Contribution of triglyceride-rich lipoproteins to plasma free fatty acids.

Free fatty acids are the major lipid fuel of the body. Dysregulation of adipose tissue lipolysis results in increased plasma free fatty acid concentrations, and via that mechanism contributes to insulin resistance in obesity and type 2 diabetes mellitus. Adipose tissue hormone sensitive lipase is thought to be responsible for the production of the majority of free fatty acids. However, a separate contribution comes from the action of endothelial lipases, especially lipoprotein lipase, on triglyceride-rich lipoproteins via a process known as spillover. The primary substrate for spillover appears to be chylomicrons derived from dietary fat. The spillover of fatty acids into the free fatty acid pool varies from one tissue to another. For example, spillover is low ( approximately 14%) in the forearm of healthy volunteers, suggesting that triglyceride fatty acid storage is relatively efficient in skeletal muscle. In contrast, spillover appears to be higher in adipose tissue and may also be higher in the splanchnic bed, based on preliminary data. If systemic spillover is increased in insulin resistant states such as diabetes, this could represent a mechanism contributing to the abnormal increases in plasma concentrations of free fatty acids in that condition.

Norepinephrine spillover from human adipose tissue before and after a 72-hour fast.

Adipose tissue lipolysis is at least in part stimulated by the sympathetic nervous system (SNS). Although there is a generalized decrease in SNS activity with fasting, the rate of lipolysis during fasting increases. The aim of this study was to determine whether there is an association between activation of sympathetic nerves innervating adipose tissue and the increase in lipolysis seen during fasting in humans. We used the isotope dilution technique to measure regional norepinephrine spillover from abdominal sc adipose tissue from seven healthy subjects before and after a 72-h fast. Our results showed a significant increase in adipose tissue spillover of norepinephrine (mean +/- SEM, 0.40 +/- 0.09 vs. 1.08 +/- 0.18 pmol.100 g(-1).min(-1), P < 0.05) and arterial norepinephrine concentrations (0.92 +/- 0.10 vs. 1.23 +/- 0.08 nmol.liter(-1), P < 0.05) after the fast with no significant change in total body norepinephrine spillover, forearm norepinephrine spillover, epinephrine concentrations, or energy expenditure. We show for the first time, in humans, a selective regional increase in adipose tissue norepinephrine spillover in response to a 72-h fast and suggest that the SNS may play a greater role in the regulation of lipid metabolism during fasting than previously thought.

Measurement of human chylomicron triglyceride clearance with a labeled commercial lipid emulsion.

Human chylomicron triglyceride (TG) kinetics has been difficult to determine directly owing to technical limitations. This report describes a new method for studying chylomicron metabolism. Healthy volunteers (n = 10) sipped a drink providing 175 mg fat x kg(-1) h(-1) for 7.5 h to produce a steady-state chylomicronemia. A commercial 10% intravenous lipid emulsion was labeled with [3H]triolein, purified by high-performance liquid chromatography, and sterilized. A trace amount of labeled emulsion was injected intravenously 30 min before (i.e., in the fasting state) and 5, 6, and 7 h after sipping began (i.e., triplicate determinations in the fed state). Chylomicron half-lives were calculated from the monoexponential decay curves, and apparent distribution volumes were estimated by back-extrapolation to time zero. Plasma and estimated chylomicron TG concentrations increased from 89+/-13 and 0.8+/-0.3 to 263+/-43 and 91+/-39 mg/dL (mean +/- SEM), respectively, with feeding. Tracer-determined chylomicron TG half-lives were 5.34+/-0.58 and 6.51+/-0.58 min during the fasting and fed states, respectively (P < 0.01). The apparent distribution volume during the fasting state was 24% greater than plasma volume (4515+/-308 vs. 3630+/-78 mL, P < 0.02), consistent with significant margination of lipid emulsion particles to endothelial binding sites. Margination was reduced during the fed state, suggesting that native chylomicrons competed with lipid emulsion particles for endothelial lipoprotein lipase. The results indicate that a radiolabeled commercial lipid emulsion is metabolized in a fashion similar to native chylomicron TG, and thus can be used to study chylomicron TG kinetics.

