Topiramate Treatment Improves Hypothalamic Insulin and Leptin Signaling and Action and Reduces Obesity in Mice

Endocrinology ◽  
2012 ◽  
Vol 153 (9) ◽  
pp. 4401-4411 ◽  
Author(s):  
Andrea M. Caricilli ◽  
Erica Penteado ◽  
Lélia L. de Abreu ◽  
Paula G. F. Quaresma ◽  
Andressa C. Santos ◽  
...  
Keyword(s):  
Food Intake ◽  
Molecular Mechanisms ◽  
Janus Kinase ◽  
Mrna Levels ◽  
Obese Mice ◽  
Short Term ◽  
Short Term Treatment ◽  
Peripheral Tissues ◽  
Leptin Signaling ◽  
Brown Adipose

Topiramate (TPM) treatment has been shown to reduce adiposity in humans and rodents. The reduction in adiposity is related to decreased food intake and increased energy expenditure. However, the molecular mechanisms through which TPM induces weight loss are contradictory and remain to be clarified. Whether TPM treatment alters hypothalamic insulin, or leptin signaling and action, is not well established. Thus, we investigate herein whether short-term TPM treatment alters energy balance by affecting insulin and leptin signaling, action, or neuropeptide expression in the hypothalamus of mice fed with a high-fat diet. As expected, short-term treatment with TPM diminished adiposity in obese mice mainly due to reduced food intake. TPM increased anorexigenic signaling by enhancing the leptin-induced leptin receptor/Janus kinase 2/signal transducer and activator of transcription 3 pathway and the insulin-induced insulin receptor substrate/Akt/forkhead box O1 pathway in parallel to reduced phosphatase protein expression in the hypothalamus of obese mice. These effects were independent of body weight. TPM also raised anorexigenic neuropeptides such as POMC, TRH, and CRH mRNA levels in obese mice. In addition, TPM increased the activation of the hypothalamic MAPK/ERK pathway induced by leptin, accompanied by an increase in peroxisome proliferator-activated receptor-coactivator α and uncoupling protein 1 protein levels in brown adipose tissue. Furthermore, TPM increased AMP-activated protein kinase and acetyl-coenzyme A carboxylase phosphorylation in peripheral tissues, which may help improve energy metabolism in these tissues. Together, these results provide novel insights into the molecular mechanisms through which TPM treatment reduces adiposity.

scholarly journals Leptin Signaling in the Hypothalamus during Chronic Central Leptin Infusion

Endocrinology ◽  
2003 ◽  
Vol 144 (9) ◽  
pp. 3789-3798 ◽  
Author(s):  
Rekha Pal ◽  
Abhiram Sahu
Keyword(s):  
Food Intake ◽  
Leptin Receptor ◽  
Binding Activity ◽  
Janus Kinase ◽  
Male Rats ◽  
Leptin Resistance ◽  
Cytokine Signaling ◽  
Mrna Levels ◽  
Leptin Signaling ◽  
Initial Decrease

Abstract Using a rat model of chronic central leptin infusion in which neuropeptide Y neurons develop leptin resistance, we examined whether leptin signal transduction mechanism in the hypothalamus is altered during central leptin infusion. Adult male rats were infused chronically into the lateral cerebroventricle with leptin (160 ng/h) or vehicle via Alzet pumps for 16 d. In the leptin-infused group, the initial decrease in food intake was followed by a recovery to their preleptin levels by d 16, although food intake remained significantly lower than in artificial cerebrospinal fluid controls; and body weight gradually decreased reaching a nadir at d 11 and remained stabilized at lower level thereafter. Phosphorylated leptin receptor and phosphorylated signal transducer and activator of transcription-3 (p-STAT3) remained elevated in association with a sustained elevation in DNA-binding activity of STAT3 in the hypothalamus throughout 16-d period of leptin infusion. However, phosphorylated Janus kinase-2 was increased during the early part of leptin infusion but remained unaltered on d 16. Although hypothalamic suppressors of cytokine signaling-3 (SOCS3) mRNA levels were increased throughout leptin infusion, SOCS3 protein levels were increased only on d 16. This study demonstrates a sustained elevation in hypothalamic leptin receptor signaling through Janus kinase-STAT pathway despite an increased expression of SOCS3 during chronic central leptin infusion. We propose that an alteration in leptin signaling in the hypothalamus through pathways other than STAT3 and/or a defect in downstream of STAT3 signaling may be involved in food intake recovery seen after an initial decrease during chronic central leptin infusion.

