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Novel roles for JNK1 in metabolism.

Belgardt BF, Mauer J, Brüning JC - Aging (Albany NY) (2010)

Bottom Line: Activation of stress-kinase signaling has recently been recognized as an important pathophysiological mechanism in the development of diet-induced obesity, type 2 diabetes mellitus and other aging-related pathologies.Nonetheless, the tissue-specific role of JNK1-activation in the development of the metabolic syndrome has been poorly defined so far.Recently, it was demonstrated that JNK1 signaling plays a crucial role in the central nervous system (CNS) and in the pituitary to control systemic glucose and lipid metabolism partially through regulation of hormones involved in growth and energy expenditure.

View Article: PubMed Central - PubMed

Affiliation: Institute for Genetics, Department of Mouse Genetics and Metabolism, Center for Molecular Medicine, University of Cologne (CMMC), Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), 2nd Department for Internal Medicine University of Cologne 50674 Cologne, Germany.

ABSTRACT
Activation of stress-kinase signaling has recently been recognized as an important pathophysiological mechanism in the development of diet-induced obesity, type 2 diabetes mellitus and other aging-related pathologies. Here, c-Jun N-terminal Kinase (JNK) 1 knockout mice have been shown to exhibit protection from diet-induced obesity, glucose intolerance, and insulin resistance. Nonetheless, the tissue-specific role of JNK1-activation in the development of the metabolic syndrome has been poorly defined so far. Recently, it was demonstrated that JNK1 signaling plays a crucial role in the central nervous system (CNS) and in the pituitary to control systemic glucose and lipid metabolism partially through regulation of hormones involved in growth and energy expenditure.

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Insulin-like signalling plays a central role in growth, metabolism and the aging process. Insulin, derived from pancreatic beta-cells in mammals or insulin-like peptides derived from neuroendocrine cells in invertebrates signals via binding to and activation of the membrane bound receptors. This event subsequently activates PI3K, which through phosphorylation of membrane lipids (phosphorinositides) regulates activity of the downstream kinase AKT. AKT eventually phosphorylates forkhead transcript-tion factors such as FOXO1, which are then exported from the nucleus and degraded. FOXOs regulate transcription of many genes involved in glucose and lipid metabolism, growth, stress response and the aging process. Thus, insulin-like signalling is able to control all of these processes through FOXO regulation and other signalling cascades, in the end impinging on crucial physiological processes and lifespan itself. Nonetheless, chronic intake of energy-dense food coupled with little physical activity leads to hyperlipidemia and hyperglycemia, which through several mechanisms (including JNK1 activation) reduce cellular insulin sensitivity, thereby disrupting metabolic homeostasis.
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Figure 1: Insulin-like signalling plays a central role in growth, metabolism and the aging process. Insulin, derived from pancreatic beta-cells in mammals or insulin-like peptides derived from neuroendocrine cells in invertebrates signals via binding to and activation of the membrane bound receptors. This event subsequently activates PI3K, which through phosphorylation of membrane lipids (phosphorinositides) regulates activity of the downstream kinase AKT. AKT eventually phosphorylates forkhead transcript-tion factors such as FOXO1, which are then exported from the nucleus and degraded. FOXOs regulate transcription of many genes involved in glucose and lipid metabolism, growth, stress response and the aging process. Thus, insulin-like signalling is able to control all of these processes through FOXO regulation and other signalling cascades, in the end impinging on crucial physiological processes and lifespan itself. Nonetheless, chronic intake of energy-dense food coupled with little physical activity leads to hyperlipidemia and hyperglycemia, which through several mechanisms (including JNK1 activation) reduce cellular insulin sensitivity, thereby disrupting metabolic homeostasis.

Mentions: The anabolic peptide hormone insulin is secreted from the pancreas in response to an increase of blood glucose concentrations. It acts on the liver to reduce hepatic glucose output and it promotes glucose and lipid uptake into peripheral tissues such as adipose tissue and skeletal muscle. Binding of insulin or insulin-like peptides to their receptor leads to recruitment of insulin receptor substrate (IRS) proteins, subsequently activating two major signalling branches: the phosphatidylinositol 3 kinase (PI3K)-pathway and the mitogen-activated protein kinase (MAPK)-pathway [6,7]. PI3K activity mediates activation of the kinase AKT, which phosphorylates and thereby deactivates forkhead transcription factors (FOXOs). FOXOs are transcriptional regulators of genes involved in metabolism and growth [8]. Activation of the PI3K/AKT/FOXO axis mediates many of insulin's and insulin-like peptides’ effects, including e.g. regulation of growth, glucose/fat metabolism, stress response and lifespan (Figure 1) [9]. Besides the expression and activation of this pathway in peripheral organs, the insulin/insulin-like signalling machinery is also expressed and active in the central nervous system (CNS) where it regulates fertility and body weight [10-12]. Furthermore, it was recently demonstrated that insulin action in the CNS also controls peripheral glucose and fat metabolism [13-15].


Novel roles for JNK1 in metabolism.