A new method for the study of chylomicron kinetics in vivo.

Our understanding of the metabolism of chylomicrons, the lipoprotein that transports dietary fat from the intestine to peripheral tissues, is incomplete. The present studies were conducted to determine whether a labeled intravenous lipid emulsion could be used to estimate chylomicron triglyceride (TG) rate of appearance (R(a)) and thereby quantify the rate of intestinal fat absorption. After an overnight fast, healthy volunteers (n = 6) sipped a (3)H-labeled drink over 6.5 h at a rate of 175 mg fat. kg(-1). h(-1). Beginning at hour 5, an HPLC-purified, (14)C-labeled lipid emulsion was infused intravenously for 90 min. During the study, plasma total and chylomicron TG concentrations increased from 100 +/- 21 to 237 +/- 40 mg/dl and from undetectable to steady-state levels of 35 +/- 13 mg/dl, respectively. After a minor correction for VLDL contamination, tracer-determined chylomicron TG R(a) was 175 +/- 30 mg. kg(-1). h(-1), equal to the presumed ingestion rate. In summary, a radiolabeled intravenous lipid emulsion is able to accurately estimate chylomicron TG R(a) and therefore can be used to measure in vivo fat absorption rates.

Disseminated aspergillosis involving the brain: distribution and imaging characteristics.

BACKGROUND AND PURPOSE: Systemic invasive aspergillosis involves the brain through hematogenous dissemination. A retrospective review of 18 patients with aspergillosis involving the brain was performed in order to present imaging findings and thereby broaden the understanding of the distribution and imaging characteristics of brain Aspergillus infection and to facilitate its early diagnosis. METHODS: The neuroimaging studies of 17 biopsy- or autopsy-proved cases and one clinically diagnosed case were examined retrospectively by two neuroradiologists. The studies were evaluated for anatomic distribution of lesions, signal characteristics of lesions, enhancement, hemorrhage, and progression on serial studies (when performed). Medical records, biopsy reports, and autopsy findings were reviewed. RESULTS: Thirteen of 18 patients had involvement of the basal nuclei and/or thalami. Nine of the 10 patients with lesions at the corticomedullary junction also had lesions in the basal nuclei or thalami. Callosal lesions were seen in seven patients. Progression of lesion number and size was seen in all 11 patients in whom serial studies had been performed. Enhancement was minimal or absent in most cases. There was gross hemorrhage in eight of the 18, and definite ring-enhancement in three. CONCLUSION: Among our cases, lesions in perforating artery territories were more common than those at the corticomedullary junction. Ring enhancement and gross hemorrhage may be present, but are not necessary for the prospective diagnosis.

Norepinephrine spillover in forearm and subcutaneous adipose tissue before and after eating.

The sympathetic nervous system regulates lipolysis. There are regional differences in the sensitivity of lipolysis to adrenergic regulation. Little is known about regional sympathetic activity in response to eating in humans. We studied the effect of feeding on systemic and local sympathetic nervous system activity and lipolysis in lean healthy subjects (three women and five men; age, 27.0+/-2.0; body mass index, 23.4+/-1.2 kg/m(-2)) using isotope dilution methodology and arterio-venous sampling. Feeding increased arterial norepinephrine (NE) concentration (mean premeal, 0.96+/-0.12 nmol/L x L; mean postmeal, 1.28+/-0.14 nmol/L x L; P < 0.02) and total body NE spillover (mean premeal, 2.11+/-0.30 nmol/min x L; mean postmeal, 2.76+/-0.31 nmol/min x L; P < 0.02), whereas the arterial epinephrine concentration decreased (mean premeal, 289+/-61 pmol/L; mean postmeal, 170+/-5 pmol/L; P < 0.02). Palmitate concentration and total body systemic rate of appearance of palmitate declined postprandially (mean premeal, 117 +/- 15 micromol/min; mean postmeal, 38+/-4 micromol/min; P < 0.01). NE spillover increased by the same proportion in both forearm and adipose tissue [in forearm, mean premeal and postmeal, 1.02+/-0.11 and 2.41+/-0.44. nmol/100 mL x min, respectively (P < 0.02); in adipose tissue, mean premeal and postmeal, 0.41+/-0.12 and 0.73+/-0.17 nmol/100 g x min, respectively (P < 0.02)]. The results show that a meal caused differential changes in systemic sympatho-adrenal activity and an increase in sympathetic activity in adipose tissue postprandially, However, this increase in postprandial sympathetic activity was not enough to overcome the inhibition of lipolysis by insulin.

