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ABSTRACT: Lipoic acid (LA) is a naturally occurring compound with antioxidant properties. Recent attention has been focused on the potential beneficial effects of LA on obesity and related metabolic disorders. Dietary supplementation with LA prevents insulin resistance and upregulates adiponectin, an insulin-sensitizing adipokine, in obese rodents. The aim of this study was to investigate the direct effects of LA on adiponectin production in cultured adipocytes, as well as the potential signaling pathways involved. For this purpose, fully differentiated 3T3-L1 adipocytes were treated with LA (1-500 μM) during 24 h. The amount of adiponectin secreted to media was detected by ELISA, while adiponectin mRNA expression was determined by RT-PCR. Treatment with LA induced a dose-dependent inhibition on adiponectin gene expression and protein secretion. Pretreatment with the PI3K inhibitor LY294002 inhibited adiponectin secretion and mRNA levels, and significantly potentiated the inhibitory effect of LA on adiponectin secretion. The AMPK activator AICAR also reduced adiponectin production, but surprisingly, it was able to reverse the LA-induced inhibition of adiponectin. The JNK inhibitor SP600125 and the MAPK inhibitor PD98059 did not modify the inhibitory effect of LA on adiponectin. In conclusion, our results revealed that LA reduces adiponectin secretion in 3T3-L1 adipocytes, which contrasts with the stimulation of adiponectin described after in vivo supplementation with LA, suggesting that an indirect mechanism or some in vivo metabolic processing is involved.
Journal of physiology and biochemistry 01/2013; · 1.71 Impact Factor
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ABSTRACT: BACKGROUND: Lipoic acid (LA) is an antioxidant with antiobesity and antidiabetic properties. Adiponectin is an adipokine with potent anti-inflammatory and insulin-sensitizing properties. AMP-activated protein kinase (AMPK) is a key enzyme involved in cellular energy homeostasis. Activation of AMPK has been considered as a target to reverse the metabolic abnormalities associated with obesity and type 2 diabetes. AIM OF THE STUDY: The aim of this study was to determine the effects of LA on AMPK phosphorylation and adiponectin production in adipose tissue of low-fat (control diet) and high-fat diet-fed rats. RESULTS: Dietary supplementation with LA reduced body weight and adiposity in control and high-fat-fed rats. LA also reduced basal hyperinsulinemia as well as the homeostasis model assessment (HOMA) levels, an index of insulin resistance, in high-fat-fed rats, which was in part independent of their food intake lowering actions. Furthermore, AMPK phosphorylation was increased in white adipose tissue (WAT) from LA-treated rats as compared with pair-fed animals. Dietary supplementation with LA also upregulated adiponectin gene expression in WAT, while a negative correlation between adiposity-corrected adiponectin levels and HOMA index was found. Our present data suggest that the ability of LA supplementation to prevent insulin resistance in high-fat diet-fed rats might be related in part to the stimulation of AMPK and adiponectin in WAT.
European Journal of Nutrition 06/2012; · 2.75 Impact Factor
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ABSTRACT: Nonalcoholic steatosis is an important hepatic complication of obesity linked to mitochondrial dysfunction and insulin resistance. Furthermore, lipoic acid has been reported to have beneficial effects on mitochondrial function. In this study, we analyzed the potential protective effect of lipoic acid supplementation against the development of nonalcoholic steatosis associated with a long-term high-fat diet feeding and the potential mechanism of this effect. Wistar rats were fed on a standard diet (n=10), a high-fat diet (n=10) and a high-fat diet supplemented with lipoic acid (n=10). A group pair-fed to the latter group (n=6) was also included. Lipoic acid prevented hepatic triglyceride accumulation and liver damage in rats fed a high-fat diet (-68%±11.3% vs. obese group) through the modulation of genes involved in lipogenesis and mitochondrial β-oxidation and by improving insulin sensitivity. Moreover, this molecule showed an inhibitory action on electron transport chain complexes activities (P<.01-P<.001) and adenosine triphosphate synthesis (P<.05), and reduced significantly energy efficiency. By contrast, lipoic acid induced an increase in mitochondrial copy number and in Ucp2 gene expression (P<.001 vs. obese). In summary, this investigation demonstrated the ability of lipoic acid to prevent nonalcoholic steatosis induced by a high-fat intake. Finally, the novelty and importance of this study are the finding of how lipoic acid modulates some of the mitochondrial processes involved in energy homeostasis. The reduction in mitochondrial energy efficiency could also explain, at least in part, the beneficial effects of lipoic acid not only in fatty liver but also in preventing excessive body weight gain.
