Activation of AMPK in rat hypothalamus participates in cold‐induced resistance to nutrient‐dependent anorexigenic signals

Roman, Erika; Cesquini, Maristela; Stoppa, Graziela R.; Carvalheira, José Barreto Campello; Torsoni, Márcio Alberto; Velloso, Lı́cio A.

doi:10.1113/jphysiol.2005.095687

Cited by 20 publications

(17 citation statements)

References 24 publications

(33 reference statements)

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“…However, AMPK is regulated by fasting and feeding in such a way that during fasting, AMPK is active and imposes a negative regulation on ACC. By contrast, after feeding, AMPK is rapidly inactivated and ACC activity is restored, as previously demonstrated by our group (Roman et al 2005). The data shown in the present paper were obtained from fasted animals that presented increased phosphorylation of hypothalamic AMPK.…”

Section: Discussionsupporting

confidence: 67%

Intracerebroventricular injection of citrate inhibits hypothalamic AMPK and modulates feeding behavior and peripheral insulin signaling

Stoppa¹,

Cesquini²,

Roman³

et al. 2008

Journal of Endocrinology

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We hypothesized that citrate might modulate the AMP-activated protein kinase/acetyl-CoA carboxylase (AMPK)/(ACC) pathway and participate in neuronal feeding control and glucose homeostasis. To address this issue, we injected citrate into the lateral ventricle of rats. Intracerebroventricular (ICV) injection of citrate diminished the phosphorylation of hypothalamic AMPK/ACC, increased the expression of anorexigenic neuropeptide (pro-opiomelanocortin and corticotropinreleasing hormone), elevated the level of malonyl-CoA in the hypothalamus, and reduced food intake. No change was observed in the concentration of blood insulin after the injection of citrate. With a euglycemic-hyperinsulinemic clamp, the glucose infusion rate was higher in the citrate group than in the control group (28 . 6G0 . 8 vs 19 . 3G0 . 2 mU/kg body weight/min respectively), and so was glucose uptake in skeletal muscle and the epididymal fat pad. Concordantly, insulin receptor (IR), IR substrate type 1 (IRS1), IRS2, and protein kinase B (AKT) phosphorylation in adipose tissue and skeletal muscle was improved by citrate ICV treatment. Moreover, the treatment with citrate for 7 days promoted body weight loss and decreased the adipose tissue. Our results suggest that citrate and glucose may serve as signals of energy and nutrient availability to hypothalamic cells.

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Section: Discussionsupporting

confidence: 67%

Intracerebroventricular injection of citrate inhibits hypothalamic AMPK and modulates feeding behavior and peripheral insulin signaling

Stoppa¹,

Cesquini²,

Roman³

et al. 2008

Journal of Endocrinology

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“…9). Finally, others have shown that insulin-induced PI 3-kinase signaling inhibits AMPK in the hypothalamus (33). Our data suggest that PI 3-kinase-induced nNOS phosphorylation outweighs decreased nNOS phosphorylation resulting from PI 3-kinase inhibition of AMPK.…”

Section: Discussionmentioning

confidence: 49%

Glucose, insulin, and leptin signaling pathways modulate nitric oxide synthesis in glucose-inhibited neurons in the ventromedial hypothalamus

