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Recent Insights into the Role of Hypothalamic AMPK Signaling Cascade upon Metabolic Control.

Schneeberger M, Claret M - Front Neurosci (2012)

Bottom Line: In 2004, two seminal papers focused on the role of AMP-activated protein kinase (AMPK) in the hypothalamus opened new avenues of research in the field of the central regulation of energy homeostasis.In this review article we aim to discuss the most recent findings in this particular area of research, highlighting the function of hypothalamic AMPK in appetite, thermogenesis, and peripheral glucose metabolism.The diversity of mechanisms by which hypothalamic AMPK regulates energy homeostasis illustrates the importance of this evolutionary-conserved energy signaling cascade in the control of this complex and fundamental biological process.

View Article: PubMed Central - PubMed

Affiliation: Diabetes and Obesity Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer Barcelona, Spain ; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas Barcelona, Spain ; Department of Endocrinology and Nutrition, Hospital Clínic, School of Medicine, University of Barcelona Barcelona, Spain.

ABSTRACT
In 2004, two seminal papers focused on the role of AMP-activated protein kinase (AMPK) in the hypothalamus opened new avenues of research in the field of the central regulation of energy homeostasis. Over the following 8 years, hundreds of studies have firmly established hypothalamic AMPK as a key sensor and integrator of hormonal and nutritional signals with neurochemical and neurophysiological responses to regulate whole-body energy balance. In this review article we aim to discuss the most recent findings in this particular area of research, highlighting the function of hypothalamic AMPK in appetite, thermogenesis, and peripheral glucose metabolism. The diversity of mechanisms by which hypothalamic AMPK regulates energy homeostasis illustrates the importance of this evolutionary-conserved energy signaling cascade in the control of this complex and fundamental biological process.

No MeSH data available.


Hypothalamic AMPK regulates appetite. Schematic representation of a generic hypothalamic neuron depicting a summary of the recently uncovered signaling mechanisms implicated in appetite control. Pathways in red inhibit AMPK activity and subsequently reduce food intake and body weight (negative energy balance), while pathways in green activate it and lead to the opposite physiological outputs (positive energy balance). A diagram of the role of presynaptic AMPK can be found elsewhere (Yang et al., 2011; Hardie et al., 2012). LepR, leptin receptor; Ghsr1a, growth hormone secretagogue receptor type 1a; PI3K, phosphatidylinositol 3-kinase; Akt, protein kinase B; mTOR, mammalian target of rapamycin; KSR2, kinase suppressor of Ras 2; PLCβ, phospholipase C; IP3, inositol-1,4,5-triphosphate; Ca2+, calcium; LKB1, liver kinase B1; CamKKβ, Ca2+/Calmodulin kinase kinase β; Sirt-1, sirtuin 1; IPMK, inositol polyphosphate multikinase.
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Figure 1: Hypothalamic AMPK regulates appetite. Schematic representation of a generic hypothalamic neuron depicting a summary of the recently uncovered signaling mechanisms implicated in appetite control. Pathways in red inhibit AMPK activity and subsequently reduce food intake and body weight (negative energy balance), while pathways in green activate it and lead to the opposite physiological outputs (positive energy balance). A diagram of the role of presynaptic AMPK can be found elsewhere (Yang et al., 2011; Hardie et al., 2012). LepR, leptin receptor; Ghsr1a, growth hormone secretagogue receptor type 1a; PI3K, phosphatidylinositol 3-kinase; Akt, protein kinase B; mTOR, mammalian target of rapamycin; KSR2, kinase suppressor of Ras 2; PLCβ, phospholipase C; IP3, inositol-1,4,5-triphosphate; Ca2+, calcium; LKB1, liver kinase B1; CamKKβ, Ca2+/Calmodulin kinase kinase β; Sirt-1, sirtuin 1; IPMK, inositol polyphosphate multikinase.

Mentions: The regulation of AMPK activity is complex, but mainly achieved through phosphorylation of threonine172 on the catalytic α subunit by upstream kinases, such as liver kinase B1 (LKB1) and Ca2+/Calmodulin kinase kinase β (CamKKβ; Hardie et al., 2012). A recent study has reported that inositol polyphosphate multikinase (IPMK) may be an upstream physiologic regulator of AMPK activity in the hypothalamus (Bang et al., 2012). IPMK inhibits AMPK activity during the fasting/refed transition through binding between these two proteins, an interaction facilitated by IPMK phosphorylation on tyrosine174. The working hypothesis is that the AMPK/IPMK complex is a worse substrate than AMPK alone for upstream kinases such as LKB1, and/or is more susceptible to protein phosphatases thus preventing AMPK phosphorylation and activation (Figure 1). The binding of IPMK to AMPK might represent an additional and perhaps physiologically relevant mechanism of AMPK activity regulation. In this regard, it would be interesting to explore the identity of the kinase that phosphorylates IPMK, and also if this event is also modulated by metabolic hormones or other nutrients. These findings emphasize the importance of a fine-tuning balance of the phosphorylation status of threonine172 to exert the diversity of AMPK functions, and suggest a potential target to modulate AMPK activity.


