Inhibition Of Leptin Secretion Research Articles

Effects of rapamycin on blood lipid metabolism in renal transplant recipients

In recent years, rapamycin has been used as an immunosuppressive agent in clinical practice. Rapamycin has the effect of accelerating lipid metabolism in the test, but it has the adverse reaction of hyperlipidemia at the same time. In view of this double-side conclusion, this article mainly analyzes the following aspects: direct inhibition of mTOR pathway, reduce expression of peroxisome proliferator-activated receptor γ, inhibition of leptin secretion, down-regulation of cholesterol-regulating element binding protein and excitation cell autophagy. Based on current research at home and abroad, it suggested that the the effects of dose-response effects of rapamycin and the exact mechanism of interaction between PI3K/PKB/mTOR signaling pathways and other cytokines can be a further research direction, so that the relationship between rapamycin and blood lipid metabolism can be learn more about in a quantify way. Key words: Kidney transplantation; Lipid metabolism disorders; Cytokines; Autophagy; Rapamycin

Effect of quercetin on secretion and gene expression of leptin in breast cancer

ObjectiveTo investigate the possible inhibitory action of pure quercetin on secretion and gene expression of leptin in the T47D breast cancer cell line. MethodsIn this experimental study, T47D cells were cultured in monolayers in RPMI 1640. IC50 was determined by MTT (3-[4,5-dimethylthiazol-2-yl]-2, 5-diphenyltetrazolium bromide) assay after 24 h treatment at different concentrations of quercetin. The levels of leptin gene expression were measured by reverse-transcription real-time polymerase chain reaction (PCR). Secreted leptin was measured in the supernatant of cells by an enzyme-linked immuno sorbent assay. ResultsAnalysis of MTT assay data showed that quercetin has a cytotoxic effect on T47D breast cancer cells with 40 µM IC50 after 24 h exposure. Data analysis of real-time PCR showed that with increases in quercetin concentration, a decreasing trend was seen in mRNA levels of leptin of treated cells compared with the control cells (P < 0.05). Also, measurement of secreted leptin in the culture media showed a similar decreasing trend in the amount of leptin protein in the treated cells compared with the control cells (P < 0.05). ConclusionQuercetin significantly inhibits the growth of T47D cells through inhibition of leptin secretion and gene expression in T47D breast cancer cells. Therefore, it might be an alternative approach to breast cancer therapy through leptin targeting.

Antioxidative Activity of Blueberry Leaf Extract Prevents High-fat Diet-induced Obesity in C57BL/6 Mice.

Background:Health beneficial effects of blueberry have been well documented. Obesity is health hazard that is associated with metabolic abnormalities. We investigated the effect of blueberry leaf extract (BBLE) on high-fat diet (HFD)-induced obesity in C57BL/6J mice.Methods:C57BL/6 mice were fed HFD with or without BBLE for 10 weeks. Body weight, serum parameter, and adipose tissues morphology were assessed. The expression of mRNA associated with adipogenesis was measured using real-time polymerase chain reaction (RT-PCR) analysis.Results:Administration of BBLE to mice challenged with HFD significantly decreased the body weight gain, the levels of plasma triglyceride (TG) and liver lipid peroxidation, and reduced the adipocyte size and improved hepatic status compared with the group treated with HFD only. BBLE treatment significantly improved glucose control compared with the HFD group. Moreover, BBLE showed an inhibitory effect on adipocyte differentiation in obese mice together with significant decrease in the lipid accumulation by downregulating gene expression of adipocyte-specific transcription factors, such as peroxisome proliferation-activity receptor and acetyl coenzyme A carboxylase and upregulating the mRNA expression of adiponectin, which are critical for adipogenesis.Conclusion:BBLE suppressed the body weight gain in the HFD-fed C57BL/6 mice. Intake of BBLE reduced body weight in HFD-fed mice by 20%. Furthermore, BBLE supplementation significantly decreased the TG level in the liver and inhibited leptin secretion. BBLE supplementation also improved insulin resistance. Therefore, BBLE is a possible agent to prevent obesity.

