Biomedical subjects

W I Sivitz

Publications and source records attributed to W I Sivitz.

At least 19 recordsLinked to original sources

PubMed2001

Does leptin cause functional peripheral sympatholysis?

Leptin is a protein produced by adipocytes. Leptin is known to markedly and rapidly increase sympathetic nerve activity to the kidney and hindlimb of experimental animals. Recent studies suggest that leptin may stimulate endothelial production of nitric oxide, which could oppose sympathetically induced vasoconstriction. We tested the hypothesis that such actions of leptin may produce peripheral functional sympatholysis. In Sprague-Dawley rats, we intermittently stimulated the abdominal sympathetic trunk and measured renal and hindlimb blood flows before and after 3 h of infusion of leptin (1000 microg/kg, n = 7) or vehicle (n = 7). Leptin did not change arterial pressure, heart rate, or renal or hindlimb conductance over the course of 3 h. In addition, leptin did not significantly alter sympathetically mediated vasomotor responses to electrical stimulation, as compared with vehicle. Thus, we conclude that leptin does not change regional blood flows, and that leptin also does not appear to have vascular or neural actions to cause peripheral functional sympatholysis.

Animals↗

PubMed2001

Leptin interacts with heart rate but not sympathetic nerve traffic in healthy male subjects.

OBJECTIVE: Administration of leptin to animals increases sympathetic nerve activity and heart rate. We therefore tested the hypothesis that plasma leptin is linked independently to muscle sympathetic nerve activity (MSNA) and heart rate in healthy humans. METHODS: We measured plasma leptin, plasma insulin, body mass index (BMI), percent body fat, waist: hip ratio, MSNA, heart rate and blood pressure in 88 healthy individuals (50 men and 38 women). RESULTS: In men, plasma leptin concentration correlated significantly with BMI (r = 0.75, P < 0.001), percent body fat (r = 0.70, P< 0.001), waist: hip ratio (r = 0.69, P < 0.001), insulin (r = 0.37, P = 0.009), and age (r = 0.38, P = 0.006). Only BMI and waist: hip ratio were linked independently to plasma leptin concentration (r = 0.78, P < 0.001). Plasma leptin concentrations also correlated with heart rate (r = 0.39, P = 0.006) and mean arterial pressure (MAP; r = 0.38, P = 0.007), but not with MSNA (r = 0.17, P = 0.24). After adjustment for BMI and waist: hip ratio, plasma leptin concentration correlated significantly only with heart rate (r = 0.29, P = 0.04), and not with MAP (r = 0.21, P = 0.14). Individuals were divided into high-leptin and low-leptin subgroups on the basis of plasma leptin concentrations adjusted for BMI and waist: hip ratio. Those with high leptin concentrations had significantly faster heart rates than those with low leptin. MAP and MSNA were similar in both subgroups. No relationship between leptin and either heart rate or MSNA was evident in women. CONCLUSIONS: In normal men, heart rate, but not MSNA, is linked to plasma leptin concentration. This sex-specific relationship between heart rate and plasma leptin is independent of plasma insulin, BMI, waist:hip ratio and percentage body fat.

Adult↗

PubMed2001

Leptin acts in the central nervous system to produce dose-dependent changes in arterial pressure.