The Journal of nutritional biochemistry 03/2012; · 4.29 Impact Factor
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ABSTRACT: Cardiotrophin-1 (CT-1) is a member of the gp130 family of cytokines. We observed that ct-1(-/-) mice develop mature-onset obesity, insulin resistance, and hypercholesterolemia despite reduced calorie intake. Decreased energy expenditure preceded and accompanied the development of obesity. Acute treatment with rCT-1 decreased blood glucose in an insulin-independent manner and increased insulin-stimulated AKT phosphorylation in muscle. These changes were associated with stimulation of fatty acid oxidation, an effect that was absent in AMPKα2(-/-) mice. Chronic rCT-1 treatment reduced food intake, enhanced energy expenditure, and induced white adipose tissue remodeling characterized by upregulation of genes implicated in the control of lipolysis, fatty acid oxidation, and mitochondrial biogenesis and genes typifying brown fat phenotype. Moreover, rCT-1 reduced body weight and corrected insulin resistance in ob/ob and in high-fat-fed obese mice. We conclude that CT-1 is a master regulator of fat and glucose metabolism with potential applications for treatment of obesity and insulin resistance.
Cell metabolism 08/2011; 14(2):242-53. · 17.35 Impact Factor
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ABSTRACT: The incidence of obesity and associated co-morbidities such as insulin resistance, dyslipidemia and cardiovascular diseases has reached epidemic proportions worldwide. As a result, new therapeutic options for the treatment of these conditions are clearly warranted. Comment on: Moreno-Aliaga MJ et al. Cell Metab. 2011; 14: 242-253.
Aging 08/2011; 3(8):698-9. · 5.13 Impact Factor
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ABSTRACT: 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.
Molecular Nutrition & Food Research 02/2011; 55(7):1059-69. · 4.30 Impact Factor
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ABSTRACT: Obesity is a complex disease caused by the interaction of a myriad of genetic, dietary, lifestyle and environmental factors, which favors a chronic positive energy balance, leading to increased body fat mass. There is emerging evidence of a strong association between obesity and an increased risk of cancer. However, the mechanisms linking both diseases are not fully understood. Here, we analyze the current knowledge about the potential contribution that expanding adipose tissue in obesity could make to the development of cancer via dysregulated secretion of pro-inflammatory cytokines, chemokines and adipokines such as TNF-α, IL-6, leptin, adiponectin, visfatin and PAI-1. Dietary factors play an important role in the risk of suffering obesity and cancer. The identification of bioactive dietary factors or substances that affect some of the components of energy balance to prevent/reduce weight gain as well as cancer is a promising avenue of research. This article reviews the beneficial effects of some bioactive food molecules (n-3 PUFA, CLA, resveratrol and lipoic acid) in energy metabolism and cancer, focusing on the molecular mechanisms involved, which may provide new therapeutic targets in obesity and cancer.
Biochimica et Biophysica Acta 11/2010; 1807(6):664-78. · 4.66 Impact Factor
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ABSTRACT: The aim of the present study was to investigate the relationship between the differential expression of genes related to lipid metabolism in subcutaneous adipose tissue and metabolic syndrome features in lean and obese subjects with habitual high fat intake.
Microarray and RT-PCR analysis were used to analyze and validate differential gene expression in subcutaneous abdominal adipose tissue samples from lean and obese phenotype subjects.
