The Effect of AMP‐Activated Kinase Activation on Gonadotrophin‐Releasing Hormone Secretion in GT1‐7 Cells and its Potential Role in Hypothalamic Regulation of the Oestrous Cyclicity in Rats

Coyral-Castel, Stéphanie; Tosca, Lucie; Ferreira, Guillaume; Jeanpierre, Eric; Ramé, Christelle; Lomet, Didier; Caraty, Alain; Monget, Philippe; Chabrolle, Christine; Dupont, Joëlle

doi:10.1111/j.1365-2826.2007.01643.x

Cited by 61 publications

(34 citation statements)

References 67 publications

(81 reference statements)

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“…It is worth noting, however, that direction-appropriate changes in AMPK activity (i.e. increase or decrease in activity) have been reported for both AICAR and compound C, that alterations in AMPK activity by one drug are antagonized by the other, and that each pharmacological agent is widely used to examine AMPK-mediated effects both in vivo and in vitro (20,21,41,43,(45)(46)(47)(48).…”

Section: Discussionmentioning

confidence: 98%

Dorsal Hindbrain 5′-Adenosine Monophosphate-Activated Protein Kinase as an Intracellular Mediator of Energy Balance

et al. 2008

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The fuel-sensing enzyme AMP-activated protein kinase (AMPK) has been implicated in central nervous system control of energy balance. Hypothalamic AMPK activity is increased by food deprivation, and this elevation is inhibited by refeeding or by leptin treatment. The contribution of extrahypothalamic AMPK activity in energy balance control has not been addressed. Here, we investigate the effects of physiological state on the AMPK activity in hindbrain nucleus tractus solitarius (NTS) neurons because treatments that reduce energy availability in these neurons trigger behavioral, endocrine, and autonomic responses to restore energy balance. Food-deprived rats showed significantly increased AMPK activity in both NTS- and hypothalamus-enriched lysates compared with those that were ad libitum fed. Pharmacological inhibition of AMPK activity in medial NTS neurons, by intraparenchymal injection of compound C, suppressed food intake and body weight gain compared with vehicle. Fourth ventricle (4th i.c.v.) compound C delivery increased heart rate and spontaneous activity in free-moving rats. Suppression of AMPK activity has been implicated in leptin's anorectic action in the hypothalamus. Given the role of leptin signaling in food intake inhibition within the medial NTS, we also examined whether stimulation of hindbrain AMPK by 4th i.c.v. administration of 5-aminoimidazole-4-carboxamide-riboside (AICAR), an AMP-mimicking promoter of AMPK activity, could attenuate the inhibition of food intake by 4th i.c.v. leptin. The intake-suppressive effects of leptin (at 2 and 4 h) were completely reversed by AICAR. We conclude that 1) hindbrain AMPK activity contributes to energy balance control through regulation of food intake and energy expenditure, 2) leptin's intake-reducing effects in the NTS are mediated by AMPK, and 3) central nervous system AMPK controls whole-body homeostasis at anatomically distributed sites across the neuraxis.

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Section: Discussionmentioning

confidence: 98%

Dorsal Hindbrain 5′-Adenosine Monophosphate-Activated Protein Kinase as an Intracellular Mediator of Energy Balance

et al. 2008

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“…Activation of AMPK in the hypothalamus by the AMPK activator 5-aminoimidazole-4-carboxamide-1-b-D-ribofuranoside (AICAR) has been shown to stimulate phosphorylation of AMPK and ACC as well as upregulating expression of NPY and AgRP (Coyral-Castel et al 2008;Shimizu et al 2008). Molecular and pharmacological inhibition of hypothalamic AMPK decreases hepatic glucose production (Yang et al 2010).…”