Systemic leptin increases energy expenditure through sympathetic mechanisms, decreases appetite, and increases arterial pressure. We tested the hypothesis that the pressor action of leptin is mediated by the central nervous system. The interaction of dietary salt with leptin was also studied. Leptin was infused for 2 to 4 weeks into the third cerebral ventricle of Sprague-Dawley rats. Arterial pressure was measured by radiotelemetry. To control for the effects of leptin on body weight, vehicle-treated rats were pair-fed to the leptin group. Intracerebroventricular infusion of leptin at 200 ng/h in salt-depleted rats caused a reduction in food intake, weight loss, tachycardia, and decreased arterial pressure. Leptin at 1000 ng/h caused further reduction in food intake, weight loss, and tachycardia and prevented the hypotensive effect of weight loss observed in pair-fed, vehicle-treated animals. Intracerebroventricular leptin at 1000 ng/h in high-salt-fed rats also caused a sustained pressor response (+3+/-1 mm Hg), but high-salt intake did not potentiate the pressor effect of leptin. Intracerebroventricular leptin potentiated the pressor effect of air-jet stress. Intravenous administration of the same dose of leptin (1000 ng/h) did not change weight or arterial pressure, suggesting a direct central nervous system action. In contrast, a high dose of intravenous leptin (18 000 ng/h) caused weight loss and prevented the depressor effect of weight loss. In conclusion, this study demonstrates that high-dose leptin increases arterial pressure and heart rate through central neural mechanisms but leptin does not enhance salt sensitivity of arterial pressure. Leptin appears to oppose the depressor effect of weight loss.

Animals↗

PubMed2001

Role of corticotrophin-releasing factor in effects of leptin on sympathetic nerve activity and arterial pressure.

Leptin and corticotrophin-releasing factor increase sympathetic nervous activity to interscapular brown adipose tissue, kidneys, and adrenal glands. Leptin is known to increase hypothalamic corticotrophin-releasing factor. In this study, we tested the hypothesis that leptin-dependent increases in sympathetic nervous activity are mediated through increases in central nervous system corticotrophin-releasing factor activity. We examined the effects of intracerebroventricular administration of corticotrophin-releasing factor and intravenous leptin on sympathetic nervous activity to interscapular brown adipose tissue through multifiber neurography in anesthetized Sprague-Dawley rats pretreated with intracerebroventricular alpha-helical corticotrophin-releasing factor(9-41) (corticotrophin-releasing factor receptor antagonist) or vehicle. Centrally administered corticotrophin-releasing factor substantially increased interscapular brown adipose tissue sympathetic nervous activity. The responses to corticotrophin-releasing factor were substantially attenuated in animals pretreated with alpha-helical corticotrophin-releasing factor(9-41). Leptin-dependent increases in interscapular brown adipose tissue sympathetic nervous activity were significantly inhibited by pretreatment with alpha-helical corticotrophin-releasing factor(9-41). Interestingly, leptin also significantly increased arterial pressure over 6 hours, but this pressor action was not attenuated by the corticotrophin-releasing factor receptor antagonist. These results suggest that corticotrophin-releasing factor may mediate the sympathoexcitatory effect of leptin on thermogenic tissue without altering its cardiovascular actions.

Adipose Tissue, Brown↗

PubMed2001

Does leptin stimulate nitric oxide to oppose the effects of sympathetic activation?

Leptin decreases appetite and increases sympathetic nerve activity and arterial pressure. Recent reports suggest that leptin may also have peripheral vasodilator actions that would tend to reduce arterial pressure. We tested the hypothesis that the direct vascular actions of leptin oppose sympathetically mediated vasoconstriction. We evaluated the effects of intravenous leptin (1 mg/kg over 3 hours) on arterial pressure and mesenteric, hindlimb, and renal blood flows in conscious rats. We then tested whether blockade of nitric oxide or the sympathetic nervous system would unmask a pressor or depressor effect of leptin, consistent with direct vascular actions. Acute intravenous administration of leptin alone did not change arterial pressure or regional blood flows. This was despite a significant increase in lumbar sympathetic nerve activity. Administration of the nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester significantly increased arterial pressure and caused vasoconstriction. However, leptin did not have any significant effect on hemodynamics in the presence of N(G)-nitro-L-arginine methyl ester despite continued sympathoactivation. alpha-Adrenoceptor blockade with prazosin alone or combined with yohimbine significantly decreased arterial pressure and caused vasodilation. Again, leptin did not have any effect on arterial pressure or regional blood flow in the presence of sympathetic blockade. These data demonstrate that leptin does not have vasodilator actions in vivo at concentrations that are sufficient to increase sympathetic nerve activity. The absence of a pressor effect of leptin-induced sympathetic activation may merely reflect the brief duration of leptin administration. These data support the concept that the chronic hemodynamic actions of leptin are likely to be related to sympathetic activation.