Several genes and transcripts involved in lipolysis were down-regulated, such as AKAP1, PRKAR2B, Gi and CIDEA, whereas NPY1R and CES1 were up-regulated, when comparing obese to lean subjects. Similarly, transcripts associated with cholesterol and lipoprotein metabolism showed a differential expression, with APOE and ABCA being decreased and VLDLR being increased in obese versus lean subjects. In addition, positive correlations were found between different markers of the metabolic syndrome and CES1 and NPY1R mRNA expressions, while APOE showed an inverse association with some of them.
Different expression patterns in transcripts encoding for proteins involved in lipolysis and lipoprotein metabolism were found between lean and obese subjects. Moreover, the dysregulation of genes such as CES1 and APOE seems to be associated with some physiopathological markers of insulin resistance and cardiovascular risk factors in obesity.
Obesity Facts 10/2010; 3(5):312-8. · 1.86 Impact Factor
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ABSTRACT: Obesity leads to several chronic morbidities including type 2 diabetes, dyslipidaemia, atherosclerosis and hypertension, which are major components of the metabolic syndrome. White adipose tissue (WAT) metabolism and WAT-derived factors (fatty acids and adipokines) play an important role in the development of these metabolic disturbances. In fact, dysregulated adipokine secretion from the expanded WAT of obese individuals contributes to the development of systemic low-grade inflammation, insulin resistance and metabolic syndrome. The n-3 PUFA EPA and DHA have been widely reported to have protective effects in a range of chronic inflammatory conditions including obesity. In fact, n-3 PUFA have been shown to ameliorate low-grade inflammation in adipose tissue associated with obesity and up-regulate mitochondrial biogenesis and induce beta-oxidation in WAT in mice. Moreover, the ability of n-3 PUFA to regulate adipokine gene expression and secretion has been observed both in vitro and in vivo in rodents and human subjects. The present article reviews: (1) the physiological role of adiponectin, leptin and pre-B cell colony-enhancer factor/visfatin, three adipokines with immune-modulatory properties involved in the regulation of metabolism and insulin sensitivity and (2) the actions of n-3 PUFA on these adipokines focusing on the underlying mechanisms and the potential relationship with the beneficial effects of these fatty acids on obesity-associated metabolic disorders. It can be concluded that the ability of n-3 PUFA to improve obesity and insulin resistance conditions partially results from the modulation of WAT metabolism and the secretion of bioactive adipokines including leptin, adiponectin and visfatin.
Proceedings of The Nutrition Society 08/2010; 69(3):324-32. · 2.77 Impact Factor
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ABSTRACT: The precise mechanisms by which omega-3 fatty acids improve fat metabolism are not completely understood. This study was designed to determine the effects of eicosapentaenoic acid (EPA) ethyl ester administration on the expression levels of several muscle, liver and adipose tissue genes involved in lipogenesis and fatty acid oxidation pathways. Male Wistar rats fed a standard diet (control animals) or a high-fat diet were treated daily by oral gavage with EPA ethyl ester (1g/kg) for 5 weeks. The high-fat diet caused a very significant increase in plasma cholesterol (P<.01) levels, which was reverted by EPA (P<.001). A significant decrease in circulating triglyceride levels (P<.05) was also observed in EPA-treated groups. EPA administration induced a significant down-regulation in some lipogenic genes such as muscle acetyl CoA carboxylase beta (ACC beta) (P<.05) and liver fatty acid synthase (FAS) (P<.05). Furthermore, a decrease in glucokinase (GK) gene expression was observed in EPA-treated animals fed a control diet (P<.01), whereas a significant increase in GK mRNA levels was found in groups fed a high-fat diet. On the other hand, no alterations in genes involved in beta-oxidation, such acetyl CoA synthase 4 (ACS4), acetyl CoA synthase 5 (ACS5) or acetyl CoA oxidase (ACO), were found in EPA-treated groups. Surprisingly and opposite to the expectations, a very significant decrease in the expression levels of liver PPARalpha (P<.01) was observed after EPA treatment. These findings show the ability of EPA ethyl ester treatment to down-regulate some genes involved in fatty acid synthesis without affecting the transcriptional activation of beta-oxidation-related genes.