Sources and physiological significance of plasma dopamine sulfate.

Dopamine in the circulation occurs mainly as dopamine sulfate, the sources and physiological significance of which have been obscure. In this study, plasma concentrations of dopamine sulfate were measured after a meal, after fasting for 4 days, and during i.v. L-DOPA, nitroprusside, or trimethaphan infusion in volunteers; after dopamine infusion in patients with L-aromatic-amino-acid decarboxylase deficiency; in arterial and portal venous plasma of gastrointestinal surgery patients; and in patients with sympathetic neurocirculatory failure. Meal ingestion increased plasma dopamine sulfate by more than 50-fold; however, prolonged fasting decreased plasma dopamine sulfate only slightly. L-DOPA infusion produced much larger increments in dopamine sulfate than in dopamine; the other drugs were without effect. Patients with L-aromatic amino acid decarboxylase deficiency had decreased dopamine sulfate levels, and patients with sympathetic neurocirculatory failure had normal levels. Decarboxylase-deficient patients undergoing dopamine infusion had a dopamine sulfate/dopamine ratio about 25 times less than that at baseline in volunteers. Surgery patients had large arterial-portal venous increments in plasma concentrations of dopamine sulfate, so that mesenteric dopamine sulfate production accounted for most of urinary dopamine sulfate excretion, a finding consistent with the localization of the dopamine sulfoconjugating enzyme to gastrointestinal tissues. The results indicate that plasma dopamine sulfate derives mainly from sulfoconjugation of dopamine synthesized from L-DOPA in the gastrointestinal tract. Both dietary and endogenous determinants affect plasma dopamine sulfate. The findings suggest an enzymatic gut-blood barrier for detoxifying exogenous dopamine and delimiting autocrine/paracrine effects of endogenous dopamine generated in a "third catecholamine system."

Improving the adverse cardiovascular prognosis of type 2 diabetes.

Approximately 80% of all patients with diabetes die of cardiovascular disease. The traditional management of type 2 diabetes has been ineffective in altering this dismal prognosis. Insulin resistance is the fundamental defect of type 2 diabetes. Insulin resistance often leads to hyperinsulinemia, which is associated with hypertension, atherogenic dyslipidemia, left ventricular hypertrophy, impaired fibrinolysis, visceral obesity, and sedentary lifestyle. Although all these conditions are associated with atherosclerosis and adverse cardiovascular events, the therapeutic efforts in patients with diabetes have focused predominantly on normalizing glucose levels. Improved insulin sensitivity through lifestyle modifications or pharmacologic therapy (troglitazone and metformin) will lower both insulin and glucose levels as well as diminish dyslipidemia and hypertension. In contrast, sulfonylurea agents lower glucose by increasing insulin levels and may increase the risk of cardiovascular events. Therapy including aspirin, lipid agents (for example, statins), angiotensin-converting enzyme inhibitors, beta-adrenergic blockers, postmenopausal estrogen replacement, and vitamin E should be considered for patients with type 2 diabetes. In most patients with diabetes who have multivessel coronary artery disease, coronary artery bypass grafting is superior to coronary angioplasty for improving long-term cardiovascular prognosis. This superiority is mediated in part by the use of a left internal mammary graft to the left anterior descending coronary artery. Urgent coronary angioplasty or thrombolytic therapy should be considered for all patients with diabetes who have acute myocardial infarction.