scholarly journals Anorexigenic effect of cholecystokinin is lost but that of CART (Cocaine and Amphetamine Regulated Transcript) peptide is preserved in monosodium glutamate obese mice

2009 ◽  
pp. 717-723 ◽  
Author(s):  
B Železná ◽  
J Maixnerová ◽  
R Matyšková ◽  
R Haugvicová ◽  
D Blokešová ◽  
...  
Keyword(s):  
Food Intake ◽  
Arcuate Nucleus ◽  
Monosodium Glutamate ◽  
Central Administration ◽  
Obese Mice ◽  
Male Mice ◽  
Short Term ◽  
Leptin Signaling ◽  
Cart Peptide ◽  
Anorexigenic Effect

Monosodium glutamate (MSG) treatment of neonatal mice results in a selective damage to the arcuate nucleus (ARC) and development of obesity with increased adiposity at sustained body weight in the adulthood. Feeding pattern of the MSG obese mice is unusual. Our previous results showed that after 24-h fasting, MSG mice consumed negligible amount of food in several hours and therefore, it was impossible to register the effect of peptides attenuating food intake such as cholecystokinin (CCK) or cocaine- and amphetamine-regulated transcript (CART) peptide. To overcome this problem, two findings were used: firstly, orexigenic effect of neuropeptide Y (NPY) was attenuated both by CCK or CART peptide in lean fed mice and secondly, orexigenic effect of NPY was preserved in fed rats with MSG obesity. In this study, short-term food intake in fed lean and MSG obese C57BL/6 male mice was measured after simultaneous central administration of orexigenic NPY with either CART peptide or peripherally administered CCK. Anorexigenic action of exogenous CART peptide was preserved in MSG obese mice. On the other hand, satiety effect of exogenous CCK was completely lost in MSG obese mice. In conclusion, effective leptin signaling in ARC is necessary for satiety effect of CCK.

scholarly journals Oxytocin Administration Alleviates Acute but Not Chronic Leptin Resistance of Diet-Induced Obese Mice

2018 ◽  
Vol 20 (1) ◽  
pp. 88 ◽  
Author(s):  
Mehdi Labyb ◽  
Chloé Chrétien ◽  
Aurélie Caillon ◽  
Françoise Rohner-Jeanrenaud ◽  
Jordi Altirriba
Keyword(s):  
Body Weight ◽  
Weight Gain ◽  
Food Intake ◽  
Body Weight Gain ◽  
Leptin Resistance ◽  
Obese Mice ◽  
Short Term ◽  
Continuous Administration ◽  
Pre Treatment ◽  
Treatment Of Obesity

Whereas leptin administration only has a negligible effect on the treatment of obesity, it has been demonstrated that its action can be improved by co-administration of leptin and one of its sensitizers. Considering that oxytocin treatment decreases body weight in obese animals and humans, we investigated the effects of oxytocin and leptin cotreatment. First, lean and diet-induced obese (DIO) mice were treated with oxytocin for 2 weeks and we measured the acute leptin response. Second, DIO mice were treated for 2 weeks with saline, oxytocin (50 μg/day), leptin (20 or 40 µg/day) or oxytocin plus leptin. Oxytocin pre-treatment restored a normal acute leptin response, decreasing food intake and body weight gain. Chronic continuous administration of oxytocin or leptin at 40 µg/day decreased body weight in the presence (leptin) or in the absence (oxytocin) of cumulative differences in food intake. Saline or leptin treatment at 20 µg/day had no impact on body weight. Oxytocin and leptin cotreatments had no additional effects compared with single treatments. These results point to the fact that chronic oxytocin treatment improves the acute, but not the chronic leptin response, suggesting that this treatment could be used to improve the short-term satiety effect of leptin.

