leptin and trecadrine

Leptin, a hormone produced in adipocytes, is a key signal in the regulation of food intake and energy expenditure. Beta-adrenergic agonists have been shown to inhibit leptin gene expression and leptin secretion. The mechanisms underlying the inhibitory effects of beta-adrenergic agonists have not been established. In this study, we examined the effects of Trecadrine, a novel beta3-adrenergic agonist, on basal and insulin-stimulated leptin secretion in isolated rat adipocytes. Because insulin-stimulated glucose metabolism is an important regulator of leptin expression and secretion by the adipocytes, the effects of Trecadrine on indices of adipocyte metabolism were also examined.. Isolated adipocytes were incubated with Trecadrine (10(-8)-10(-4) M) in the absence or presence of insulin (1.6 nM). Leptin secretion, glucose utilization, lactate production, glucose incorporation into CO(2) and triglyceride, as well as lipolysis (glycerol release) were determined.. Trecadrine induced a concentration-dependent inhibition of basal leptin secretion. Trecadrine also decreased insulin-stimulated leptin secretion; however, the effect was not as pronounced as in the absence of insulin. Treatment of adipocytes with Trecadrine increased basal glucose utilization and produced a further increase in insulin-stimulated glucose utilization. Basal lactate production was also increased by Trecadrine; however, the proportion (percentage) of glucose carbon released as lactate was unaffected. In the presence of insulin, absolute lactate production was unaffected by Trecadrine at 96 h. However, the percentage of glucose carbon released as lactate was significantly decreased by insulin treatment, and was further decreased by the co-treatment with Trecadrine. Trecadrine induced a dose-dependent increase of the absolute amount of glucose incorporated into triglyceride. However, the percentage of glucose utilized that was incorporated into triglyceride was unaffected by Trecadrine. Trecadrine did not modify the proportion of glucose utilized that was oxidized to CO(2). Trecadrine increased glycerol release after 96 h of treatment. Glycerol release was negatively correlated with leptin secretion.. These results suggest that alterations of glucose metabolism are not directly involved in the effects of beta3-adrenergic agonists to inhibit leptin expression and secretion. The inverse relationship between leptin secretion and the increase of glycerol levels, which is an index of the activation of cAMP-dependent protein kinases, suggests that activation of the cAMP signaling pathway mediates the inhibitory effects of Trecadrine on leptin gene expression and secretion.

Topics: Adipocytes; Adrenergic beta-Agonists; Animals; Benzyl Alcohols; Cells, Cultured; Gene Expression; Glucose; Lactic Acid; Leptin; Lipid Metabolism; Lipolysis; Male; Oxidation-Reduction; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic, beta-3; RNA, Messenger; Triglycerides

Peroxisome proliferator-activated receptor-gamma coactivator-1 (PGC-1) is highly expressed in brown adipose tissue (BAT) and plays an important role in adaptive thermogenesis. The aim of this study was to assess the acute effect of a beta(3)-adrenergic agonist (Trecadrine) and leptin on the expression of PGC-1 and PPARgamma2 mRNA in BAT. Trecadrine produced a marked increase (4.5-fold) in PGC-1 mRNA compared to controls (P<0.001) without changes in PPARgamma2 mRNA, whereas leptin administration did not alter either PGC-1 or PPARgamma2 expression. These results show that selective stimulation of the beta(3)-adrenoceptor rapidly upregulates the expression of PGC-1 in brown adipocytes without a concomitant increase in PPARgamma2. Moreover, our results show that PGC-1 and PPARgamma2 expression in BAT seems not to be acutely regulated by leptin.