Adrenergic alpha-Antagonists↗

PubMed2001

Effects of adenoviral overexpression of uncoupling protein-2 and -3 on mitochondrial respiration in insulinoma cells.

The brown adipose tissue uncoupling protein 1 (UCP1) catalyzes proton reentry without ATP synthesis, thereby dissipating energy as heat. In contrast, the function(s) of the recently described homologs, UCP2 and UCP3, are less clear. The aim of the present study was to determine whether overexpressed UCP subtypes affect mitochondrial respiration and substrate oxidation in cultured insulin-secreting INS-1 insulinoma cells. Adenoviral overexpression of UCP2 significantly decreased the ADP/O ratio by 31% and 39% in comparison to beta-galactosidase (beta-gal) or the mitochondrial protein manganese superoxide dismutase (MnSOD), respectively, and increased state 4 respiration in the presence of succinate and oligomycin by 52% and 59% in comparison to beta-gal or MnSOD, respectively. Adenoviral overexpression of UCP3 also decreased the ADP/O ratio by 18% (nonsignificant) and increased state 4 respiration by 24% (nonsignificant) in comparison to ss-gal and significantly decreased the ADP/O ratio by 32% and increased state 4 respiration by 35% in comparison to MnSOD. Both UCP2 and UCP3 expression significantly increased whole cell lipid oxidation by 34% (P < 0.01) and 30% (P < 0.05), respectively, compared with cells expressing Ad5CMVlacZ. However, glucose oxidation was not significantly altered by UCP2 or UCP3 expression. Adenoviral UCP2 expression, but not UCP3 (compared with beta-gal), significantly inhibited insulin secretion in the presence of 15 mM glucose [6.17 +/- 0.42 ng/mg cell protein for beta-gal compared with 4.69 +/- 0.39 for UCP2 (P < 0.05) and 5.51 +/- 0.50 for UCP3]. Both overexpressed UCPs significantly reduced INS-1 cell ATP content. Within certain limitations, which are discussed, these data are the first to demonstrate increased respiration and impaired coupling of oxidative phosphorylation as a result of UCP homolog expression in isolated mammalian mitochondria. Our results also suggest an important role for UCP in lipid metabolism and, possibly, insulin secretion.

Adenoviridae↗

PubMed2001

Effect of acute and antecedent hypoglycemia on sympathetic neural activity and catecholamine responsiveness in normal rats.

Adrenergic responsiveness to acute hypoglycemia is impaired after prior episodes of hypoglycemia. Although circulating epinephrine responses are blunted, associated alterations in adrenal sympathetic nerve activity (SNA) have not been reported. We examined adrenal nerve traffic in normal conscious rats exposed to acute insulin-induced hypoglycemia compared with insulin with (clamped) euglycemia. We also examined adrenal SNA and catecholamine responses to insulin-induced hypoglycemia in normal conscious rats after two antecedent episodes of hypoglycemia (days -2 and -1) compared with prior episodes of sham treatment. Acute insulin-induced hypoglycemia increased adrenal sympathetic nerve traffic compared with insulin administration with clamped euglycemia (165 +/- 12 vs. 118 +/- 21 spikes/s [P < 0.05]; or to 138 +/- 8 vs. 114 +/- 10% of baseline [P < 0.05]). In additional experiments, 2 days of antecedent hypoglycemia (days -2 and -1) compared with sham treatment significantly enhanced baseline adrenal SNA measured immediately before subsequent acute hypoglycemia on day 0 (180 +/- 11 vs. 130 +/- 12 spikes/s, respectively; P < 0.005) and during subsequent acute hypoglycemia (229 +/- 17 vs. 171 +/- 16 spikes/s; P < 0.05). However, antecedent hypoglycemia resulted in a nonsignificant reduction in hypoglycemic responsiveness of adrenal SNA when expressed as percent increase over baseline (127 +/- 5% vs. 140 +/- 14% of baseline). Antecedent hypoglycemia, compared with sham treatment, resulted in diminished epinephrine responsiveness to subsequent hypoglycemia. Norepinephrine responses to hypoglycemia were not significantly altered by antecedent hypoglycemia. In summary, prior hypoglycemia in normal rats increased adrenal sympathetic tone, but impaired epinephrine responsiveness to acute hypoglycemia. Hence, these data raise the intriguing possibility that increased sympathetic tone resulting from antecedent hypoglycemia downregulates subsequent epinephrine responsiveness to hypoglycemia. Alternatively, it is possible that the decrease in epinephrine responsiveness after antecedent hypoglycemia could be the result of reduced adrenal sympathetic nerve responsiveness.