The Journal of nutritional biochemistry 10/2008; 20(9):705-14. · 4.29 Impact Factor
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ABSTRACT: Previous studies have demonstrated that the n-3 fatty acid EPA improves insulin resistance induced by high-fat diets. The aim of the present study was to investigate the potential role of visfatin and apelin in the insulin-sensitising effects of EPA ethyl ester. The effects of EPA on muscle and adipose GLUT mRNA, as well as on liver glucokinase (GK) and glucose-6-phosphatase (G6Pase) activity, were investigated. Male Wistar rats fed on a standard diet or a high-fat cafeteria diet were daily treated by oral administration with EPA ethyl ester (1 g/kg) for 5 weeks. A significant decrease (P < 0.01) in white adipose tissue (WAT) visfatin mRNA levels was found in the cafeteria-fed rats, which was reversed by EPA administration (P < 0.05). Moreover, a negative relationship was observed between homeostatic model assessment (HOMA) and the visfatin:total WAT ratio. In contrast, cafeteria-diet feeding caused a significant increase (P < 0.01) in apelin mRNA in visceral WAT. EPA increased (P < 0.01) apelin gene expression, and a negative relationship between HOMA index with visceral apelin mRNA and serum apelin:total WAT ratio was also observed. EPA treatment did not induce changes in skeletal muscle GLUT1, GLUT4 or insulin receptor mRNA levels. Neither liver GK and G6Pase activity nor the GK:G6Pase ratio was modified by EPA. These data suggest that somehow the insulin-sensitising effects of EPA could be related to its stimulatory action on both visfatin and apelin gene expression in visceral fat, while changes in skeletal muscle GLUT, as well as in hepatic glucose production, are not likely to be the main contributing factors in the improvement in insulin resistance induced by EPA.
The British journal of nutrition 09/2008; 101(7):1059-67. · 3.45 Impact Factor
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ABSTRACT: A number of studies have yielded controversial results on the association between polymorphisms in UCP2 and UCP3 genes with obesity and its comorbidities. The discrepancy among studies might be partially explained by the lack of consideration of the effect of adjacent loci in the same haplotype and the exclusion of key lifestyle factors in the statistical analysis. In this study, we have assessed the association between three genetic variants of the UCP2-UCP3 gene cluster, the -866G/A (rs659366) and the 45bp insertion (in position 173247 of the AC019121) of the UCP2 gene, the -55C/T (rs1800849) polymorphism of the UCP3 gene and their estimated haplotypes with childhood obesity and insulin resistance. This research was designed as a case-control study and information about several environmental parameters such as leisure time physical activity and time spent watching television were included. The study sample consisted in 193 obese children and adolescents (cases) and 170 controls aged 6-18. We found that the individual polymorphisms were not associated with obesity, but the (-866G; rs659366)-(Del; 45bp)-(-55T; rs1800849) haplotype was significantly associated with obesity and its presence in the control group increased about nine times the insulin resistance risk. Thus, the (-866A; rs659366)-(Ins; 45bp)-(-55C; rs1800849) haplotype may protect against insulin resistance in the obese population group.
Molecular Genetics and Metabolism 01/2008; 92(4):351-8. · 3.19 Impact Factor
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ABSTRACT: The aim of this study was to identify and characterize factors associated with childhood obesity risk related to lifestyle and perinatal life influences (dietary pattern, physical activity, family history of obesity, breast-feeding, sedentary behavior, and birth weight) in a case-control study design.
Cases were 185 obese (body mass index >97th percentile) children and adolescents (6-18 y old) from the Navarra region of Spain and control subjects were matched by sex and age. Anthropometric data were collected, and a personal interview about lifestyle parameters (dietary patterns, physical activity, family history of obesity, breast-feeding and sedentary behaviors) was performed with each participant. Conditional logistic regression was used to identify predictive factors of obesity.