Section: Ampk and Its Role In Food Intakementioning

confidence: 99%

The regulation of food intake in mammalian hibernators: a review

Florant

Healy

2011

J Comp Physiol B

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One of the most profound hallmarks of mammalian hibernation is the dramatic reduction in food intake during the winter months. Several species of hibernator completely cease food intake (aphagia) for nearly 7 months regardless of ambient temperature and in many cases, whether or not food is available to them. Food intake regulation has been studied in mammals that hibernate for over 50 years and still little is known about the physiological mechanisms that control this important behavior in hibernators. It is well known from lesion experiments in non-hibernators that the hypothalamus is the main brain region controlling food intake and therefore body mass. In hibernators, the regulation of food intake and body mass is presumably governed by a circannual rhythm since there is a clear seasonal rhythm to food intake: animals increase food intake in the summer and early autumn, food intake declines in autumn and actually ceases in winter in many species, and resumes again in spring as food becomes available in the environment. Changes in circulating hormones (e.g., leptin, insulin, and ghrelin), nutrients (glucose, and free fatty acids), and cellular enzymes such as AMP-activated protein kinase (AMPK) have been shown to determine the activity of neurons involved in the food intake pathway. Thus, it appears likely that the food intake pathway is controlled by a variety of inputs, but is also acted upon by upstream regulators that are presumably rhythmic in nature. Current research examining the molecular mechanisms and integration of environmental signals (e.g., temperature and light) with these molecular mechanisms will hopefully shed light on how animals can turn off food intake and survive without eating for months on end.

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“…In dispersed primary rat hypothalamic neuronal cell cultures, metformin inhibited PRKA activity in hypothalamic neurons, thus modulating the expression of the orexigenic peptide NPY [18]. Our laboratory has also shown that metformin inhibits gonadotropin-releasing hormone (GnRH) release from immortalized hypothalamic GT1-7 cells via PRKA activation, whereas compound C (Comp C), a well-known PRKA inhibitor, completely eliminates this effect [19]. Furthermore, adiponectin has been shown to reduce LH secretion in pituitary gonadotrophs in a PRKAdependent manner [20].…”

Section: Introductionmentioning

confidence: 94%

Metformin Decreases GnRH- and Activin-Induced Gonadotropin Secretion in Rat Pituitary Cells: Potential Involvement of Adenosine 5' Monophosphate-Activated Protein Kinase (PRKA)

Tosca

Froment

Ramé

et al. 2010

Biology of Reproduction

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Metformin is an insulin sensitizer molecule used for the treatment of infertility in women with polycystic ovary syndrome and insulin resistance. It modulates the reproductive axis, affecting the release of gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH). However, metformin's mechanism of action in pituitary gonadotropin-secreting cells remains unclear. Adenosine 5' monophosphate-activated protein kinase (PRKA) is involved in metformin action in various cell types. Here, we investigated the effects of metformin on gonadotropin secretion in response to activin and GnRH in primary rat pituitary cells (PRP), and studied PRKA in rat pituitary. In PRP, metformin (10 mM) reduced LH and follicle-stimulating hormone (FSH) secretion induced by GnRH (10(-8) M, 3 h), FSH secretion, and mRNA FSHbeta subunit expression induced by activin (10(-8) M, 12 or 24 h). The different subunits of PRKA are expressed in pituitary. In particular, PRKAA1 is detected mainly in gonadotrophs and thyrotrophs, is less abundant in lactotrophs and somatotrophs, and is undetectable in corticotrophs. In PRP, metformin increased phosphorylation of both PRKA and acetyl-CoA carboxylase. Metformin decreased activin-induced SMAD2 phosphorylation and GnRH-induced mitogen-activated protein kinase (MAPK) 3/1 (ERK1/2) phosphorylation. The PRKA inhibitor compound C abolished the effects of metformin on gonadotropin release induced by GnRH and on FSH secretion and Fshb mRNA induced by activin. The adenovirus-mediated production of dominant negative PRKA abolished the effects of metformin on the FSHbeta subunit mRNA and SMAD2 phosphorylation induced by activin and on the MAPK3/1 phosphorylation induced by GnRH. Thus, in rat pituitary cells, metformin decreases gonadotropin secretion and MAPK3/1 phosphorylation induced by GnRH and FSH release, FSHbeta subunit expression, and SMAD2 phosphorylation induced by activin through PRKA activation.

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The Effect of AMP‐Activated Kinase Activation on Gonadotrophin‐Releasing Hormone Secretion in GT1‐7 Cells and its Potential Role in Hypothalamic Regulation of the Oestrous Cyclicity in Rats

Cited by 61 publications

References 67 publications

Dorsal Hindbrain 5′-Adenosine Monophosphate-Activated Protein Kinase as an Intracellular Mediator of Energy Balance

Dorsal Hindbrain 5′-Adenosine Monophosphate-Activated Protein Kinase as an Intracellular Mediator of Energy Balance

The regulation of food intake in mammalian hibernators: a review

Metformin Decreases GnRH- and Activin-Induced Gonadotropin Secretion in Rat Pituitary Cells: Potential Involvement of Adenosine 5' Monophosphate-Activated Protein Kinase (PRKA)

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