Topics: Adipose Tissue, Brown; Adrenergic beta-Agonists; Animals; Benzyl Alcohols; Body Temperature; Carrier Proteins; Fasting; Fatty Acids, Nonesterified; Ion Channels; Leptin; Male; Membrane Proteins; Mitochondrial Proteins; Oxygen Consumption; Rats; Rats, Wistar; Receptors, Cytoplasmic and Nuclear; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Transcription Factors; Uncoupling Protein 1; Up-Regulation

This study was undertaken in order to test the hypothesis that selective beta3-AR stimulation and simultaneous blockade of alpha2-AR would result in an increase of lipolysis and thermogenesis in rats. Incubation of isolated white adipocytes with the alpha2-AR antagonist yohimbine produced a concentration-dependent increase in glycerol release (P<0.001) for all assayed concentrations (10-12-10-6 M) and potentiated the lipolytic effect of the beta3-AR agonist Trecadrine. However, in vivo administration of yohimbine produced a marked decrease in body temperature (1.3-1.5 degrees C, P<0.001) and blocked the thermogenic effect of Trecadrine when simultaneously administered. A similar response was observed for whole body oxygen consumption. Furthermore, yohimbine did not modify brown adipose tissue oxygen consumption, but blocked the beta3-AR-mediated increase triggered by Trecadrine. Brown adipose tissue UCP-2 and -3 mRNA expression was not changed by yohimbine. In conclusion, the present work indicates that in vitro alpha2-AR blockade by yohimbine potentiates the beta3-AR-mediated stimulation of lipolysis. On the other hand, in vivo alpha2-AR antagonism blocks the thermogenic effects mediated by beta3-AR stimulation, suggesting a possible interplay between the receptors.

Topics: Adipocytes; Adipose Tissue, Brown; Adrenergic alpha-2 Receptor Antagonists; Adrenergic alpha-Antagonists; Adrenergic beta-3 Receptor Agonists; Adrenergic beta-Agonists; Animals; Benzyl Alcohols; Blood Glucose; Body Temperature; Carrier Proteins; Dose-Response Relationship, Drug; Drug Interactions; Gene Expression Regulation; Glycerol; Insulin; Ion Channels; Leptin; Lipolysis; Male; Membrane Proteins; Mitochondrial Proteins; Oxygen Consumption; Rats; Rats, Wistar; Rectum; RNA, Messenger; Thermogenesis; Uncoupling Protein 1; Yohimbine

The anti-obesity properties of a new beta3-adrenergic agonist (Trecadrine) were examined in a diet-induced obesity model, including the effects on OB and uncoupling protein (UCP-1 and -2) gene expression.. Control rats and cafeteria-fed rats were treated with placebo or Trecadrine for 35 days. Leptin and UCP (1 and 2) mRNA levels were determined by reverse transcription-polymerase chain reaction (RT-PCR) methodology in adipose tissue and gastrocnemius muscle.. Animals fed a cafeteria diet increased body weight, fat content, white adipose tissue (WAT), brown adipose tissue (BAT) weights and oxygen consumption in relation to lean controls. A rise in plasma leptin, WAT OB gene expression as well as circulating free fatty acids levels was found in obese rats as compared with lean controls. Trecadrine administration to cafeteria-fed animals decreased fat content, WAT weight, circulating leptin and fatty acids concentrations, and WAT OB gene expression, reaching comparable values to lean controls, while WAT O2 consumption was increased in these animals. Also, an increase in BAT UCP1 mRNA levels was found through a two-way analysis of variance in control and obese animals after Trecadrine administration. Gastrocnemius muscle UCP2 gene expression was reduced in lean Trecadrine-treated and diet-induced obese animals as compared to controls, while an increase was found in cafeteria-fed animals after Trecadrine administration. A negative correlation between WAT O2 consumption and UCP2 expression was found in control animals, but not in the cafeteria-fed groups, suggesting a differential response to the beta3-adrenergic compound in lean and obese animals, which is in agreement with the reported statistical interactions between obesity and Trecadrine administration found for WAT O2 consumption and muscle UCP2 expression, as well as for plasma leptin and WAT leptin expression.. The new beta3-adrenergic agonist, Trecadrine, decreases fat content and increases gastrocnemius muscle UCP2 gene expression in a diet-induced obesity model. This sheds additional light on the action mechanism of compounds with affinity for beta3-adrenoceptors and other potential anti-obesity agents.