Glycerol and nonesterified fatty acid metabolism in human muscle and adipose tissue in vivo.

To determine the relationship between glycerol and nonesterified fatty acid (NEFA) release from adipose tissue, and to test whether forearm muscle and abdominal adipose tissue are capable of extracting these two lipolytic products from the circulation, 13 male subjects were studied after an overnight fast during combined infusion of radiolabeled palmitate and glycerol. Blood samples were taken from a radial artery, a deep forearm vein, and a superficial abdominal vein before and during a 2-h infusion of glucose at approximately 7 mg. kg-1. min-1. The ratio of the appearance rates of total NEFA to glycerol was approximately 3/1 during the baseline period but decreased to 1.3/1 during glucose infusion. There was significant extraction of both glycerol and NEFA by forearm muscle. In contrast, there was no apparent uptake of glycerol by adipose tissue. Adipose tissue NEFA uptake was undetectable during the baseline period but became significant during glucose infusion. These data indicate that there is very little to no in situ reesterification of NEFA in adipose tissue after an overnight fast. During glucose infusion, there was apparently a relative increase in the fraction of glycerol derived from the action of lipoprotein lipase and an increase in reesterification in situ.

Attenuation of gossypol cytotoxicity by cyclic AMP in a rat liver cell line.

The effect of pretreatment of a rat liver cell line (Clone 9) with 8-bromo-cyclic adenosine monophosphate (8-Br-cAMP), an agent previously shown to increase gap junctional intercellular communication (GJIC), was used to determine if increased GJIC would attenuate the cytotoxic effects of gossypol acetic acid (GAA). Pretreatment with 8-Br-cAMP increased the inhibitory concentration 50% (IC50) for gossypol from 4.1 to 6.1 microM in Clone 9 cells. GJIC was suppressed by about 57% within 5 min when Clone 9 cells were treated with 1.0 microM GAA alone, whereas cells treated with 3.0 or 10 microM GAA were completely uncoupled within the same time frame. In contrast, GJIC was maintained near control levels in Clone 9 cells preincubated with 1.0 mM 8-Br-cAMP for 10 min prior to 1.0 microM GAA exposure. 8-Br-cAMP partially restored GJIC in cells treated with 3.0 microM GAA but was unable to protect cells exposed to 10 microM GAA. The effects of GAA and 8-Br-cAMP pretreatment on connexin43 (Cx43) protein expression was analyzed with Western blots. GAA treatment at concentrations of 1 and 3 microM caused a time- and dose-dependent increase in phosphorylation of Cx43 over a 20-min period, whereas 10 microM GAA caused a time-dependent degradation of Cx43 over the same interval. Pretreatment of cells for 10 min with 8-Br-cAMP completely reversed the effect of 1 microM GAA and partially blocked the effect of 3 microM GAA on Cx43 phosphorylation and suppressed Cx43 degradation at 10 microM. Additional fluorescence endpoints associated with cellular homeostasis mechanisms were also monitored to evaluate cytotoxicity and potential protective effects of 8-Br-cAMP pretreatment in cells exposed to GAA, including generation of reactive oxygen species (ROS), cytoplasmic acidification, glutathione (GSH) content, intracellular calcium levels ([Ca2+]i), and mitochondrial and plasma membrane potential. The adverse effects of GAA on the production of ROS, cytoplasmic acidification, GSH content, and [Ca2+]i were also attenuated. The primary protective effect of 8-Br-cAMP was observed at or below the IC50 of GAA, with greatest protective effects detected on early endpoints affected by GAA exposure. These studies suggest that the protective effect of 8-Br-cAMP in GAA-treated cells results from enhanced GJIC, which facilitates cellular homeostasis by providing cell-cell diffusion of essential metabolites, ions, and regulatory and informational molecules.