Adrenal Glands↗

PubMed2001

Lipotoxicity and glucotoxicity in type 2 diabetes. Effects on development and progression.

Excess fat, excess glucose, or both act on diverse cells and tissues to counteract insulin-mediated glucose uptake, hepatic regulation of glucose output, and insulin secretion. These effects are labeled lipotoxicity and glucotoxicity because, when severe enough, each may contribute to the diabetic state. Lifestyle modifications and certain new pharmacologic agents may be effective in modulating these effects and could prove useful in primary prevention of type 2 diabetes.

Animals↗

PubMed2000

Pubertal adolescent male-female differences in insulin sensitivity and glucose effectiveness determined by the one compartment minimal model.

Most studies of insulin sensitivity in puberty have been cross-sectional and have not been able to longitudinally address changes that might occur. In addition, these studies were unable to separate out glucose's ability to stimulate its own disposal (glucose effectiveness, S(G)) from insulin sensitivity (S(I)) or to separate the hepatic and peripheral effects of insulin. To address these problems, we used the frequently sampled i.v. glucose tolerance test with [6,6]D2 glucose to study S(G)* and S(I)* in 24 children (Tanner stage 1-3) at 6-mo intervals over an 18-mo period. Mean overnight GH and fasting GH binding protein (GHBP), IGF-1, and leptin levels were also measured. S(G)* did not differ between the sexes or Tanner stages. S(I)* did not differ between Tanner stages for either sex and was higher in boys than in girls. Hepatic insulin resistance did not differ between sexes or Tanner stages. S(G)* was not related to any of the other variables measured. S(I)* was negatively related to BMI, GHBP, IGF1, and leptin. These results demonstrate that insulin sensitivity is greater in prepubertal and early pubertal boys than in girls and is primarily determined by body mass effects.

Adolescent↗

PubMed1999

Heritability of plasma leptin levels: a twin study.

OBJECTIVE: To examine the influence of genetic factors on plasma leptin levels. SUBJECTS AND METHODS: We measured plasma leptin levels, body mass index and body fat distribution in healthy young female monozygotic (n = 19) and dizygotic (n = 14) twins. The twin zygosity was verified by determination of short tandem repeat and amplified fragment length polymorphism systems. The genetic analysis included analysis of variance-based and maximum likelihood-based methods. RESULTS: Plasma leptin levels were correlated significantly with body mass index (r = 0.59, P < 0.001), waist circumference (r = 0.54, P < 0.001) and hip circumference (r = 0.63, P < 0.001), but not with age (r = -0.17) or the waist:hip ratio (r = 0.02). The heritability estimates derived from intraclass correlations were significant for body mass index (P = 0.001), waist circumference (P = 0.004), hip circumference (P = 0.01) and plasma leptin levels (P = 0.005), but not for the waist:hip ratio (P = 0.22). In the maximum likelihood-based path analysis, heritability was estimated at 79% for body mass index and at 73% for plasma leptin levels. After adjustment for body mass index, the heritability estimate for leptin levels from the model-fitting approach was 55%. CONCLUSIONS: Genetic factors are major determinants of plasma leptin levels in humans and may account for as much as half of the variance in leptin levels.