scholarly journals Pharmacological Inhibition of Soluble Epoxide Hydrolase by t-TUCB Improves Brown Adipose Tissue Activities in Diet-Induced Obesity

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 1703-1703
Author(s):  
Yang Yang ◽  
Xinyun Xu ◽  
Katie Graham ◽  
Ahmed Bettaieb ◽  
Christophe Morisseau ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Adipose Tissue ◽  
Food Intake ◽  
Brown Adipose Tissue ◽  
Epoxide Hydrolase ◽  
Soluble Epoxide Hydrolase ◽  
Obese Mice ◽  
Treatment And Prevention ◽  
Insulin Tolerance ◽  
Brown Adipose

Abstract Objectives Brown adipose tissue (BAT), responsible for energy expenditure through nonshivering thermogenesis, has emerged as a novel target for obesity treatment and prevention. Soluble epoxide hydrolase (sEH), encoded by Ephx2 gene, is a cytosolic enzyme that converts epoxy fatty acids (EpFAs) that are produced by cytochrome P-450 enzymes from polyunsaturated fatty acids into less active diols. Pharmacological inhibitors of sEH, such as trans-4-{4-[3-(4-trifluoromethoxyphenyl)-ureido] cyclohexyloxy} benzoic acid (t-TUCB), have been shown to be beneficial for chronic diseases by inhibiting the degradation of EpFAs. We have previously shown that t-TUCB dose-dependently promotes brown adipogenesis in vitro. This study investigated the therapeutic effects of t-TUCB on BAT activation in diet-induced obese mice. Methods Male C57BL6/J mice were fed a high-fat diet (60% kcal from fat) for 8 weeks followed by random assignment into either the control or t-TUCB group (n = 10 per group) to receive either the vehicle control or t-TUCB (3 mg/kg/day) via osmotic minipump delivery at the subcutaneous area near the interscapular BAT for 6 weeks. Bodyweight and food intake, glucose and insulin tolerance tests, cold tolerance tests, and indirect calorimetry were measured before the mice were euthanized for further biochemical analysis. Results sEH inhibition by t-TUCB in the obese mice did not change body weight, fat pad weight, food intake, fasting blood glucose, glucose and insulin tolerance, or cold tolerance, but significantly decreased blood triglyceride levels and increased heat production during both day and night. Moreover, t-TUCB significantly increased protein expression of brown marker gene PGC-1alpha and lipid droplet-associated protein perilipin (PLIN), but not uncoupling protein 1 (UCP1), in the interscapular BAT of diet-induced obese mice. Conclusions Our results suggest that sEH pharmacological inhibition may be beneficial for BAT activation by increasing mitochondrial biogenesis and lipolysis in the BAT. Further studies using the sEH inhibitors and/or EpFA generating diets for obesity treatment and prevention are warranted. Funding Sources The work was supported by NIH 1R15DK114790–01A1 (to L.Z.), K99DK100736 and R00DK100736 (to A.B.), R15AT008733 (to S.W.), R35 ES030443 and P42ES004699 (to B.D.H).

scholarly journals Co-ordinate decrease in the expression of the mitochondrial genome and nuclear genes for mitochondrial proteins in the lactation-induced mitochondrial hypotrophy of rat brown fat

1995 ◽  
Vol 308 (3) ◽  
pp. 749-752 ◽  
Author(s):  
I Martin ◽  
M Giralt ◽  
O Viñas ◽  
R Iglesias ◽  
T Mampel ◽  
...  
Keyword(s):  
Cytochrome C ◽  
Mitochondrial Genome ◽  
Cytochrome C Oxidase ◽  
Molecular Mechanisms ◽  
Uncoupling Protein ◽  
Relative Content ◽  
Nuclear Genes ◽  
Mitochondrial Proteins ◽  
Mrna Levels ◽  
Brown Adipose