The effect of acute swimming exercise on plasma leptin in rats

Exercise is known to increase free fatty acid and glucose metabolism. In consideration of such physiological effects of leptin such as reducing food intake and increasing energy consumption, many researchers have studied the relation between leptin and exercise. Despite the inconsistency between results, it is generally accepted that physical activity causes changes in leptin secretion. The present study aims to determine the changes that occur in plasma leptin levels of the rats subjected to acute swimming exercise, immediately after exercise, and in the 24th and 48th hours following exercise.Forty adult male rats of Spraque Dawley species were equally allocated to 4 groups. Group 1: General Control Group. Group 2: Swimming Group, the group that was decapitated just after 30-minutes of acute swimming exercise. Group 3: Swimming Group, the group that was decapitated 24 hours after 30-minutes of acute swimming exercise. Group 4: Swimming Group, the group that was decapitated 48 hours after 30-minutes of acute swimming exercise. Plasma leptin levels of the experimental animals were determined according to RIA method in the blood samples collected by decapitation method. Comparison of plasma leptin levels between groups revealed that the Group 3 had the highest plasma leptin levels (p <0.01). Plasma leptin levels in the Group 1 (control) and 4 were not different and the Group 2 had the lowest plasma leptin levels (p <0.01). Results of the present study show that an acute swimming exercise and/or stress factors associated with an acute exercise inhibit leptin secretion from the adipose tissue (Tab. 1, Ref. 21).

Plasma leptin and energy expenditure during prolonged, moderate intensity, treadmill exercise.

Current literature shows conflicting results regarding the possible direct role of exercise on leptin concentrations, mainly because of a non-homogeneous level of energy expenditure (EE) and the lack of standardization of energy balance. The aim of the study was to evaluate the effect of exercise duration and its corresponding EE on leptin levels, during prolonged treadmill exercise, in a well-controlled laboratory setting. Seven young trained males underwent a 4-h treadmill exercise. The starting intensity was set at 65% of maximal oxygen consumption. At the start of the test and throughout the exercise, venous blood samples were drawn for the assays of leptin, glucose, free fatty acids (FFA), cortisol, epinephrine (E) and norepinephrine (NE). Hourly and total EE was monitored with gas analysis. Plasma leptin levels decreased from 1.10±0.15 to 0.85±0.26 μg/l (p<0.01) at the end of the exercise, reaching a significant reduction already after the second hour. FFA and cortisol showed a progressive significant increase, while glucose did not significantly change throughout the test. Plasma E and NE significantly increased at all sampling times compared to basal values (48.1±30.3 to 352.3±187.7 pg/ml, p<0.001 and 238.1±118.9 to 1798.7±413.5 pg/ml, p<0.001). The random-effects model for panel data analysis showed negative correlation between leptin, NE and the values of progressive EE (r2=0.745, p<0.05). Our data demonstrate that, during a prolonged moderate intensity exercise, leptin decrease is significantly related to the total EE. Further, NE concentrations seem to play an important role in the inhibition of leptin secretion.

Lipoic acid inhibits leptin secretion and Sp1 activity in adipocytes

Lipoic acid (LA) is an antioxidant with therapeutic potential on several diseases such as diabetes and obesity. Hyperleptinemia and oxidative stress play a major role in the development of obesity-linked diseases. The aim of this study was to examine in vivo and in vitro the effects of LA on leptin production, as well as to elucidate the mechanisms and signalling pathways involved in LA actions. Dietary supplementation with LA decreased both circulating leptin, and adipose tissue leptin mRNA in rats. Treatment of 3T3-L1 adipocytes with LA caused a concentration-dependent inhibition of leptin secretion and gene expression. Moreover, LA stimulated the anaerobic utilization of glucose to lactate, which negatively correlated with leptin secretion. Furthermore, LA enhanced phosphorylation of Sp1 and inhibited Sp1 transcriptional activity in 3T3-L1 adipocytes. Moreover, LA inhibited Akt phosphorylation, a downstream target of phosphatidylinositol 3-kinase (PI3K). Treatment with the PI3K inhibitor LY294002 mimicked LA actions, dramatically inhibiting both leptin secretion and gene expression and stimulating Sp1 phosphorylation. All of these data suggest that the phosphorylation of Sp1 and the accompanying reduced DNA-binding activity are likely to be involved in the inhibition of leptin induced by LA, which could be mediated in part by the abrogation of the PI3K/Akt pathway.

