<i>In vivo</i> activation of insulin receptor tyrosine kinase by melatonin in the rat hypothalamus

Anhê, Gabriel Forato; Caperuto, Luciana C.; Pereira-da-Silva, Márcio; Souza, L C.; Hirata, Aparecida Emiko; Velloso, Lı́cio A.; Cipolla‐Neto, José; Carvalho, Carla Roberta de Oliveira

doi:10.1111/j.1471-4159.2004.02514.x

Cited by 106 publications

(75 citation statements)

References 54 publications

(52 reference statements)

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“…This mechanism is attenuated in the presence of obesity to suggest that fat loading blunts intrinsic cellular clock activity [35]. Bearing in mind that adipocytes express melatonin receptors through which melatonin is able to phosphorylate and co-activate the insulin receptor to enhance insulin sensitivity [29,39], there appears to be complex circadian regulation of adipocyte function, which, when interrupted, may contribute to the insulin resistance phenotype.…”

Section: Seasonal and Circadian Responses In Mammalsmentioning

confidence: 99%

Neel revisited: the adipocyte, seasonality and type 2 diabetes

Scott

Grant

2006

Diabetologia

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The modern epidemic of obesity and insulin resistance with cardiovascular risk factor clustering is related to the development of type 2 diabetes and cardiovascular disease. Over 40 years ago, Neel postulated that insulin resistance should confer survival benefit. Extrapolating Neel's hypothesis, we propose that the cluster of associated abnormalities also confers survival benefit and is related to metabolic responses seen in seasonally responsive animals. Weight gain in preparation for winter is accompanied by a range of acute metabolic changes virtually identical to the long-term changes seen in type 2 diabetes. In seasonal animals the responses are acute, physiological and protective. In man, similar responses that would once have conferred survival benefit have become chronic, pathological and harmful in modern life. We hypothesise that type 2 diabetes and cardiovascular disease in man are the result of chronic and inappropriate pinealhypothalamic-adipocyte interactions biologically related to seasonal change.Keywords Adipocyte . Cardiovascular disease . Circadian and circannual rhythm . Clock genes . Hypothalamus . Inflammation . Insulin resistance . Melatonin . Metabolic syndrome . Seasonality . Type 2 diabetes Neel revisitedThe world is currently in the midst of an epidemic of type 2 diabetes, and around 300 million individuals are predicted to develop this disorder by the year 2025 [1]. The close biological relationship between diabetes and cardiovascular disease has focused attention on the common genetic and environmental antecedents of these conditions-the common soil hypothesis [2]-but the pathophysiological basis of these associations remains obscure. In 1962, Neel proposed the thrifty genotype hypothesis, which postulated that insulin overproduction must at one time have had a beneficial effect, in that it would provide 'an important energy conserving mechanism when food intake was irregular and obesity rare' [3]. Although Neel recognised insulin antagonism rather than insulin resistance, he hypothesised that the combination of obesity with increased insulin (or the presence of insulin antagonists) would lead to the development of diabetes. With hindsight, Neel was essentially speculating on the potential metabolic benefits of insulin resistance. The recognition in the last 20 years of an insulin resistance risk cluster [4] indicates that, under certain circumstances, elements of the risk cluster should also be beneficial to the survival of the organism, a response that, by analogy with Neel's original hypothesis, may coincidentally lead to the development of cardiovascular disease in times of plenty. The development of both insulin resistance and inflammation are physiological responses to increasing adiposity that, by definition, should be beneficial to the survival of the organism. The observation that the chronic metabolic milieu associated with type 2 diabetes is harmful raises the possibility that the adipocyte response to fat loading is beneficial when acute and short-lived, as is o...

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Section: Seasonal and Circadian Responses In Mammalsmentioning

confidence: 99%

Neel revisited: the adipocyte, seasonality and type 2 diabetes

Scott

Grant

2006

Diabetologia

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“…The anesthetized rats were decapitated at the intervals after icv injections, as indicated in the figure legends. The hypothalamus was removed and processed for Western blotting, as described previously (2). The primary antibodies anti-Akt1/2/3 and anti-p-Akt1/2/3 (Ser 473 ) were obtained from Santa Cruz Biotechnology (Santa Cruz, CA).…”

Section: Methodsmentioning

confidence: 99%

“…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 phosphatidylinositol 3-kinase/insulin-stimulated RAC-␣ serine/threonine-protein kinase (PI3K/Akt) pathway through a mechanism that is dependent on MT1/MT2 receptors (2). However, the metabolic relevance of this signal triggered by melatonin remains unknown.…”

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confidence: 99%

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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“…у вихiдному станi; p < 0,05) [19]. Останнє узгоджується з iсну-ючими в науковiй лiтературi даними, якими показано, що мелатонiн здiйснює стимулюю-чий рецептор-опосередкований ефект на iн-сулiн-залежний транспорт глюкози в клiти-нах скелетних м'язiв мишей та гiпоталамусi щурiв [20,21]. Згiдно з результатами цих дослiджень механiзм такої дiї гормону пов'я-заний з посиленням фосфорилювання по ти-розину субстрата iнсулiнового рецептора-1 та активностi фосфатидилiнозiтол-3-кiнази (IRS-1/PI-3-кiназний каскад).…”

Section: результати та їх обговоренняunclassified

Features of Changes in Circadian Rhythm of Circulating Levels of Insulin and Glucose in the Metabolic Syndrome Induced Experimental Hypopinealism

Mishchenko¹,

Gladkih²,

Poltorak³

2021

PEP

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In the experimental study on young adult male rabbits it was found leveling of circadian rhythm in insulin concentration and violation of circadian pattern of glucose (inversion, which is replaced by leveling) in the dynamics of the formation of metabolic syndrome, which develops in the hypopinealism induced by long-term exposure to low-light in the dark. Change in the circadian rhythm of secretion of insulin, glucose, and hyperinsulinemia that result of chronic disturbance of natural light/dark cycle, are the basis of the manifestation of the metabolic syndrome in hypopinealism.

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In vivo activation of insulin receptor tyrosine kinase by melatonin in the rat hypothalamus

Cited by 106 publications

References 54 publications

Neel revisited: the adipocyte, seasonality and type 2 diabetes

Neel revisited: the adipocyte, seasonality and type 2 diabetes

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

Features of Changes in Circadian Rhythm of Circulating Levels of Insulin and Glucose in the Metabolic Syndrome Induced Experimental Hypopinealism

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