Fructose-Induced Hypothalamic AMPK Activation Stimulates Hepatic PEPCK and Gluconeogenesis due to Increased Corticosterone Levels

Kinote, Andrezza Pinheiro Bezerra de Menezes; Faria, Juliana A.; Roman, Erika; Solon, Carina; Razolli, Daniela S.; Ignácio-Souza, Letícia Martins; Sollon, Carolina; Nascimento, Lucas F.; Araújo, Thiago Matos de; Barbosa, Ana Paula L.; Lellis‐Santos, Camilo; Velloso, Lı́cio A.; Bordin, Silvana; Anhê, Gabriel Forato

doi:10.1210/en.2012-1341

Cited by 61 publications

(40 citation statements)

References 44 publications

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“…Moreover, food intake is increased in rats given an oral sucrose preload compared with a starch preload (13). When administered centrally, the sucrose metabolite fructose enhances hypothalamic AMPK activation and subsequently stimulates food intake (7,24). We expand upon these observations and show that icv pretreatment with fructose attenuates the anorectic effect of icv Ex-4.…”

Section: Discussionmentioning

confidence: 77%

Central glucagon-like peptide 1 receptor-induced anorexia requires glucose metabolism-mediated suppression of AMPK and is impaired by central fructose

Burmeister

Ayala

Drucker

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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Burmeister MA, Ayala J, Drucker DJ, Ayala JE. Central glucagon-like peptide 1 receptor-induced anorexia requires glucose metabolism-mediated suppression of AMPK and is impaired by central fructose. Am J Physiol Endocrinol Metab 304: E677-E685, 2013. First published January 22, 2013 doi:10.1152/ajpendo.00446.2012.-Glucagon-like peptide-1 (GLP-1) suppresses food intake via activation of a central (i.e., brain) GLP-1 receptor (GLP-1R). Central AMP-activated protein kinase (AMPK) is a nutrient-sensitive regulator of food intake that is inhibited by anorectic signals. The anorectic effect elicited by hindbrain GLP-1R activation is attenuated by the AMPK stimulator AICAR. This suggests that central GLP-1R activation suppresses food intake via inhibition of central AMPK. The present studies examined the mechanism(s) by which central GLP-1R activation inhibits AMPK. Supporting previous findings, AICAR attenuated the anorectic effect elicited by intracerebroventricular (icv) administration of the GLP-1R agonist exendin-4 (Ex-4). We demonstrate that Ex-4 stimulates glycolysis and suppresses AMPK phosphorylation in a glucose-dependent manner in hypothalamic GT1-7 cells. This suggests that inhibition of AMPK and food intake by Ex-4 requires central glucose metabolism. Supporting this, the glycolytic inhibitor 2-deoxyglucose (2-DG) attenuated the anorectic effect of Ex-4. However, icv glucose did not enhance the suppression of food intake by Ex-4. AICAR had no effect on Ex-4-mediated reduction in locomotor activity. We also tested whether other carbohydrates affect the anorectic response to Ex-4. Intracerebroventricular pretreatment with the sucrose metabolite fructose, an AMPK activator, attenuated the anorectic effect of Ex-4. This potentially explains the increased food intake observed in sucrose-fed mice. In summary, we propose a model whereby activation of the central GLP-1R reduces food intake via glucose metabolism-dependent inhibition of central AMPK. We also suggest that fructose stimulates food intake by impairing central GLP-1R action. This has significant implications given the correlation between sugar consumption and obesity.glucagon-like peptide 1; adenosine 5=-monophosphate-activated kinase; food intake; glucose; fructose HEALTH RISKS ASSOCIATED WITH OBESITY, including cardiovascular disease, diabetes, and cancer, highlight the importance of understanding mechanisms that control food intake and how they become impaired. Food intake is regulated by neural and hormonal signals that match caloric intake with the chronic and acute energy needs of the organism. Although significant attention has been given to understanding mechanisms associated with adiposity signals such as leptin and insulin, less is known about acute satiety mechanisms regulated by signals such as glucagon-like peptide-1 (GLP-1).GLP-1 is secreted from intestinal L cells in response to nutrient intake and was identified for its ability to stimulate insulin secretion via activation of a pancreatic ␤-cell GLP-1 receptor (GLP-1R) (3). GLP-1 also r...