Vitamin C inhibits leptin secretion and some glucose/lipid metabolic pathways in primary rat adipocytes

Antioxidant-based treatments are emerging as an interesting approach to possibly counteract obesity fat accumulation complications, since this is accompanied by an increased systemic oxidative stress. The aim of this study was to analyze specific metabolic effects of vitamin C (VC) on epididymal primary rat adipocytes. Cells were isolated and incubated for 72 h in culture medium, in the absence or presence of 1.6 nM insulin, within a range of VC concentrations (5-1000 microM). Glucose- and lipid-related variables as well as the secretion/expression patterns of several obesity-related genes were assessed. It was observed that VC dose dependently inhibited glucose uptake and lactate production, and also reduced glycerol release in both control and insulin-treated cells. Also, VC caused a dramatic concentration-dependent fall in leptin secretion especially in insulin-stimulated cells. In addition, VC (200 microM) induced Cdkn1a and Casp8, partially inhibited Irs3, and together with insulin drastically reduced Gpdh (listed as Gpd1 in the MGI database) gene expressions. Finally, VC and insulin down-regulatory effects were observed on extracellular and intracellular reactive oxygen species production respectively. In summary, this experimental assay describes a specific effect of VC in isolated rat adipocytes on glucose and fat metabolism, and on the secretion/expression of important obesity-related proteins.

The inhibitory effect of resveratrol on leptin secretion from rat adipocytes

Resveratrol was found to alleviate consequences of some metabolic disturbances which may be due to inappropriate dietary habits. It decreases mortality, increases insulin sensitivity and improves motor functions; these effects are accompanied by reduced plasma leptin and insulin. Leptin plays a significant role in the regulation of food intake and energy expenditure - elevated level in blood is one of the reasons of leptin-resistance and obesity. In this study, the direct effect of resveratrol on leptin secretion from isolated adipocytes was investigated. Isolated rat adipocytes were incubated with resveratrol (62.5, 125 or 250 microM) and its effects on leptin secretion were studied. Cells were incubated with resveratrol in the presence of glucose (5 and 20 mM) and insulin (10 nM); glucose and nicotinic acid (1 mM); glucose and insulin in the presence of an inhibitor of protein kinase A (H-89, 50 microM) or alanine (10 mM) and insulin. The glucose uptake, glycerol release to the incubation medium, lactate and ATP produced by the cells were also measured. Resveratrol inhibited leptin secretion in all experimental designs in a dose-dependent manner. The effect was not accompanied by changes in glycerol release and glucose uptake. Adipocyte exposure to resveratrol enhanced the lactate formation. It was found that resveratrol dramatically reduced ATP in adipocytes. The obtained results revealed the direct ability of resveratrol to reduce leptin secretion from isolated rat adipocytes. Resveratrol is therefore a compound affecting the endocrine function of adipocytes.

Evidence for inhibition of leptin secretion by catecholamines in man.

The regulation of leptin secretion is complex and not entirely understood in humans. Insulin has been shown to stimulate leptin secretion in humans, whereas in vitro data suggest that catecholamines inhibit leptin secretion. The present studies were therefore undertaken to examine the leptin response to hyperinsulinemia in the presence and absence of elevated plasma levels of endogenous catecholamines in humans. Leptin concentrations were determined during both a euglycemic and hypoglycemic hyperinsulinemic clamp study in 10 normal and 10 type I diabetic subjects. Serum leptin increased during the hyperinsulinemic euglycemic clamp in normal (from 6.1 +/- 0.9 to 7.2 +/- 1.1 ng/dl, p = 0.003) and diabetic subjects (from 6.2 +/- 1.4 to 7.8 +/- 1.8 ng/dl, p = 0.001). During hyperinsulinemic hypoglycemia leptin concentrations increased significantly in type 1 diabetic patients (from 5.6 +/- 1.1 to 7.6 +/- 1.7 ng/dl, p = 0.003) but remained unaltered in normals (from 5.5 +/- 0.7 to 5.7 +/- 0.9 ng/dl, p = 0.7). During hypoglycemia in all subjects the increase in leptin was negatively correlated with the increase in epinephrine (r = 0.60, p = 0.005) and positively with the decrease in free fatty acids (r = 0.71, p = 0.003). In conclusion our results indicate that catecholamines play a suppressive role in the regulation of leptin secretion.