Canabal¹,

Song²,

Potian³

et al. 2007

American Journal of Physiology-Regulatory, Integrative and Comp

123

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Canabal DD, Song Z, Potian JG, Beuve A, McArdle JJ, Routh VH. Glucose, insulin and leptin signaling pathways modulate nitric oxide synthesis in glucose-inhibited neurons in the ventromedial hypothalamus. Am J Physiol Regul Integr Comp Physiol 292: R1418 -R1428, 2007. First published December 24, 2006; doi:10.1152/ajpregu.00216.2006.-Glucose-sensing neurons in the ventromedial hypothalamus (VMH) are involved in the regulation of glucose homeostasis. Glucosesensing neurons alter their action potential frequency in response to physiological changes in extracellular glucose, insulin, and leptin. Glucose-excited neurons decrease, whereas glucose-inhibited (GI) neurons increase, their action potential frequency when extracellular glucose is reduced. Central nitric oxide (NO) synthesis is regulated by changes in local fuel availability, as well as insulin and leptin. NO is involved in the regulation of food intake and is altered in obesity and diabetes. Thus this study tests the hypothesis that NO synthesis is a site of convergence for glucose, leptin, and insulin signaling in VMH glucose-sensing neurons. With the use of the NO-sensitive dye 4-amino-5-methylamino-2Ј,7Ј-difluorofluorescein in conjunction with the membrane potential-sensitive dye fluorometric imaging plate reader, we found that glucose and leptin suppress, whereas insulin stimulates neuronal nitric oxide synthase (nNOS)-dependent NO production in cultured VMH GI neurons. The effects of glucose and leptin were mediated by suppression of AMP-activated protein kinase (AMPK). The AMPK activator 5-aminoimidazole-4-carboxamide-1-␤-4-ribofuranoside (AICAR) increased both NO production and neuronal activity in GI neurons. In contrast, the effects of insulin on NO production were blocked by the phosphoinositide 3-kinase inhibitors wortmannin and LY-294002. Furthermore, decreased glucose, insulin, and AICAR increase the phosphorylation of VMH nNOS, whereas leptin decreases it. Finally, VMH neurons express soluble guanylyl cyclase, a downstream mediator of NO signaling. Thus NO may mediate, in part, glucose, leptin, and insulin signaling in VMH glucose-sensing neurons. ventromedial hypothalamus; glucose-sensing neurons; leptin; insulin; nitric oxide; adenosine 5Ј-monophosphate-activated protein kinase THE VENTROMEDIAL HYPOTHALAMUS (VMH), which contains the ventromedial (VMN) and arcuate (ARC) nuclei, is critical for the regulation of glucose and energy homeostasis (34). This region contains specialized neurons whose activity is regulated by physiologically relevant changes in extracellular glucose (36,37,42). Glucose-excited (GE) neurons decrease, whereas glucose-inhibited (GI) neurons increase, their action potential frequency (APF) when extracellular glucose is reduced (36). GE neurons activate ATP-sensitive K ϩ (K ATP ) channels in response to decreased glucose. GI neurons appear to close an ATP-activated Cl Ϫ channel, although the identity of this channel is unknown (36). Glucose-sensing neurons also possess insulin and leptin receptors (22,39,40,42). Thus gluc...

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“…Even though AICAR represses SREBP1c mRNA expression levels, insulin may stabilize its protein levels, which could increase FAS gene expression. In addition, based on the findings that the insulin-PI3 kinase pathway can inhibit AMPK [10,16], insulin signaling could attenuate AMPK's inhibitory action on FAS expression, which should be further addressed in hypothalamic neurons.…”

Section: Discussionmentioning

confidence: 99%

Fatty acid synthase gene regulation in primary hypothalamic neurons

Kim

Kleman

Ronnett

2007

Neuroscience Letters

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Understanding the mechanisms that regulate feeding is critical to the development of therapeutic interventions for obesity. Many studies indicate that enzymes within fatty acid metabolic pathways may serve as targets for pharmacological tools to treat this epidemic. We, and others have previously demonstrated that C75, a fatty acid synthase (FAS) inhibitor, induced significant anorexia and weight loss by both central and peripheral mechanisms. Because the hypothalamus is important in the regulation of homeostatic processes for feeding control, we have identified pathways that alter the gene expression of FAS in primary hypothalamic neuronal cultures. Insulin, glucose and AICAR (an activator of AMP-activated protein kinase) affected changes in hypothalamic FAS mRNA, which may be regulated via the SREBP1c dependent or independent pathway.

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Activation of AMPK in rat hypothalamus participates in cold‐induced resistance to nutrient‐dependent anorexigenic signals

Cited by 20 publications

References 24 publications

Intracerebroventricular injection of citrate inhibits hypothalamic AMPK and modulates feeding behavior and peripheral insulin signaling

Intracerebroventricular injection of citrate inhibits hypothalamic AMPK and modulates feeding behavior and peripheral insulin signaling

Glucose, insulin, and leptin signaling pathways modulate nitric oxide synthesis in glucose-inhibited neurons in the ventromedial hypothalamus

Fatty acid synthase gene regulation in primary hypothalamic neurons

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