The relative abundance of the mitochondrial-encoded mRNAs for cytochrome c oxidase subunit II and NADH dehydrogenase subunit I was lower in brown adipose tissue (BAT) from lactating rats than in virgin controls. This decrease was in parallel with a significant decrease in mitochondrial 16 S rRNA levels and in the relative content of mitochondrial DNA in the tissue. BAT from lactating rats showed lowered mRNA expression of the nuclear-encoded genes for the mitochondrial uncoupling protein, subunit IV of cytochrome c oxidase and the adenine nucleotide translocase isoforms ANT1 and ANT2, whereas mRNA levels for the ATP synthase beta-subunit were unchanged. However, the relative content of this last protein was lower in BAT mitochondria from lactating rats than in virgin controls. It is concluded that lactation-induced mitochondrial hypotrophy in BAT is associated with a co-ordinate decrease in the expression of the mitochondrial genome and nuclear genes for mitochondrial proteins. This decrease is caused by regulatory events acting at different levels, including pre- and post-transcriptional regulation. BAT appears to be a useful model with which to investigate the molecular mechanisms involved in the co-ordination of the expression of the mitochondrial and nuclear genomes during mitochondrial biogenesis.

Reduced adiposity and improved insulin sensitivity in obese mice with antisense suppression of 4E-BP2 expression

2008 ◽  
Vol 294 (3) ◽  
pp. E530-E539 ◽  
Author(s):  
Xing Xian Yu ◽  
Sanjay K. Pandey ◽  
Sheri L. Booten ◽  
Susan F. Murray ◽  
Brett P. Monia ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Energy Homeostasis ◽  
Fatty Acid Synthase ◽  
Initiation Factor ◽  
Synthesis Rate ◽  
Mrna Levels ◽  
Obese Mice ◽  
Brown Adipose ◽  
Hepatic Glucose ◽  
Glucose Output

To investigate the possible role of eukaryotic initiation factor 4E-binding protein-2 (4E-BP2) in metabolism and energy homeostasis, high-fat diet-induced obese mice were treated with a 4E-BP2-specific antisense oligonucleotide (ASO) or a control 4E-BP2 ASO at a dose of 25 mg/kg body wt or with saline twice a week for 6 wk. 4E-BP2 ASO treatment reduced 4E-BP2 levels by >75% in liver and white (WAT) and brown adipose (BAT) tissues. Treatment did not change food intake but lowered body weight by ∼7% and body fat content by ∼18%. Treatment decreased liver triglyceride (TG) content by >50%, normalized plasma glucose and insulin levels, and reduced glucose excursion during glucose tolerance test. 4E-BP2 ASO-treated mice showed >8.5% increase in metabolic rate, >40% increase in UCP1 levels in BAT, >45% increase in β3-adrenoceptor mRNA, and 40–55% decrease in mitochondrial dicarboxylate carrier, fatty acid synthase, and diacylglycerol acyltransferase 2 mRNA levels in WAT. 4E-BP2 ASO-transfected mouse hepatocytes showed an increased fatty acid oxidation rate and a decreased TG synthesis rate. In addition, 4E-BP2 ASO-treated mice demonstrated ∼60 and 29% decreases in hepatic glucose-6-phosphatase and phospho enolpyruvate carboxykinase mRNA, respectively, implying decreased hepatic glucose output. Furthermore, increased phosphorylation of AktSer473 in both liver and fat of 4E-BP2 ASO-treated mice and increased GLUT4 levels in plasma membrane in WAT of the ASO-treated mice were observed, indicating enhanced insulin signaling and increased glucose uptake as a consequence of reduced 4E-BP2 expression. These data demonstrate for the first time that peripheral 4E-BP2 plays an important role in metabolism and energy homeostasis.

scholarly journals Hypothalamic signaling in anorexia induced by indispensable amino acid deficiency

2012 ◽  
Vol 303 (12) ◽  
pp. E1446-E1458 ◽  
Author(s):  
Xinxia Zhu ◽  
Stephanie M. Krasnow ◽  
Quinn R. Roth-Carter ◽  
Peter R. Levasseur ◽  
Theodore P. Braun ◽  
...  
Keyword(s):  
Gene Expression ◽  
Adipose Tissue ◽  
Amino Acid ◽  
Food Intake ◽  
Molecular Mechanisms ◽  
Uncoupling Protein ◽  
Deficient Diet ◽  
Indispensable Amino Acid ◽  
Brown Adipose ◽  
Melanocortin Signaling