Growth hormone/insulin-like growth factor I axis, glucose metabolism, and lypolisis but not leptin show some degree of refractoriness to snort-term fasting in acromegaly

Starvation exerts critical influence on somatotroph and leptin secretion. Fasting enhances GH levels in normal subjects, but not in GH hyposecretory states, while it always inhibits leptin secretion. We aimed to clarify the GH/IGF-I and metabolic response to short-term fasting in a GH hypersecretory state such as acromegaly. To this goal, in 8 active acromegalic (ACRO) and in 7 normal women (NS) we evaluated mean GH (mGHc), leptin (mLEPc), insulin (mINSc), glucose (mGLUc) concentrations as well as IGF-I, IGF binding protein (IGFBP)-3, IGFBP-1, and free fatty acid (FFA) levels before and after 36-h fasting. Before fasting, mGHc, IGF-I, mINSc, mGLUc, and FFA levels in ACRO were higher (p<0.01) than in NS. IGFBP-3, IGFBP-1, and mLEPc were similar in ACRO and in NS. Fasting clearly (p<0.02) increased mGHc in NS only. After 36-h fasting, significant IGF-I reduction was recorded in NS only (p<0.03). IGFBP-3 did not change both in ACRO and NS. IGFBP-1 significantly increased (p<0.05) after fasting in both groups but in ACRO were lower (p<0.03) than in NS. Fasting decreased (p<0.03) mLEPc, mGLUc, and mINSc in ACRO as well as in NS; mINSc and mGLUc after fasting in ACRO persisted higher (p<0.005) than in NS. FFA levels were increased by fasting in NS (p<0.02), but not in ACRO. This study shows that GH/IGF-I axis, glucose metabolism, and lypolisis but not leptin display some degree of refractoriness to short-term fasting in acromegaly. The lack of any GH response to fasting in acromegaly would likely reflect neuroendocrine alterations secondary to the GH hypersecretory state. On the other hand, the lack of somatotropic response and the peculiarly blunted metabolic reaction to short-term fasting would partially reflect the delayed adaptation of insulin resistance to starvation.

Fructose Induced Leptin Dysfunction and Improvement by Quercetin and Rutin in Rats

To investigate the dysfunction of leptin underlying insulin resistance syndrome in fructose-fed rats and improvement by lowing uric acid with natural products quercetin and rutin. Rats were fed with fructose solution for 8 weeks. At week 4, animals received quercetin and rutin, as well as allopurinol. Serum uric acid and insulin levels were measured before and after drug treatment. Leptin levels in serum and hypothalamus, leptin secretion from adipose tissue were used to evaluate the responses of leptin to hyperuricemia and hyperinsulinemia in rats with insulin resistance syndrome. Triglyceride (TG), high dense lipid (HDL) and low dense lipid (LDL) in serum were examined to evaluate dyslipidemia in fructose-fed rats. Fructose consumption significantly increased serum uric acid, insulin and leptin levels in rats, and induced a significant increase of leptin secretion by upregulating ob gene expression in adipose tissue. Quercetin and rutin, as well as allopurinol reduced hyperleptinemia and inhibited leptin secretion from adipose tissue. Moreover, fructose-fed rats exhibited leptin level increase in hypothalamus accompanying dyslipidemia. Quercetin, rutin and allopurinol attenuated fructose-induced dyslipidemia in rats, but failed to improve leptin insufficiency in hypothalamus. These results indicated that fructose consumption might cause hyperleptinemia and leptin insufficiency in the brain, which might be indirectly mediated by hyperinsulinemia and hypertriglyceridemia in rats. Hopouricemic agents quercetin, rutin and allopurinol improved hyperinsulinemia and dyslipidemia, and subsequently regulated leptin dysfunction in fructose-fed rats. This study provided direct evidence that hyperuricemia was associated with hyperleptinemia during fructose consumption, and another pharmacological explanation for lowing uric acid agents to prevent hyperuricemia and leptin dysfunctions in fructose-induced insulin resistance syndrome in rats.