Measurement of plasma glycerol specific activity by high performance liquid chromatography to determine glycerol flux.

Previous methods for measuring plasma glycerol specific activity (SA) are suboptimal, making the determination of glycerol kinetics in vivo with radiotracers difficult. A new high performance liquid chromatography (HPLC) method is described that permits the accurate and specific measurement of glycerol SA. The method involves isolation of glycerol from plasma and the formation of a tribenzoyl derivative. Glycerol rate of appearance was measured in five human volunteers using both [2-3H]glycerol and [2H5] glycerol. There was close agreement between the glycerol appearance rates measured using the two approaches (1.66 +/- 0.14 vs. 1.70 +/- 0.10 micromol x kg(-1) x min(-1), respectively, P = NS). This HPLC method offers improved specificity over existing methods of measuring glycerol turnover using radiotracers.

Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-alpha, in vivo.

We measured arterio-venous differences in concentrations of tumor necrosis factor-alpha (TNF alpha) and interleukin-6 (IL-6) across a sc adipose tissue bed in the postabsorptive state in 39 subjects [22 women and 17 men; median age, 36 yr (interquartile range, 26-48 yr); body mass index, 31.8 kg/m2 (range, 22.3- 38.7 kg/m2); percent body fat, 28.7% (range, 17.6-50.7%)]. A subgroup of 8 subjects had arteriovenous differences measured across forearm muscle. Thirty subjects were studied from late morning to early evening; 19 ate a high carbohydrate meal around 1300 h, and 11 continued to fast. We found a greater than 2-fold increase in IL-6 concentrations across the adipose tissue bed [arterial, 2.27 pg/mL (range, 1.42-3.53 pg/mL); venous, 6.71 pg/mL (range, 3.36-9.62 pg/mL); P < 0.001], but not across forearm muscle. Arterial plasma concentrations of IL-6 correlated significantly with body mass index (Spearman's r = 0.48; P < 0.01) and percent body fat (Spearman's r = 0.49; P < 0.01). Subcutaneous adipose tissue IL-6 production increased by the early evening (1800-1900 h) in both subjects who had extended their fasting and those who had eaten. Neither deep forearm nor sc adipose tissue consistently released TNF alpha [across adipose tissue: arterial, 1.83 pg/mL (range, 1.36-2.34 pg/mL); venous, 1.85 pg/mL (range, 1.44-2.53 pg/mL); P = NS: across forearm muscle: arterial, 1.22 pg/mL (range, 0.74-2.76 pg/mL); venous, 0.99 pg/mL (range, 0.69-1.70 pg/mL); P = NS]. Although both IL-6 and TNF alpha are expressed by adipose tissue, our results show that there are important differences in their systemic release. TNF alpha is not released by this sc depot. In contrast, IL-6 is released from the depot and is thereby able to signal systemically.

Very-low-density lipoprotein subfraction composition and metabolism by adipose tissue.