Animals exhibit a rapid and sustained anorexia when fed a diet that is deficient in a single indispensable amino acid (IAA). The chemosensor for IAA deficiency resides within the anterior piriform cortex (APC). Although the cellular and molecular mechanisms by which the APC detects IAA deficiency are well established, the efferent neural pathways that reduce feeding in response to an IAA-deficient diet remain to be fully characterized. In the present work, we investigated whether 1) central melanocortin signaling is involved in IAA deficiency-induced anorexia (IAADA) and 2) IAADA engages other key appetite-regulating neuronal populations in the hypothalamus. Rats and mice that consumed a valine-deficient diet (VDD) for 2–3 wk exhibited marked reductions in food intake, body weight, fat and lean body mass, body temperature, and white adipose tissue leptin gene expression, as well as a paradoxical increase in brown adipose tissue uncoupling protein-1 mRNA. Animals consuming the VDD had altered hypothalamic gene expression, typical of starvation. Pharmacological and genetic blockade of central melanocortin signaling failed to increase long-term food intake in this model. Chronic IAA deficiency was associated with a marked upregulation of corticotropin-releasing hormone expression in the lateral hypothalamus, particularly in the parasubthalamic nucleus, an area heavily innervated by efferent projections from the APC. Our observations indicate that the hypothalamic melanocortin system plays a minor role in acute, but not chronic, IAADA and suggest that the restraint on feeding is analogous to that observed after chronic dehydration.

scholarly journals Leptin Sensitivity in the Developing Rat Hypothalamus

Endocrinology ◽  
2007 ◽  
Vol 148 (12) ◽  
pp. 6073-6082 ◽  
Author(s):  
A.-S. Carlo ◽  
M. Pyrski ◽  
C. Loudes ◽  
A. Faivre-Baumann ◽  
J. Epelbaum ◽  
...  
Keyword(s):  
Food Intake ◽  
Neuropeptide Y ◽  
Leptin Receptor ◽  
Primary Cultures ◽  
Cytokine Signaling ◽  
Neuronal Cultures ◽  
Mrna Levels ◽  
Leptin Signaling ◽  
Leptin Sensitivity

In adults, the adipocyte-derived hormone, leptin, regulates food intake and body weight principally via the hypothalamic arcuate nucleus (ARC). During early postnatal development, leptin functions to promote the outgrowth of neuronal projections from the ARC, whereas a selective insensitivity to the effects of leptin on food intake appears to exist. To investigate the mechanisms underlying the inability of leptin to regulate food intake during early development, leptin signaling was analyzed both in vitro using primary cultures of rat embryonic ARC neurones and in vivo by challenging early postnatal rats with leptin. In neuronal cultures, despite the presence of key components of the leptin signaling pathway, no detectable activation of either signal transducer and activator of transcription 3 or the MAPK pathways by leptin was detected. However, leptin down-regulated mRNA levels of proopiomelanocortin and neuropeptide Y and decreased somatostatin secretion. Leptin challenge in vivo at postnatal d (P) 7, P14, P21, and P28 revealed that, in contrast to adult and P28 rats, mRNA levels of neuropeptide Y, proopiomelanocortin, agouti-related peptide and cocaine- and amphetamine-regulated transcript were largely unaffected at P7, P14, and P21. Furthermore, leptin stimulation increased the suppressor of cytokine signaling-3 mRNA levels at P14, P21, and P28 in several hypothalamic nuclei but not at P7, indicating that selective leptin insensitivity in the hypothalamus is coupled to developmental shifts in leptin receptor signaling. Thus, the present study defines the onset of leptin sensitivity in the regulation of energy homeostasis in the developing hypothalamus.

scholarly journals Chrysanthemum Leaf Ethanol Extract Prevents Obesity and Metabolic Disease in Diet-Induced Obese Mice via Lipid Mobilization in White Adipose Tissue