Effect of niacin on adipocyte leptin in hypercholesterolemic rabbits

Leptin may play an important role in the development of atherosclerosis. Several transcription genes [including peroxisome proliferator-activated receptor gamma (PPARgamma) and CD36] involved in lipid and glucose metabolism and inflammatory processes may correlate to leptin expression. The aim of this study was to investigate the effect of niacin on serum leptin levels in hypercholesterolemic rabbits and the expression of leptin, PPARgamma, and CD36 in adipocytes from hypercholesterolemic rabbits. Eighteen rabbits fed with high-cholesterol diet for 8 weeks were randomly divided into two groups: (a) high-cholesterol group (n=6), which is maintained on high-cholesterol diet for 6 weeks, and (b) niacin group (n=6), which receives the same cholesterol diet plus niacin (200 mg/kg/day) for 6 weeks. The control group (n=6) was fed with normal diet for 14 weeks. Subcutaneous adipose was collected for RNA analysis. The direct effect of niacin on leptin release was assayed in hypercholesterolemic rabbit adipocytes. Leptin levels in serum and adipocyte culture supernatant were measured via enzyme-linked immunosorbent assay. RT-PCR was used to evaluate leptin, PPARgamma, and CD36 mRNA expression in adipose and adipocytes. Compared with the control group, rabbits fed with high-cholesterol diets showed higher levels of serum total cholesterol, low-density lipoprotein cholesterol, and leptin, all of which were significantly reduced by niacin treatment. After 6 weeks of treatment with niacin, the leptin level was significantly decreased by 21.8% (6.87+/-1.58 vs. 8.79+/-1.45, P<.05) and leptin mRNA expression of adipose was significantly lower in rabbits treated with niacin than in those fed with high-cholesterol diet continuously (0.58+/-0.11 vs. 0.73+/-0.15, P<.05). Niacin dose-dependently inhibited leptin secretion and increased CD36 and PPARgamma expression in cultured adipocytes. The reduction of leptin mRNA expression of hypercholesterolemic rabbits by niacin was negatively correlated with the up-regulation of PPARgamma and CD36 mRNA expression by niacin (r=-.69 and r=-.63, respectively, P<.01). Niacin can reduce serum level and adipose mRNA expression of leptin and up-regulate PPARgamma and CD36 mRNA expression in hypercholesterolemic rabbits.

Thermogenic effect of triiodothyroacetic acid at low doses in rat adipose tissue without adverse side effects in the thyroid axis

Triiodothyroacetic acid (TRIAC) is a physiological product of triiodothyronine (T(3)) metabolism, with high affinity for T(3) nuclear receptors. Its interest stems from its potential thermogenic effects. Thus this work aimed 1) to clarify these thermogenic effects mediated by TRIAC vs. T(3) in vivo and 2) to determine whether they occurred predominantly in adipose tissues. To examine this, control rats were infused with equimolar T(3) or TRIAC doses (0.8 or 4 nmolx100 g body wt(-1) x day(-1)) or exposed for 48 h to cold. Both T(3) doses and only the highest TRIAC dose inhibited plasma and pituitary thyroid-stimulating hormone (TSH) and thyroxine (T(4)) in plasma and tissues. Interestingly, the lower TRIAC dose marginally inhibited plasma T(4). T(3) infusion increased plasma and tissue T(3) in a tissue-specific manner. The highest TRIAC dose increased TRIAC concentrations in plasma and tissues, decreasing plasma T(3). TRIAC concentrations in tissues were <10% those of T(3). Under cold exposure or high T(3) doses, TRIAC increased only in white adipose tissue (WAT). Remarkably, only the lower TRIAC dose activated thermogenesis, inducing ectopic uncoupling protein (UCP)-1 expression in WAT and maximal increases in UCP-1, UCP-2, and lipoprotein lipase (LPL) expression in brown adipose tissue (BAT), inhibiting UCP-2 in muscle and LPL in WAT. TRIAC, T(3), and cold exposure inhibited leptin secretion and mRNA in WAT. In summary, TRIAC, at low doses, induces thermogenic effects in adipose tissues without concomitant inhibition of TSH or hypothyroxinemia, suggesting a specific role regulating energy balance. This selective effect of TRIAC in adipose tissues might be considered a potential tool to increase energy metabolism.