Lipoprotein lipase (LPL) plays a pivotal role in very-low-density lipoprotein (VLDL) metabolism. Within the circulation, the VLDL population is heterogeneous with respect to both size and composition. Several studies have investigated the action of LPL in vitro on different VLDL subfractions, but little is known of the action of LPL in vivo. To investigate this, arterial and adipose tissue venous plasma samples were obtained from 16 normal male healthy volunteers (aged 24.4 +/- 1.8 years; body mass index, 23.5 +/- 0.7 kg.m-2) following an overnight fast. VLDL subfractions were isolated (VLDL1 of Sf 60 to 400 and VLDL2 of Sf 20 to 60) and characterized in terms of triacylglycarol (TAG) and apolipoprotein (apo) B, E, CI, CII, and CIII content. The apolipoprotein content of VLDL1 differed from that of VLDL2: the VLDL2 fraction contained significantly more apo B (0.018 +/- 0.004 v 0.011 +/- 0.003 mumol.L-1, p = .001) but the ratios of TAG:apo B and apo CI:B, and CII:B, and CIII:B were significantly higher in VLDL1 (48,200 +/- 7,980 v 13,860 +/- 2,420, 22.7 +/- 5.5 v 12.5 +/- 2.2, 45.0 +/- 6.3 v 14.9 +/- 2.0, and 0.434 +/- 0.077 v 0.357 +/- 0.054, respectively, molar ratios, all P < .05). The venous blood draining an adipose tissue depot contained less VLDL1-TAG than arterial blood (328 +/- 68 v 381 +/- 83 mumol.L-1, respectively, P < .01), whereas VLDL2-TAG exhibited an opposite tendency (199 +/- 46 v 172 +/- 31 mumol.L-1, NS). Concentrations of VLDL1-apo B, -apo CII, and -apo CIII were significantly less in adipose tissue venous blood compared with arterial blood (0.011 +/- 0.004 v 0.013 +/- 0.004, 0.38 +/- 0.08 v 0.43 +/- 0.10, and 1.33 +/- 0.35 v 1.58 +/- 0.38 mumol.L-1, respectively, all P < .05). These studies demonstrated novel differences in VLDL1 and VLDL2 in terms of composition and metabolism by human adipose tissue LPL in vivo.

Lipolytic responsiveness to epinephrine in nondiabetic and diabetic humans.

To determine whether the sensitivity of adipose tissue lipolysis to catecholamines is increased in poorly controlled insulin-dependent diabetes, the lipolytic response to epinephrine was measured in seven nondiabetic volunteers and seven poorly controlled diabetic subjects with use of [1-(14)C]palmitate as a tracer. Subjects received sequential 1-h infusions of epinephrine, which produced epinephrine concentrations of approximately 1,000, approximately 1,750, approximately 3,500, and approximately 6,000 pmol/l. A pancreatic clamp was used to maintain constant plasma hormone levels. Concentration-response curves were constructed for each subject from the integrated lipolytic response during each epinephrine infusion. There was no difference in maximal lipolytic response (117 +/- 19 vs. 152 +/- 11 mumol.kg-1.h-1) or in maximally effective (3,171 +/- 267 vs. 3,357 +/- 349 pmol/l) or half-maximally effective (1,081 +/- 109 vs. 1,015 +/- 120 pmol/l) epinephrine concentrations between nondiabetic and diabetic subjects, respectively (all P = NS). In control subjects, maximum beta-hydroxybutyrate concentrations were achieved at lower epinephrine concentrations than those required for a maximum lipolytic effect. Thus, under pancreatic clamp conditions, the lipolytic response to epinephrine in nondiabetic and diabetic subjects was similar.

Effects of the incubation of long-chain polyunsaturated fatty acids on platelet lipids and thromboxane release.

Alterations of dietary lipids have been advocated to manipulate platelet release of thromboxane A2. We studied the effects of incubating platelets with several different polyunsaturated fatty acids on platelet-lipid profile and release of thromboxane A2 in response to platelet stimulation. Porcine platelets were isolated by centrifugation, washed three times in Tyrode's solution, and incubated with fatty acids (500 microM) in Tyrode's solution with albumin. Seven polyunsaturated fatty acids of varying lengths (18-, 20-, and 22-carbon chain) of the omega3 and omega6 families were incubated for 60 min at concentrations of 0, 10, 30, and 100 microM with saturated fatty acids comprising the remainder of the 500 microM fatty acids. The platelets were then stimulated for 5 min with A23187 (30 microM). Indomethacin was added, and the platelets were pelleted. Platelet lipids were extracted in hexane, transesterified and quantified by gas chromatography. Using radioimmunoassay, we measured thromboxane B2, the stable metabolite of thromboxane A2, in the platelets' supernatant. A 1-h incubation in each of the seven polyunsaturated fatty acids had no significant effect on platelet-lipid composition. We found a significant increase in thromboxane B2 production in arachidonic acid (100 microM) incubated platelets (324.0 +/- 63.8% of baseline) that was inhibited by eicosapentaenoic acid (81.0 +/- 26.8%, P < 0.01) and to a lesser extent by dihomogammalinolenic acid (189.8 +/- 28.3%, P < 0.03). We conclude that in altering diets to affect platelet release of thromboxane, the two fatty acids of interest are the 20-carbon chain fatty acids, dihomogammalinolenic acid and eicosapentaenoic acid. The ideal amount of each of these fatty acids to be incorporated entails supraphysiologic but pharmacologically achievable levels of fatty acids in plasma.