Nutrients ◽  
2019 ◽  
Vol 11 (6) ◽  
pp. 1347 ◽  
Author(s):  
Ri Ryu ◽  
Eun-Young Kwon ◽  
Ji-Young Choi ◽  
Jong Cheol Shon ◽  
Kwang-Hyeon Liu ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Energy Expenditure ◽  
White Adipose Tissue ◽  
Ethanol Extract ◽  
The Body ◽  
Obese Mice ◽  
Peripheral Tissues ◽  
Lipid Mobilization ◽  
Obesity And Diabetes ◽  
Brown Adipose

This study aimed to elucidate the molecular mechanism of Chrysanthemum morifolium Ramat. against obesity and diabetes, by comparing the transcriptional changes in epididymal white adipose tissue (eWAT) with those of the bioactive compound in C. morifolium, luteolin (LU). Male C57BL/6J mice were fed a normal diet, high-fat diet (HFD), and HFD supplemented with 1.5% w/w chrysanthemum leaf ethanol extract (CLE) for 16 weeks. Supplementation with CLE and LU significantly decreased the body weight gain and eWAT weight by stimulating mRNA expressions for thermogenesis and energy expenditure in eWAT via lipid mobilization, which may be linked to the attenuation of dyslipidemia. Furthermore, CLE and LU increased uncoupling protein-1 protein expression in brown adipose tissue, leading to energy expenditure. Of note, CLE and LU supplements enhanced the balance between lipid storage and mobilization in white adipose tissue (WAT), in turn, inhibiting adipocyte inflammation and lipotoxicity of peripheral tissues. Moreover, CLE and LU attenuated hepatic steatosis by suppressing hepatic lipogenesis, thereby ameliorating insulin resistance and dyslipidemia. Our data suggest that CLE helps inhibit obesity and its comorbidities via the complex interplay between liver and WAT in diet-induced obese mice.

scholarly journals C1q/TNF-related protein 4 restores leptin sensitivity by downregulating NF-κB signaling and microglial activation

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Liu Ye ◽  
Gongwei Jia ◽  
Yuejie Li ◽  
Ying Wang ◽  
Hong Chen ◽  
...  
Keyword(s):  
Food Intake ◽  
Microglial Activation ◽  
Obese Mice ◽  
Related Protein ◽  
Leptin Signaling ◽  
Leptin Sensitivity ◽  
Tnf Α ◽  
Hypothalamic Inflammation ◽  
The Impact

Abstract Objective C1qTNF-related protein 4 (CTRP4) acts in the hypothalamus to modulate food intake in diet-induced obese mice and has been shown to exert an anti-inflammatory effect on macrophages. Since high-fat diet-induced microglial activation and hypothalamic inflammation impair leptin signaling and increase food intake, we aimed to explore the potential connection between the anorexigenic effect of CTRP4 and the suppression of hypothalamic inflammation in mice with DIO. Methods Using an adenovirus-mediated hypothalamic CTRP4 overexpression model, we investigated the impact of CTRP4 on food intake and the hypothalamic leptin signaling pathway in diet-induced obese mice. Furthermore, central and plasma proinflammatory cytokines, including TNF-α and IL-6, were measured by Western blotting and ELISA. Changes in the hypothalamic NF-κB signaling cascade and microglial activation were also examined in vivo. In addition, NF-κB signaling and proinflammatory factors were investigated in BV-2 cells after CTRP4 intervention. Results We found that food intake was decreased, while leptin signaling was significantly improved in mice with DIO after CTRP4 overexpression. Central and peripheral TNF-α and IL-6 levels were reduced by central Ad-CTRP4 administration. Hypothalamic NF-κB signaling and microglial activation were also significantly suppressed in vivo. In addition, NF-κB signaling was inhibited in BV-2 cells following CTRP4 intervention, which was consistent with the decreased production of TNF-α and IL-6. Conclusions Our data indicate that CTRP4 reverses leptin resistance by inhibiting NF-κB-dependent microglial activation and hypothalamic inflammation.

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