Adipose Tissue↗

PubMed1999

Sympathetic inhibition, leptin, and uncoupling protein subtype expression in normal fasting rats.

To further investigate neural effects on leptin and uncoupling proteins (UCPs), we studied in vivo perturbations intended to block adrenergic input to peripheral tissues. We examined plasma leptin, leptin mRNA, and adipose and muscle UCP subtype mRNA in rats treated with alpha-methyl-p-tyrosine methyl ester (AMPT-ME), which inhibits catecholamine synthesis and 6-hydroxydopamine (6HDA), which is toxic to catecholinergic nerve terminals but, unlike AMPT-ME, does not enter the central nervous system. Intraperitoneal AMPT-ME, 250 mg/kg, was administered at 1800 and 0700 the following day, and rats were killed at 1200-1400. All rats were fasted with free access to water during this time. Intraperitoneal AMPT-ME increased plasma leptin by 15-fold, increased interscapular brown adipose tissue (IBAT) and epididymal fat leptin mRNA by 2- to 2.5-fold, and also increased plasma insulin and glucose concentrations. Intraperitoneal AMPT-ME decreased IBAT UCP-3 mRNA to 40% of control, while it increased epididymal adipose UCP-3 mRNA approximately twofold. Intravenous AMPT-ME, 250 mg/kg, administered to conscious rats for 5 h decreased lumbar sympathetic nerve activity, increased plasma leptin (5.89 +/- 1.43 compared with 2.75 +/- 0.31 ng/ml in vehicle-treated rats, n = 7, P < 0.05), and decreased cardiac rate with no sustained change in blood pressure. Intraperitoneal 6HDA, 100 mg/kg, as a single dose at 1800, increased plasma leptin approximately twofold after 18-20 h, increased IBAT (but not epididymal fat) leptin mRNA by two- to threefold, and decreased IBAT UCP-3 mRNA to 30-40% of control. Neither AMPT-ME nor 6HDA significantly altered mRNA encoding gastrocnemius muscle UCP-3, IBAT UCP-1, or IBAT and epididymal UCP-2. In summary, AMPT-ME and 6HDA increased plasma leptin and upregulated leptin mRNA expression. AMPT-ME also resulted in complex tissue and subtype-specific modulation of adipose UCP mRNA. These data are consistent with interaction between leptin and sympathetic nerve activity (SNA) in regulation of fat cell energy utilization. However, the in vivo modulation of leptin and UCPs appears complex and, beyond a causal effect of SNA per se, may depend on concurrent changes in plasma insulin, glucose, and circulatory hemodynamics.

Adipose Tissue↗

PubMed1999

Interactions between the melanocortin system and leptin in control of sympathetic nerve traffic.

Leptin plays an important role in regulation of body weight through regulation of food intake and sympathetically mediated thermogenesis. The hypothalamic melanocortin system, via activation of the melanocortin-4 receptor (MC4-R), decreases appetite and weight, but its effects on sympathetic nerve activity (SNA) are unknown. In addition, it is not known whether sympathoactivation to leptin is mediated by the melanocortin system. We tested the interactions between these systems in regulation of brown adipose tissue (BAT) and renal and lumbar SNA in anesthetized Sprague-Dawley rats. Intracerebroventricular administration of the MC4-R agonist MT-II (200 to 600 pmol) produced a dose-dependent sympathoexcitation affecting BAT and renal and lumbar beds. This response was completely blocked by the MC4-R antagonist SHU9119 (30 pmol ICV). Administration of leptin (1000 microg/kg IV) slowly increased BAT SNA (baseline, 41+/-6 spikes/s; 6 hours, 196+/-28 spikes/s; P=0.001) and renal SNA (baseline, 116+/-16 spikes/s; 6 hours, 169+/-26 spikes/s; P=0.014). Intracerebroventricular administration of SHU9119 did not inhibit leptin-induced BAT sympathoexcitation (baseline, 35+/-7 spikes/s; 6 hours, 158+/-34 spikes/s; P=0.71 versus leptin alone). However, renal sympathoexcitation to leptin was completely blocked by SHU9119 (baseline, 142+/-17 spikes/s; 6 hours, 146+/-25 spikes/s; P=0.007 versus leptin alone). This study demonstrates that the hypothalamic melanocortin system can act to increase sympathetic nerve traffic to thermogenic BAT and other tissues. Our data also suggest that leptin increases renal SNA through activation of hypothalamic melanocortin receptors. In contrast, sympathoactivation to thermogenic BAT by leptin appears to be independent of the melanocortin system.