Adiponectin and leptin are secreted through distinct trafficking pathways in adipocytes

Adiponectin and leptin are two adipokines secreted by white adipose tissue that regulate insulin sensitivity. Previously we reported that adiponectin but not leptin release depends on GGA-coated vesicle formation, suggesting that leptin and adiponectin may follow different secretory routes. Here we have examined the intracellular trafficking pathways that lead to the secretion of these two hormones. While adiponectin and leptin displayed distinct localization in the steady-state, treatment of adipocytes with brefeldin A inhibited both adiponectin and leptin secretion to a similar level, indicating a common requirement for class III ADP-ribosylating factors and an intact Golgi apparatus. Adiponectin secretion was significantly reduced by endosomal inactivation in both 3T3L1 and rat isolated adipocytes, whereas this treatment had no effect on leptin secretion. Importantly, endosomal inactivation completely abolished the insulin stimulatory effect on adiponectin release in rat adipocytes. Confocal microscopy studies revealed colocalization of adiponectin with endogenous rab11 a marker for the recycling endosome, and with expressed rab5-GFP mutant (rab5Q75L) a marker for the early endosome compartment. Colocalization of adiponectin and rab5Q75L was increased in endosome inactivated cells. Consistent with these findings adiponectin secretion was reduced in cells expressing mutants of Rab11 and Rab5 proteins. In contrast, expression of an inactive (kinase dead) mutant of Protein Kinase D1 moderately but significantly inhibited leptin secretion without altering adiponectin secretion. Taken together, these results suggest that leptin and adiponectin secretion involve distinct intracellular compartments and that endosomal compartments are required for adiponectin but not for leptin secretion.

The effect of pH-neutral peritoneal dialysis fluids on adipokine secretion from cultured adipocytes

Adipokines are a group of fat-secreted hormones and cytokines, including leptin and adiponectin, with important functions in humans. Peritoneal dialysis (PD) is associated with markedly raised plasma adipokines, suggesting increased production in this setting. We have shown that low pH down-regulates leptin production. The current study was designed to test if novel pH-neutral PD fluids may regulate leptin and adiponectin secretion in vitro. We exposed 3T3-L1 adipocytes to a 50 : 50 mixture of dialysate and M199 containing 10% serum for upto 48 h. Dialysates were commercial PD fluids, i.e. conventional acidic, lactate-buffered solutions (PD-acid) and pH-neutral lactate-buffered (PD-Bal) or bicarbonate-buffered solutions (PD-Bic). Leptin and adiponectin concentrations in culture-cell media were measured by ELISA. Compared with PD-acid, PD-Bal and PD-Bic produced a 25 and 43% increase, respectively, in leptin secretion at 48 h (P < 0.05). In contrast, adiponectin secretion was not affected. High glucose PD fluids (4.25%) specifically inhibited leptin secretion vs 1.5% glucose, buffer-matched solutions (P < 0.05). However, differences in leptin secretion due to pH and type of buffer remained significant. In further experiments, the pH of test media were extensively varied without the presence of dialysates. Leptin secretion was shown to increase in a parallel to pH, whereas large changes in pH did not affect adiponectin secretion. The pH-neutral PD solutions specifically induce leptin, but not adiponectin secretion from 3T3-L1 adipocytes. PD-Bic produced a greater leptin stimulation than PD-Bal, but this difference was attributable to pH per se, rather than the type of buffer.