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Section: Discussionmentioning

confidence: 77%

Central glucagon-like peptide 1 receptor-induced anorexia requires glucose metabolism-mediated suppression of AMPK and is impaired by central fructose

Burmeister

Ayala

Drucker

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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“…Cannulas were also implanted in the mediobasal hypothalamus (MBH) using the following the coordinates: 3.1 mm posterior to bregma, 0.4 mm lateral, and 9.6 mm deep. Localization of the cannula was confirmed previously by staining of the hypothalamic region after an injection with bromophenol blue (15). Angiotensin-responsive rats received their icv injections at 9 AM after a 13-h fast (fasting starting at 8 PM on the days prior to the experiments).…”

Section: Methodsmentioning

confidence: 84%

Melatonin acts through MT1/MT2 receptors to activate hypothalamic Akt and suppress hepatic gluconeogenesis in rats

Faria

Kinote

Ignácio-Souza

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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Melatonin can contribute to glucose homeostasis either by decreasing gluconeogenesis or by counteracting insulin resistance in distinct models of obesity. However, the precise mechanism through which melatonin controls glucose homeostasis is not completely understood. Male Wistar rats were administered an intracerebroventricular (icv) injection of melatonin and one of following: an icv injection of a phosphatidylinositol 3-kinase (PI3K) inhibitor, an icv injection of a melatonin receptor (MT) antagonist, or an intraperitoneal (ip) injection of a muscarinic receptor antagonist. Anesthetized rats were subjected to pyruvate tolerance test to estimate in vivo glucose clearance after pyruvate load and in situ liver perfusion to assess hepatic gluconeogenesis. The hypothalamus was removed to determine Akt phosphorylation. Melatonin injections in the central nervous system suppressed hepatic gluconeogenesis and increased hypothalamic Akt phosphorylation. These effects of melatonin were suppressed either by icv injections of PI3K inhibitors and MT antagonists and by ip injection of a muscarinic receptor antagonist. We conclude that melatonin activates hypothalamus-liver communication that may contribute to circadian adjustments of gluconeogenesis. These data further suggest a physiopathological relationship between the circadian disruptions in metabolism and reduced levels of melatonin found in type 2 diabetes patients. melatonin; gluconeogenesis; melatonin receptors; liver MELATONIN (5-methoxy-N-acetyltryptamine) is produced and secreted by the pineal gland in a circadian fashion, with peak levels during the dark phase of the light-dark cycle. The canonical function of melatonin is to transmit environmental information (i.e., the length of the dark period) to the living organism, thereby synchronizing the circadian clock in the hypothalamic suprachiasmatic nucleus (22). In vivo and in vitro experiments have demonstrated that melatonin also plays a role in energy homeostasis by regulating body mass and adiposity and leptin expression by adipocytes (1, 40). Glucose homeostasis is also altered by the absence of melatonin in such a way that pinealectomized rats display glucose intolerance and desynchronized circadian pattern of gluconeogenesis, hallmarked by increased nighttime glucose levels (17,18,23). Moreover, chronic melatonin administration has been shown to improve glucose homeostasis not only in pinealectomized rats but also in rats rendered insulin resistant by diet manipulation (16,33,34).Although it has been demonstrated that melatonin stimulates glucose uptake in adipocytes and skeletal muscle cells in vitro (10, 19), the precise mechanism by which this hormone reduces whole body glucose intolerance has not been determined precisely. In mammals, the effects of melatonin are mediated in part by specific high-affinity G protein-coupled receptors known as melatonin receptor 1 (MT1) and melatonin receptor 2 (MT2) (31). We have demonstrated previously that melatonin acts locally in the hypothalamus to activate the p...

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“…Furthermore, intracerebroventricular fructose administration causes induction of hepatic gluconeogenesis through the AMPK-mediated elevation of circulating GC levels [147], indicating that as-yet non-appreciated signaling pathways between the central nervous system (CNS) and the periphery are tightly coupled to the GC/GR axis and determine systemic metabolic control.…”

Section: Future Perspectivesmentioning

confidence: 99%

Glucocorticoid hormones and energy homeostasis

Guia

Rose

Herzig³

2014

Hormone Molecular Biology and Clinical Investigation

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Glucocorticoids (GC) and their cognate intracellular receptor, the glucocorticoid receptor (GR), have been characterised as critical checkpoints in the endocrine control of energy homeostasis in mammals. Indeed, aberrant GC action has been linked to a variety of severe metabolic diseases, including obesity, insulin resistance and type 2 diabetes. As a steroid-binding member of the nuclear receptor superfamily of transcription factors, the GR translocates into the cell nucleus upon GC binding where it serves as a transcriptional regulator of distinct GC-responsive target genes that are - in many cases - associated with glucose and lipid regulatory pathways and thereby intricately control both physiological and pathophysiological systemic energy homeostasis. Here, we summarize the current knowledge of GC/GR function in energy metabolism and systemic metabolic dysfunction, particularly focusing on glucose and lipid metabolism.

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Fructose-Induced Hypothalamic AMPK Activation Stimulates Hepatic PEPCK and Gluconeogenesis due to Increased Corticosterone Levels

Cited by 61 publications

References 44 publications

Central glucagon-like peptide 1 receptor-induced anorexia requires glucose metabolism-mediated suppression of AMPK and is impaired by central fructose

Central glucagon-like peptide 1 receptor-induced anorexia requires glucose metabolism-mediated suppression of AMPK and is impaired by central fructose

Melatonin acts through MT1/MT2 receptors to activate hypothalamic Akt and suppress hepatic gluconeogenesis in rats

Glucocorticoid hormones and energy homeostasis

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