Adipose Tissue, Brown↗

PubMed1999

Fasting and leptin modulate adipose and muscle uncoupling protein: divergent effects between messenger ribonucleic acid and protein expression.

Leptin is believed to act through hypothalamic centers to decrease appetite and increase energy utilization, in part through enhanced thermogenesis. In this study, we examined the effects of fasting for 2 days and exogenous s.c. leptin, 200 microg every 8 h for 2 days, on the regulation of uncoupling protein (UCP) subtypes in brown adipose tissue (BAT) and gastrocnemius muscle. Northern blot analysis (UCP-1) and ribonuclease protection (UCP-2 and 3) were used for quantitative messenger RNA (mRNA) analysis, and specific antibodies were used to measure UCP-1 and UCP-3 total protein expression. Leptin, compared with vehicle, did not alter BAT UCP-1 or UCP-3 mRNA or protein expression when administered to normal ad libitum fed rats. Fasting significantly decreased BAT UCP-1 and UCP-3 mRNA expression, to 31% and 30% of ad libitum fed controls, respectively, effects which were prevented by administration of leptin to fasted rats. Fasting also significantly decreased BAT UCP-1 protein expression, to 67% of control; however, that effect was not prevented by leptin treatment. Fasting also decreased BAT UCP-3 protein, to 85% of control, an effect that was not statistically significant. Fasting, with or without leptin administration, did not affect BAT UCP-2 mRNA; however, leptin administration to ad libitum fed rats significantly increased BAT UCP-2 mRNA, to 138% of control. Fasting significantly enhanced gastrocnemius muscle UCP-3 mRNA (411% of control) and protein expression (168% of control), whereas leptin administration to fasted rats did not alter either of these effects. In summary, UCP subtype mRNA and protein are regulated in tissue- and subtype-specific fashion by leptin and food restriction. Under certain conditions, the effects of these perturbations on UCP mRNA and protein are discordant.

Adipose Tissue↗

PubMed1998

Plasma leptin in diabetic and insulin-treated diabetic and normal rats.

Adipose tissue leptin mRNA levels are decreased by food deprivation or induction of insulin-deficient diabetes. To determine whether plasma leptin concentrations are similarly affected, whether treatment of diabetes with insulin restores plasma leptin, and whether this requires restoration of body weight (lost as a result of diabetes) and/or normalization of glycemia, we measured plasma leptin concentrations in control, untreated streptozotocin (STZ)-diabetic, and insulin-treated STZ-diabetic rats. Plasma leptin was markedly reduced in untreated STZ-diabetic rats. Insulin treatment for 4 to 17 days increased plasma leptin approximately twofold above control levels. However, despite the hyperleptinemia, insulin-treated diabetic rats gained weight at a rate equal to that of sham-treated controls. Epididymal adipose tissue leptin mRNA levels in 17-day insulin-treated diabetic rats were equal to but did not exceed sham-control levels, unlike plasma leptin. Plasma glucose concentrations in insulin-treated STZ-diabetic rats were lower than in sham controls. Therefore, to determine whether hypoglycemia may be important in increasing plasma leptin, we measured plasma leptin levels in diabetic rats infused with insulin for 3 hours along with a variable-rate glucose infusion targeting glycemia to 200 or 40 mg/100 mL. Plasma leptin rapidly increased in these rats irrespective of target glycemia. Plasma leptin also increased rapidly in normal rats infused with insulin and glucose (target glycemia, 200 mg/100 mL). We conclude that plasma leptin concentrations are markedly reduced under conditions of insulin deficiency and rapidly increased by insulin treatment. The increase in plasma leptin does not require restoration of body weight and, under glucose clamp conditions, does not depend on target glycemia. Hyperleptinemia in insulin-treated diabetic rats is not explained on the basis of steady-state leptin mRNA levels, at least as reflected in epididymal fat.