Belgardt BF, Mauer J, Brüning JC - Aging (Albany NY) (2010)

Insulin-like signalling plays a central role in growth, metabolism and the aging process. Insulin, derived from pancreatic beta-cells in mammals or insulin-like peptides derived from neuroendocrine cells in invertebrates signals via binding to and activation of the membrane bound receptors. This event subsequently activates PI3K, which through phosphorylation of membrane lipids (phosphorinositides) regulates activity of the downstream kinase AKT. AKT eventually phosphorylates forkhead transcript-tion factors such as FOXO1, which are then exported from the nucleus and degraded. FOXOs regulate transcription of many genes involved in glucose and lipid metabolism, growth, stress response and the aging process. Thus, insulin-like signalling is able to control all of these processes through FOXO regulation and other signalling cascades, in the end impinging on crucial physiological processes and lifespan itself. Nonetheless, chronic intake of energy-dense food coupled with little physical activity leads to hyperlipidemia and hyperglycemia, which through several mechanisms (including JNK1 activation) reduce cellular insulin sensitivity, thereby disrupting metabolic homeostasis.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2984610&req=5

Figure 1: Insulin-like signalling plays a central role in growth, metabolism and the aging process. Insulin, derived from pancreatic beta-cells in mammals or insulin-like peptides derived from neuroendocrine cells in invertebrates signals via binding to and activation of the membrane bound receptors. This event subsequently activates PI3K, which through phosphorylation of membrane lipids (phosphorinositides) regulates activity of the downstream kinase AKT. AKT eventually phosphorylates forkhead transcript-tion factors such as FOXO1, which are then exported from the nucleus and degraded. FOXOs regulate transcription of many genes involved in glucose and lipid metabolism, growth, stress response and the aging process. Thus, insulin-like signalling is able to control all of these processes through FOXO regulation and other signalling cascades, in the end impinging on crucial physiological processes and lifespan itself. Nonetheless, chronic intake of energy-dense food coupled with little physical activity leads to hyperlipidemia and hyperglycemia, which through several mechanisms (including JNK1 activation) reduce cellular insulin sensitivity, thereby disrupting metabolic homeostasis.
Mentions: The anabolic peptide hormone insulin is secreted from the pancreas in response to an increase of blood glucose concentrations. It acts on the liver to reduce hepatic glucose output and it promotes glucose and lipid uptake into peripheral tissues such as adipose tissue and skeletal muscle. Binding of insulin or insulin-like peptides to their receptor leads to recruitment of insulin receptor substrate (IRS) proteins, subsequently activating two major signalling branches: the phosphatidylinositol 3 kinase (PI3K)-pathway and the mitogen-activated protein kinase (MAPK)-pathway [6,7]. PI3K activity mediates activation of the kinase AKT, which phosphorylates and thereby deactivates forkhead transcription factors (FOXOs). FOXOs are transcriptional regulators of genes involved in metabolism and growth [8]. Activation of the PI3K/AKT/FOXO axis mediates many of insulin's and insulin-like peptides’ effects, including e.g. regulation of growth, glucose/fat metabolism, stress response and lifespan (Figure 1) [9]. Besides the expression and activation of this pathway in peripheral organs, the insulin/insulin-like signalling machinery is also expressed and active in the central nervous system (CNS) where it regulates fertility and body weight [10-12]. Furthermore, it was recently demonstrated that insulin action in the CNS also controls peripheral glucose and fat metabolism [13-15].

Bottom Line: Activation of stress-kinase signaling has recently been recognized as an important pathophysiological mechanism in the development of diet-induced obesity, type 2 diabetes mellitus and other aging-related pathologies.Nonetheless, the tissue-specific role of JNK1-activation in the development of the metabolic syndrome has been poorly defined so far.Recently, it was demonstrated that JNK1 signaling plays a crucial role in the central nervous system (CNS) and in the pituitary to control systemic glucose and lipid metabolism partially through regulation of hormones involved in growth and energy expenditure.

View Article: PubMed Central - PubMed

Affiliation: Institute for Genetics, Department of Mouse Genetics and Metabolism, Center for Molecular Medicine, University of Cologne (CMMC), Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), 2nd Department for Internal Medicine University of Cologne 50674 Cologne, Germany.

ABSTRACT
Activation of stress-kinase signaling has recently been recognized as an important pathophysiological mechanism in the development of diet-induced obesity, type 2 diabetes mellitus and other aging-related pathologies. Here, c-Jun N-terminal Kinase (JNK) 1 knockout mice have been shown to exhibit protection from diet-induced obesity, glucose intolerance, and insulin resistance. Nonetheless, the tissue-specific role of JNK1-activation in the development of the metabolic syndrome has been poorly defined so far. Recently, it was demonstrated that JNK1 signaling plays a crucial role in the central nervous system (CNS) and in the pituitary to control systemic glucose and lipid metabolism partially through regulation of hormones involved in growth and energy expenditure.

Show MeSH
Related in: MedlinePlus