Leisure time physical activity proved to be a protector factor against obesity (odds ratio [OR] 0.94, 95% confidence interval [CI] 0.92-0.96), whereas family history of obesity (OR 4.18, 95% CI 2.20-8.62), watching television (OR 2.02, 95% CI 1.09-3.77), and sugar-sweetened beverage consumption (OR 1.74, 95% CI 1.05-2.89) were associated with a higher obesity risk.
Our results suggest that leisure time physical activity, family history of obesity, watching television, and sugar-sweetened beverage consumption are important predictive variables for childhood obesity, whereas other factors including breast-feeding, birth weight, and time spent sleeping did not appear to play an important role in the development of childhood obesity.
Nutrition 05/2007; 23(5):379-84. · 3.03 Impact Factor
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ABSTRACT: n-3 PUFA have shown potential anti-obesity and insulin-sensitising properties. However, the mechanisms involved are not clearly established. The aim of the present study was to assess the effects of EPA administration, one of the n-3 PUFA, on body-weight gain and adiposity in rats fed on a standard or a high-fat (cafeteria) diet. The actions on white adipose tissue lipolysis, apoptosis and on several genes related to obesity and insulin resistance were also studied. Control and cafeteria-induced overweight male Wistar rats were assigned into two subgroups, one of them daily received EPA ethyl ester (1 g/kg) for 5 weeks by oral administration. The high-fat diet induced a very significant increase in both body weight and fat mass. Rats fed with the cafeteria diet and orally treated with EPA showed a marginally lower body-weight gain (P = 0.09), a decrease in food intake (P < 0.01) and an increase in leptin production (P < 0.05). EPA administration reduced retroperitoneal adipose tissue weight (P < 0.05) which could be secondary to the inhibition of the adipogenic transcription factor PPARgamma gene expression (P < 0.001), and also to the increase in apoptosis (P < 0.05) found in rats fed with a control diet. TNFalpha gene expression was significantly increased (P < 0.05) by the cafeteria diet, while EPA treatment was able to prevent (P < 0.01) the rise in this inflammatory cytokine. Adiposity-corrected adiponectin plasma levels were increased by EPA. These actions on both TNFalpha and adiponectin could explain the beneficial effects of EPA on insulin resistance induced by the cafeteria diet.
British Journal Of Nutrition 03/2007; 97(2):389-98. · 3.01 Impact Factor
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ABSTRACT: Eicosapentaenoic acid (EPA), one of the n-3 polyunsaturated fatty acids, has been shown to stimulate leptin mRNA expression and secretion in 3T3-L1 cells. However, other studies have reported inhibitory effects of EPA on leptin expression and secretion in vivo and in vitro. To determine the direct effects of EPA on basal and insulin-stimulated leptin secretion, isolated rat adipocytes were incubated with EPA in the absence and presence of insulin. EPA (10, 100, and 200 microM) increased basal leptin gene expression and secretion (+43.8%, P < 0.05; +71.1%, P < 0.01; and +73.7%, P < 0.01, respectively). EPA also increased leptin secretion in the presence of 1.6 nM insulin; however, the effect was less pronounced than in the absence of it. Because adipocyte glucose and lipid metabolism are involved in the regulation of leptin production, the metabolic effects of this fatty acid were also examined. EPA (200 microM) increased basal glucose uptake in isolated adipocytes (+50%, P < 0.05). Anaerobic metabolism of glucose, as assessed by lactate production and proportion of glucose metabolized to lactate, has been shown to be inversely correlated to leptin secretion and was decreased by EPA in both the absence and presence of insulin. EPA increased basal glucose oxidation as determined by the proportion of (14)C-labeled glucose metabolized to CO(2). Lipogenesis ((14)C-labeled glucose incorporation into triglyceride) was decreased by EPA in the absence of insulin, whereas lipolysis (glycerol release) was unaffected. The EPA-induced increase of basal leptin secretion was highly correlated with increased glucose utilization (r = +0.89, P < 0.01) and inversely related to the anaerobic glucose metabolism to lactate. EPA's effect on insulin-stimulated leptin secretion was not related to increased glucose utilization but was inversely correlated with anaerobic glucose metabolism to lactate (r = -0.84, P < 0.01). Together, the results suggest that EPA, like insulin, stimulates leptin production by increasing the nonanaerobic/oxidative metabolism of glucose.