Adipose Tissue↗

PubMed1998

Cardiovascular consequences of obesity: role of leptin.

1. Several mechanisms have been implicated in the association between obesity and hypertension, including salt-sensitivity, insulin resistance and sympathetic activation. Obese animals and humans exhibit exaggerated blood pressure responses to increases in salt intake. 2. Although insulin resistance is common in obesity, it is clear that abnormal insulin action is not the sole or sufficient cause of hypertension in obesity. Obesity is associated with increased activity of the sympathetic nervous system. Sympathetic blockade has been reported to attenuate sodium retention and hypertension in experimental models of obesity. 3. The mediators responsible for salt sensitivity, insulin resistance and sympathetic activation in obesity remain unclear. 4. The novel protein hormone leptin is produced almost exclusively by adipose tissue and acts in the central nervous system through a specific receptor and multiple neuropeptide pathways to decrease appetite and increase energy expenditure. 5. Increasing evidence suggests that leptin may have wider actions influencing autonomic, cardiovascular, renal and endocrine function. We have shown that leptin increases sympathetic nerve activity to kidney, hindlimb and adrenal gland, in addition to brown adipose tissue. 6. Despite this sympathoexcitatory action, acute systemic administration of leptin does not acutely increase arterial pressure or heart rate in anaesthetized animals. This may reflect opposing antihypertensive actions of leptin. For example, leptin increases renal sodium and water excretion, apparently through a direct tubular action. In addition, leptin increases systemic insulin sensitivity, even in the absence of weight loss. 7. In conclusion, leptin may act as a mediator linking body adiposity with changes in insulin action, sympathetic neural outflow and renal sodium excretion. Alterations in leptin generation or action may, in part, underlie the sympathetic, endocrine and renal consequences of obesity.

Animals↗

PubMed1997

Receptor-mediated regional sympathetic nerve activation by leptin.

Leptin is a peptide hormone produced by adipose tissue which acts centrally to decrease appetite and increase energy expenditure. Although leptin increases norepinephrine turnover in thermogenic tissues, the effects of leptin on directly measured sympathetic nerve activity to thermogenic and other tissues are not known. We examined the effects of intravenous leptin and vehicle on sympathetic nerve activity to brown adipose tissue, kidney, hindlimb, and adrenal gland in anesthetized Sprague-Dawley rats. Intravenous infusion of mouse leptin over 3 h (total dose 10-1,000 microg/kg) increased plasma concentrations of immunoreactive murine leptin up to 50-fold. Leptin slowly increased sympathetic nerve activity to brown adipose tissue (+286+/-64% at 1,000 microg/kg; P = 0.002). Surprisingly, leptin infusion also produced gradual increases in renal sympathetic nerve activity (+228+/-63% at 1,000 microg/kg; P = 0.0008). The effect of leptin on sympathetic nerve activity was dose dependent, with a threshold dose of 100 microg/kg. Leptin also increased sympathetic nerve activity to the hindlimb (+287+/-60%) and adrenal gland (388+/-171%). Despite the increase in overall sympathetic nerve activity, leptin did not increase arterial pressure or heart rate. Leptin did not change plasma glucose and insulin concentrations. Infusion of vehicle did not alter sympathetic nerve activity. Obese Zucker rats, known to possess a mutation in the gene for the leptin receptor, were resistant to the sympathoexcitatory effects of leptin, despite higher achieved plasma leptin concentrations. These data demonstrate that leptin increases thermogenic sympathetic nerve activity and reveal an unexpected stimulatory effect of leptin on overall sympathetic nerve traffic.

