maintained between 1 and 2 mM by intravenous infusion of lipid (Intralipid) and heparin. During the 20-30 min of exercise, fat and carbohydrate oxidation were measured by indirect calorimetry, and the rates of appearance (Ra) of plasma FFA and glucose were determined by the constant infusion of [6,6-2H2]glucose and [2H2]palmitate. Lipid-heparin infusion did not influence the Ra or rate of disappearance of glucose. During exercise in the control trial, Ra FFA failed to increase above resting levels (11.0 +/- 1.2 and 12.4 +/- 1.7 mumol.kg-1.min-1 for rest and exercise, respectively) and plasma FFA concentration dropped from a resting value of 0.53 +/- 0.08 to 0.29 +/- 0.02 mM. The restoration of plasma FFA concentration resulted in a 27% increase in total fat oxidation (26.7 +/- 2.6 vs. 34.0 +/- 4.4 mumol.kg-1.min-1, P < 0.05) with a concomitant reduction in carbohydrate oxidation, apparently due to a 15% (P < 0.05) reduction in muscle glycogen utilization. However, the elevation of plasma FFA concentration during exercise at 85% VO2max only partially restored fat oxidation compared with the levels observed during exercise at 65% VO2max. These findings indicate that fat oxidation is normally impaired during exercise at 85% VO2max because of the failure of FFA mobilization to increase above resting levels, but this explains only part of the decline in fat oxidation when exercise intensity is increased from 65 to 85% VO2max.

Currently available hypolipidaemic drugs and future therapeutic developments

Dyslipidaemia may be treated with a number of safe and effective pharmacological agents that target specific lipid disorders through a variety of mechanisms. The bile-acid sequestrants--cholestyramine and colestipol--primarily decrease LDL cholesterol by binding bile acids, thereby decreasing intrahepatic cholesterol, and by increasing the activity of LDL receptors. Nicotinic acid lowers LDL cholesterol and triglyceride by decreasing VLDL synthesis and by decreasing free fatty acid mobilization from peripheral adipocytes. The HMG-CoA reductase inhibitors--fluvastatin, lovastatin, pravastatin and simvastatin--lower LDL cholesterol by partially inhibiting HMG-CoA reductase (the rate-limiting enzyme of cholesterol biosynthesis) and by increasing the activity of LDL receptors. The fibric-acid derivatives--bezafibrate, ciprofibrate, clofibrate, fenofibrate and gemfibrozil--primarily decrease triglyceride by increasing lipoprotein lipase activity and by decreasing the release of free fatty acids from peripheral adipose tissue. Probucol decreases LDL cholesterol by increasing non-receptor-mediated LDL clearance; as an anti-oxidant, probucol also decreases LDL oxidation; oxidized LDL which is thought to lead to atherogenesis. Although these agents have been proven safe in clinical trials, like any drug, they carry the risk for adverse effects. The bile-acid sequestrants may cause constipation, reflux oesophagitis, and dyspepsia, and may bind coadministered medications such as digitalis glycosides, beta blockers, warfarin, and exogenous thyroid hormone. Nicotinic acid use is commonly associated with flushing and pruritus and may also cause non-specific gastrointestinal complaints, hepatotoxicity (hepatic necrosis, hepatitis, or elevated liver enzymes), gout, myolysis, decreased glucose tolerance and increased fasting glucose levels, and ophthalmological complications including decreased visual acuity, toxic amblyopia, and cystic maculopathy. The HMG-CoA reductase inhibitors may produce liver enzyme elevations, creatine kinase elevations and rhabdomyolysis. The combination of a reductase inhibitor and a fibrate increases the risk for rhabdomyolysis. Possible adverse effects of the fibric-acid derivatives include abdominal discomfort, nausea, flatulence, increased lithogenicity of bile, liver enzyme elevations and creatine kinase elevations. Probucol may increase the QTc interval and may cause non-specific gastrointestinal complaints.

Thyroid status and exercise tolerance. Cardiovascular and metabolic considerations.

Both hypo- and hyperthyroidism are characterised by exercise intolerance. In hypothyroidism, inadequate cardiovascular support appears to be the principal factor involved. Insufficient skeletal muscle blood flow compromises exercise capacity via reduced oxygen delivery, and endurance through decreased delivery of blood-borne substrates. The latter effect results in increased dependence on intramuscular glycogen. Additionally, decreased mobilisation of free fatty acids from adipose tissue and, consequently, lower plasma free fatty acid levels compound the problem of reduced lipid delivery to active skeletal muscle in the hypothyroid state. In contrast, cardiovascular support is enhanced in hyperthyroidism, implicating other factors in exercise tolerance. Greater reliance on muscle glycogen appears to be the primary reason for decreased endurance. Biochemical changes with hyperthyroidism that would favour enhanced flux through glycolysis may account for this dependence on glycogen. Deviations from normal thyroid function, and the ensuing exercise tolerance, require appropriate medical therapy to attain euthyroid status.

Mobilization of free fatty acids is a function of fat mass

Mobilization of free fatty acids is a function of fat mass

A pathogenic role of visceral fat beta 3-adrenoceptors in obesity.

Increased release of free fatty acids (FFA) from visceral fat cells to the portal venous system may cause several metabolic disturbances in obesity. However, this hypothesis and the underlying mechanism remain to be demonstrated. In this study catecholamine-induced lipid mobilization through lipolysis in omental adipose tissue was investigated in vitro in 25 markedly obese subjects (body mass index range 35-56 kg/m2) undergoing weight reduction surgery and in 19 nonobese subjects (body mass index range 20-28 kg/m2) undergoing cholecystectomy. Release of FFA and glycerol, induced by norepinephrine or adrenergic receptor subtype-specific agonists, were determined in isolated omental fat cells. The obese subjects had higher fat cell volume, blood pressure, plasma insulin levels, blood glucose, plasma triglycerides, and plasma cholesterol than the controls. There was evidence of upper-body fat distribution in the obese group. The rate of FFA and glycerol response to norepinephrine was increased twofold in the cells of obese subjects; no significant reutilization of FFA during catecholamine-induced lipolysis was observed in any of the groups (glycerol/FFA ratio near 1:3). There were no differences in the lipolytic sensitivity to beta 3- or beta 2-adrenoceptor specific agonists between the two groups. However, beta 3-adrenoceptor sensitivity was approximately 50 times enhanced (P = 0.0001), and the coupling efficiency of these receptors was increased from 37 to 56% (P = 0.01) in obesity. Furthermore, the obese subjects demonstrated a sixfold lower alpha 2-adrenoceptor sensitivity (P = 0.04). beta 3-Adrenoceptor sensitivity, but not alpha 2-, beta 1-, or beta 2-adrenoceptor sensitivity, correlated with norepinephrine-induced lipolysis (r = -0.67, P = 0.0001) and fat cell volume (r = -0.71, P = 0.0001). In conclusion, catecholamine-induced rate of FFA mobilization from omental fat cells is accelerated due to elevated rate of lipolysis in obesity, mainly because of an increased beta 3-adrenoceptor function, but partly also because of a decreased alpha 2-adrenoceptor function. This promotes an increased release of FFA to the portal system, which may contribute to the parallel metabolic disturbances observed in upper-body obesity.

Fatty acids, hyperinsulinemia, and insulin resistance: which comes first?

The inhibiting effect of insulin on the mobilization of free fatty acids (FFA) from adipose tissue is halted in prevalent conditions with systemic insulin resistance. The nature and cause of this perturbation are unknown, but steroid hormones may be involved. The consequence is the creation or amplification of insulin resistance in muscle and liver.