Nitric oxide-induced downregulation of leptin production by 3T3-L1 adipocytes

Leptin secreted mainly by adipocytes plays an important role in insulin sensitivity in metabolic syndrome. Inducible nitric oxide synthase (iNOS) in 3T3-L1 adipocytes is induced by lipopolysaccharide (LPS) and several proinflammatory cytokines such as tumor necrosis factor-alpha and interferon-gamma (IFN-gamma). Because the role of iNOS-derived nitric oxide (NO) in adipocyte function has not been fully clarified, the question that we addressed in the present study was whether iNOS-derived NO is involved in regulation of leptin secretion by adipocytes. Incubation of 3T3-L1 adipocytes for 12h with a mixture of IFN-gamma and LPS caused not only a 55% reduction in leptin secretion and a 52% reduction in leptin mRNA, but also significant induction of iNOS at both protein and mRNA levels. Inhibition of leptin secretion that had been induced by the IFN-gamma-LPS mixture was completely nullified by NOS inhibitors such as Nomega-monomethyl-L-arginine and aminoguanidine. Treatment of adipocytes with NO donors such as an NONOate and S-nitrosoglutathione produced an effect on leptin secretion similar to that of the IFN-gamma-LPS mixture. It is likely therefore that NO mediates downregulation of leptin caused by the IFN-gamma-LPS mixture in 3T3-L1 adipocytes, which suggests an important role for NO in adipocyte functions.

Hyperinsulinemia and Insulin Insensitivity in Women with Nonclassical Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency: The Relationship between Serum Leptin Levels and Chronic Hyperinsulinemia

Background/Aim: Nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency (NC-CAH) is associated with hyperandrogenemia, chronic anovulation, hirsutism, acne and adrenal hyperplasia. A few studies have shown hyperinsulinemia and insulin insensitivity in NC-CAH. Hyperinsulinemia can stimulate leptin secretion, and androgens can inhibit leptin secretion. Thus, we designed a study to investigate the insulin levels and insulin sensitivity and the effect of chronic endogenous hyperinsulinemia and androgens on leptin in patients with NC-CAH. Methods: Eighteen women with untreated NC-CAH and 26 normally cycling control women with a similar body mass index (BMI) were studied. Basal hormones, fasted and fed insulin levels, leptin and stimulated 17-hydroxyprogesterone (17-OHP) concentrations were studied. Homeostasis model assessment was used to assess insulin sensitivity. Results: The basal 17-OHP, the free testosterone (fT) and dehydroepiandrosterone sulfate (DHEA-S) were significantly different in the 2 groups (p < 0.05). Fasting and fed insulin levels of the NC-CAH group were higher than those of the control group (p < 0.05) and insulin sensitivity was lower in NC-CAH than in controls (p < 0.05). Insulin levels were correlated with fT and 17-OHP (p < 0.05). Serum leptin levels for NC-CAH (25.9 ± 12.5 µg/l) did not differ from the controls (25.4 ± 12.06 µg/l) and were positively correlated with BMI (r = 0.725) and percent body fat (r = 0.710) for both groups (both p < 0.001). Leptin levels were not correlated with estrogen or androgens, gonadotropins or insulin levels. Conclusion: Hyperinsulinemia and insulin insensitivity associated with hyperandrogenism were detected in untreated NC-CAH patients as in previous reports, whereas serum leptin levels did not differ from those of controls.

Dual Roles of P2 Purinergic Receptors in Insulin-stimulated Leptin Production and Lipolysis in Differentiated Rat White Adipocytes