AJP Regulatory Integrative and Comparative Physiology 06/2005; 288(6):R1682-8. · 3.34 Impact Factor
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ABSTRACT: We have previously reported that glucose metabolism mediates the effects of insulin to increase leptin gene expression and leptin secretion by isolated adipocytes. The aim of the present study was to investigate the role of transcription and translation in the regulation of basal and insulin-stimulated leptin production. The short-term (4 h) and long-term (24-48 h) effects of actinomycin D, a transcriptional inhibitor, and cycloheximide, an inhibitor of protein synthesis, on leptin gene expression and leptin secretion by isolated adipocytes were determined. Actinomycin D (5 microg/ml) increased both basal and insulin-stimulated (1.6 nM) leptin secretion at 4 and 24h (193+/-14.9% and 153.8+/-10.4% of respective controls at 24h, both p<0.001). Similar effects of actinomycin D were observed on basal and insulin-stimulated leptin mRNA levels. 5,6-dichlororibofuranosyl benzimidazole (DRB), another inhibitor of transcription, also increased basal (175.4+/-18.2% of control; p<0.01) and insulin-stimulated leptin secretion (141.0+/-11.1% of insulin-treated cells; p<0.05) at 24 h. The effect of actinomycin D and DRB to increase basal leptin secretion observed at 4 and 24 h was not present at 48 h when actinomycin D and DRB both markedly inhibited insulin-stimulated leptin secretion (to 36+/-16%, p<0.05 and 21.9+/-5.6% of control, for actinomycin D and DRB, respectively, both p<0.001). Neither actinomycin D nor DRB had any effect on adipocyte glucose utilization between 24 and 48 h. The observed effects of inhibitors of transcription on leptin gene expression and leptin secretion are consistent with a long-term transcriptional mechanism for insulin-stimulated glucose metabolism to increase leptin production. Cycloheximide treatment (10 microg/ml) abolished the effects of insulin to stimulate leptin secretion (29+/-11% of control, p<0.01) during the first 4 h of treatment and at all later time points, which indicate that de novo protein synthesis is required for insulin-mediated glucose metabolism to increase leptin secretion.
Biochemical and Biophysical Research Communications 08/2003; 307(4):907-14. · 2.48 Impact Factor
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ABSTRACT: The increase in body and white adipose tissue weights induced by a high-fat diet were prevented by treatment with the beta3-adrenergic agonist Trecadrine. Plasma insulin levels were slightly elevated in overweight rats, while a decrease was observed in Trecadrine-treated groups. Insulin-dependent glucose uptake was impaired in adipocytes of the overweight rats in relation to lean animals. The beta3-adrenergic agonist induced an increase in insulin-stimulated glucose uptake by adipocytes as compared to the nontreated animals. In fact, Trecadrine treatment was able to restore to control values the impairment in insulin-mediated glucose uptake induced by the cafeteria diet, suggesting that Trecadrine prevents the development of insulin resistance in overweight animals. Basal leptin secretion was increased in adipocytes of the overweight rats in relation to lean animals. Trecadrine treatment induced a decrease in basal leptin secretion compared to the untreated animals. Insulin-stimulated leptin secretion reached similar levels in adipocytes of the overweight rats as in lean animals. There was a trend for insulin-induced leptin secretion to be lower at 24 h in Trecadrine-treated rats, but it did not reach statistical significance. In conclusion, adipocytes of diet-induced overweight animals have a higher basal leptin secretion, which is reduced by treatment with Trecadrine. However, neither the cafeteria diet nor the Trecadrine treatment significantly alters the ability of adipocytes to increase leptin secretion in response to insulin.
Biochemical and Biophysical Research Communications 04/2002; 291(5):1201-7. · 2.48 Impact Factor