Action Potentials↗

PubMed1997

Sympathetic and cardiorenal actions of leptin.

Body weight is tightly regulated physiologically. The recent discovery of the peptide hormone leptin has permitted more detailed evaluation of the mechanisms responsible for control of body fat. Leptin is almost exclusively produced by adipose tissue and acts in the CNS through a specific receptor and multiple neuropeptide pathways to decrease appetite and increase energy expenditure. Leptin thus functions as the afferent component of a negative feedback mechanism to control adipose tissue mass. Increasing evidence suggests that leptin may have wider actions influencing autonomic, cardiovascular, and endocrine function. Intravenous leptin increases norepinephrine turnover and sympathetic nerve activity to thermogenic brown adipose tissue. Studies from our laboratory suggest that leptin also increases sympathetic nerve activity to kidney, hindlimb, and adrenal gland. However, systemic administration of leptin does not acutely increase arterial pressure or heart rate in anesthetized animals. Thus, longer-term exposure to hyperleptinemia may be necessary for full expression of the expected pressor effect of renal sympathoexcitation. Alternatively, leptin may have additional cardiovascular actions to oppose sympathetically mediated vasoconstriction. Leptin in high doses increases renal sodium and water excretion, apparently through a direct tubular action. In addition, leptin appears to increase systemic insulin sensitivity, even in the absence of weight loss. Although we are at an early stage of understanding, we speculate that abnormalities in the actions of leptin may have implications for the sympathetic, cardiovascular, and renal changes associated with obesity.

Adipose Tissue↗

PubMed1997

Effect of maternal diabetes upon fetal rat myocardial and skeletal muscle glucose transporters.

We investigated the effect of streptozotocin-induced short-term maternal diabetes upon fetal rat myocardial and skeletal muscle glucose transporter Glut 1 (basal form) and Glut 4 (insulin-responsive form) protein concentrations by Western blot analysis. In the severely diabetic group (SEVERE-D, n = 17), a 3-fold increase in maternal and fetal glucose concentrations (p < 0.01) was associated with a 3-fold decline in maternal (p < 0.01) with no change in fetal insulin levels when compared with the streptozotocin-treated nondiabetic (n = 10) and vehicle-treated control (control, n = 14) groups. These changes in the SEVERE-D group when compared with controls were associated with a 30 and 65% decline, respectively, in fetal myocardial and skeletal muscle (forelimb and hind limb) Glut 1 protein concentrations. The fetal myocardium also demonstrated a 45% decline in Glut 4 protein levels. Fetal skeletal muscle Glut 4 protein, which was expressed only at very low levels in controls showed no change in SEVERE-D. Immunohistochemical analysis revealed a myocyte-plasma membrane association of Glut 1 and an intracellular Glut 4 distribution in the fetal myocardium and skeletal muscle. No Glut 1 immunoreactivity was noted in either the fetal myocardial or skeletal muscle perineural sheaths, blood vessels, or the entrapped fetal red blood cells. This subcellular localization pattern was unaltered in all three treatment groups. We conclude that maternal diabetes causing fetal hyperglycemia with normoinsulinemia suppresses fetal myocardial Glut 1 and Glut 4 and fetal skeletal muscle Glut 1. The decline in the plasma membrane associated Glut 1 concentrations may serve a protective function by reducing the glucose transport rate into fetal myocardial and skeletal muscle cells, which otherwise could be vulnerable to high circulating glucose. The in-utero maternal diabetes induced decrease in fetal myocardial intracellular-Glut 4 concentration could herald the emergence of insulin resistance.

Animals↗