Topics: Adipose Tissue; Adrenergic beta-Agonists; Animals; Benzyl Alcohols; Disease Models, Animal; DNA Primers; Fatty Acids; Female; Gene Expression Regulation; Ion Channels; Leptin; Membrane Transport Proteins; Mitochondrial Proteins; Muscle, Skeletal; Obesity; Proteins; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Uncoupling Protein 2

Previous studies have reported that beta3-adrenergic agonists regulate plasma glucose, triglycerides and free fatty acids in situations of hyperglycaemia and dyslipidaemia in rodents. In this study Trecadrine, a novel compound with affinity for beta3-adrenergic receptors, has been tested in an alloxan-induced model of hyperglycaemia in rats. Alloxan-induced hyperglycaemic rats were orally treated with Trecadrine (1 mg/kg/day for 4 days), resulting in an improvement of hyperglycaemia (from 16.6 to 8.3 mmol L(-1), P < 0.001). This effect was not associated with statistical differences in plasma insulin levels, which may be explained by changes in insulin resistance and carbohydrate oxidation in peripheral tissues. Furthermore, a reduction in internal white fat weight (-39%), which was not statistically significant, as well as in plasma triglycerides (from 1.89 to 0.33 mmol L(-1), P < 0.001) and free fatty acids (from 0.70 to 0.39 mmol L(-1), P < 0.001), was found after Trecadrine administration. Trecadrine apparently induced lipolytic activity in adipocytes, as suggested by the increase of oxygen consumption in white adipose tissue (+282%, P < 0.001), while free fatty acids decreased apparently through their utilisation in other tissues. Furthermore, the increase in brown adipose tissue oxygen consumption (+50%, P < 0.01) and in rectal temperature (P < 0.05) suggests that both glucose and fatty acid oxidation may be enhanced in this tissue. These results give support to the possible therapeutic use of beta3-adrenergic compounds in situations of hyperglycaemia, particularly when this is accompanied by hypertriglyceridaemia.

Topics: Absorption; Administration, Oral; Adrenergic beta-3 Receptor Agonists; Adrenergic beta-Agonists; Animals; Benzyl Alcohols; Body Weight; Carbohydrate Metabolism; Diabetes Mellitus, Experimental; Female; Leptin; Lipid Metabolism; Lipoprotein Lipase; Muscle, Skeletal; Rats; Rats, Wistar

The short-term effects of leptin and a beta 3-adrenoceptor agonist on thermogenesis and expression of uncoupling proteins (UCPs) in brown adipose tissue (BAT) and muscle and their possible interactions were assessed. One hour after administration of the beta 3-adrenoceptor agonist Trecadrine, a statistically significant increase in UCP1 messenger RNA (mRNA) expression in BAT was observed, whereas UCP2 and UCP3 in both BAT and gastrocnemius muscle were unaffected. Leptin induced an upregulation of UCP3 mRNA in muscle, with no changes in BAT UCP1 mRNA. A statistical interaction was found between leptin and Trecadrine in rectal temperature. The present study provides evidence, for the first time, of the induction of UCP3 mRNA expression in skeletal muscle by leptin in nongenetically obese animals.

Topics: Adipose Tissue, Brown; Adrenergic beta-Agonists; Animals; Benzyl Alcohols; Body Temperature Regulation; Carrier Proteins; Gene Expression Regulation; Ion Channels; Leptin; Male; Membrane Proteins; Membrane Transport Proteins; Mitochondrial Proteins; Muscle Proteins; Muscle, Skeletal; Obesity; Organ Specificity; Protein Biosynthesis; Proteins; Rats; Rats, Wistar; Receptors, Adrenergic, beta; Receptors, Adrenergic, beta-3; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Uncoupling Protein 1; Uncoupling Protein 2; Uncoupling Protein 3