Phenylalanine kinetics in human adipose tissue.

Very little is known about the regulation of protein metabolism in adipose tissue. In this study systemic, adipose tissue, and forearm phenylalanine kinetics were determined in healthy postabsorptive volunteers before and during a 2-h glucose infusion (7 mg.kg-1.min-1). [3H]Phenylalanine was infused and blood was sampled from a radial artery, a subcutaneous abdominal vein, and a deep forearm vein. Adipose tissue and forearm blood flow were measured with 133Xe and plethysmography, respectively, and body fat mass was determined by dual energy x-ray absorptiometry. During glucose infusion, glucose concentration increased from 86 +/- 2 to 228 +/- 13 mg/dl and insulin concentration increased from 6.6 +/- 0.6 to 35.0 +/- 3.9 mU/liter, both P < 0.001. Systemic phenylalanine appearance decreased from 40.3 +/- 1.9 to 37.0 +/- 1.6 mumol/min during glucose infusion (P < 0.05). Baseline whole body adipose tissue phenylalanine release (5.2 +/- 1.4 mumol/min) was approximately 12% of systemic phenylalanine appearance and decreased (P < 0.05) to 2.3 +/- 0.9 mumol/min during glucose infusion. In contrast, phenylalanine release from the forearm did not change during glucose infusion. These results indicate that adipose tissue is a small but significant contributor to systemic phenylalanine appearance. Phenylalanine release from adipose tissue like lipolysis, is relatively sensitive to hyperinsulinemia.

Effects of pulsatile delivery of basal growth hormone on lipolysis in humans.

Growth hormone (GH) excess stimulates lipolysis, but its role in the hierarchy of lipolysis regulation is not clear. We studied whether pulsatile GH delivery is required for its lipolytic effect. With use of the pancreatic clamp, eight subjects were randomized to three protocols: protocol A, GH deficiency; protocol B, constant GH infusion; protocol C, pulsatile GH delivery (same total GH as protocol B). Pulsatile GH was given in four consecutive bursts, with symmetric peak width (60 min), amplitude of 10.7 (men) and 15 (women) ng.kg-1.min-1, and peak width at half-height of 15 min. Palmitate flux (PF) was measured at baseline and in the last hour of each study with [3H]palmitate. GH (ng/ml) decreased from approximately 3.5 to 2.0 in protocol A (P < 0.05), it remained between 3.2 and 4.0 in protocol B (P < 0.05), but in protocol C it fluctuated between approximately 2.7 and approximately 5.0 (P < 0.05). Palmitate concentration (in mumol/l) was approximately 150 at baseline; it did not change in protocols A and B (137 +/- 17 and 136 +/- 12, respectively) but increased to 198 +/- 16 (P < 0.05) in protocol C. PF (mumol.kg-1.min-1) was approximately 2.7 at baseline and did not change in protocol B (2.4 +/- 0.2); it decreased to 2.2 +/- 0.1 in protocol A (P < 0.05); it increased to 3.1 +/- 0.3 (P < 0.05) in protocol C. These experiments provide evidence that pulsatile secretion of GH is required for its lipolytic effect.