ATP is co-localized with norepinephrine at the sympathetic nerve terminals and may be released simultaneously upon neuronal stimulation, which results in activation of purinergic receptors. To examine whether leptin synthesis and lipolysis are influenced by P2 purinergic receptor activation, the effects of ATP and other nucleotides on leptin secretion and glycerol release have been investigated in differentiated rat white adipocytes. Firstly, insulin-induced leptin secretion was inhibited by nucleotide treatment with the following efficacy order: 3'-O-(4-benzoyl)benzoyl ATP (BzATP) > ATP >> UTP. Secondly, treatment of adipocytes with ATP increased both intracellular Ca(2+) concentration and cAMP content. Intracellular calcium concentration was increased by ATP and UTP, but not BzATP, an effect attributed to phospholipase C-coupled P2Y(2). On the other hand, cAMP was generated by treatment with BzATP and ATPgammaS, but not UTP, indicating functional expression of adenylyl cyclase-coupled P2Y(11) receptors in white adipocytes. Thirdly, lipolysis was significantly activated by BzATP and ATP, which correlated with the characteristics of the P2Y(11) subtype. Taken together, the data presented here suggest that white adipocytes express at least two different types of P2Y receptors and that activation of P2Y(11) receptor might be involved in inhibition of leptin production and stimulation of lipolysis, suggesting that purinergic transmission can play an important role in white adipocyte physiology.

Atorvastatin reduces serum leptin concentration in hypercholesterolemic rabbits

Background Leptin may play an important role in the development of atherosclerosis. We evaluated the effect of atorvastatin on leptin secretion in vivo and in vitro. Methods Sixteen rabbits fed with high-cholesterol diet for 8 weeks were randomly divided into 2 groups: (1) high cholesterol diet for 6 weeks ( n = 8), and (2) the same cholesterol diet plus atorvastatin (2.5 mg/kg/day) for 6 weeks ( n = 8). A control group ( n = 5) was fed with normal diet for 14 weeks. Subcutaneous adipose was collected for RNA analysis. The direct effect of atorvastatin on leptin release was assayed in primary rabbit adipocytes. Leptin levels in serum and adipocytes culture supernatant were measured by ELISA. RT–PCR was used to evaluate leptin mRNA expressions in adipose and adipocytes. Results Compared with control group, rabbits fed with high cholesterol diet showed higher levels of serum total cholesterol, LDL cholesterol and leptin, all of which were significantly reduced by atorvastatin treatment. Leptin mRNA expression of adipose was significant lower in rabbits treated with atorvastatin than those fed with high cholesterol diet continuously (0.81 ± 0.31 vs. 1.23 ± 0.36, P < 0.05). Atorvastatin dose-dependently inhibited leptin secretion and mRNA expression in cultured adipocytes. Conclusion Atorvastatin can inhibit leptin release and mRNA expression, and reduces serum leptin level in hypercholesterolemic rabbits.

Acute regulation of plasma leptin by isoprenaline in lean and obese fasted subjects

In human obesity, there is some evidence for impaired adrenergic sensitivity with respect to catecholamine-induced lipolysis. The beta-adrenoceptor agonist isoprenaline has been shown to suppress plasma leptin levels in lean humans in vivo. We hypothesized that a reduced adrenergic sensitivity in obese humans would result in impaired suppression of leptin secretion. Eight obese [Ob, body mass index (BMI) = 33.3 kg/m2] and seven lean (Ln, BMI = 21.8 kg/m2) men were studied after an overnight fast. Intravenous isoprenaline infusion was initiated at a rate of 8 ng/kg/min, titrated up to 24 ng/kg/min over 30 min and continued at this rate for a further 120 min with continuous electrocardiogram monitoring. Baseline fasting plasma leptin was higher in obese compared with lean subjects (Ob 12.2 +/- 1.8, Ln 2.6 +/- 0.6 ng/ml, p < 0.05 unpaired t-test). Baseline fasting glycerol as a measure of lipolysis was similar in both groups (Ob 62.9 +/- 7.6, Ln 42.4 +/- 8.9 micromol/l) and increased from baseline to 150 min by equivalent amounts (Ob +66.9%, Ln +81.2%, p = NS). Plasma leptin decreased from baseline to 150 min with similar relative changes in both groups (Ob -29.2%, Ln -27.8%). Obese subjects show a similar lipolytic and leptin response to acute isoprenaline infusion compared with lean subjects. Impaired beta-adrenergic-induced inhibition of leptin secretion does not appear to contribute to hyperleptinaemia in obese human subjects.