Recent Insights into the Role of Hypothalamic AMPK Signaling Cascade upon Metabolic Control.

Schneeberger M, Claret M - Front Neurosci (2012)

Hypothalamic AMPK regulates appetite. Schematic representation of a generic hypothalamic neuron depicting a summary of the recently uncovered signaling mechanisms implicated in appetite control. Pathways in red inhibit AMPK activity and subsequently reduce food intake and body weight (negative energy balance), while pathways in green activate it and lead to the opposite physiological outputs (positive energy balance). A diagram of the role of presynaptic AMPK can be found elsewhere (Yang et al., 2011; Hardie et al., 2012). LepR, leptin receptor; Ghsr1a, growth hormone secretagogue receptor type 1a; PI3K, phosphatidylinositol 3-kinase; Akt, protein kinase B; mTOR, mammalian target of rapamycin; KSR2, kinase suppressor of Ras 2; PLCβ, phospholipase C; IP3, inositol-1,4,5-triphosphate; Ca2+, calcium; LKB1, liver kinase B1; CamKKβ, Ca2+/Calmodulin kinase kinase β; Sirt-1, sirtuin 1; IPMK, inositol polyphosphate multikinase.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3526739&req=5

Figure 1: Hypothalamic AMPK regulates appetite. Schematic representation of a generic hypothalamic neuron depicting a summary of the recently uncovered signaling mechanisms implicated in appetite control. Pathways in red inhibit AMPK activity and subsequently reduce food intake and body weight (negative energy balance), while pathways in green activate it and lead to the opposite physiological outputs (positive energy balance). A diagram of the role of presynaptic AMPK can be found elsewhere (Yang et al., 2011; Hardie et al., 2012). LepR, leptin receptor; Ghsr1a, growth hormone secretagogue receptor type 1a; PI3K, phosphatidylinositol 3-kinase; Akt, protein kinase B; mTOR, mammalian target of rapamycin; KSR2, kinase suppressor of Ras 2; PLCβ, phospholipase C; IP3, inositol-1,4,5-triphosphate; Ca2+, calcium; LKB1, liver kinase B1; CamKKβ, Ca2+/Calmodulin kinase kinase β; Sirt-1, sirtuin 1; IPMK, inositol polyphosphate multikinase.
Mentions: The regulation of AMPK activity is complex, but mainly achieved through phosphorylation of threonine172 on the catalytic α subunit by upstream kinases, such as liver kinase B1 (LKB1) and Ca2+/Calmodulin kinase kinase β (CamKKβ; Hardie et al., 2012). A recent study has reported that inositol polyphosphate multikinase (IPMK) may be an upstream physiologic regulator of AMPK activity in the hypothalamus (Bang et al., 2012). IPMK inhibits AMPK activity during the fasting/refed transition through binding between these two proteins, an interaction facilitated by IPMK phosphorylation on tyrosine174. The working hypothesis is that the AMPK/IPMK complex is a worse substrate than AMPK alone for upstream kinases such as LKB1, and/or is more susceptible to protein phosphatases thus preventing AMPK phosphorylation and activation (Figure 1). The binding of IPMK to AMPK might represent an additional and perhaps physiologically relevant mechanism of AMPK activity regulation. In this regard, it would be interesting to explore the identity of the kinase that phosphorylates IPMK, and also if this event is also modulated by metabolic hormones or other nutrients. These findings emphasize the importance of a fine-tuning balance of the phosphorylation status of threonine172 to exert the diversity of AMPK functions, and suggest a potential target to modulate AMPK activity.

Bottom Line: In 2004, two seminal papers focused on the role of AMP-activated protein kinase (AMPK) in the hypothalamus opened new avenues of research in the field of the central regulation of energy homeostasis.In this review article we aim to discuss the most recent findings in this particular area of research, highlighting the function of hypothalamic AMPK in appetite, thermogenesis, and peripheral glucose metabolism.The diversity of mechanisms by which hypothalamic AMPK regulates energy homeostasis illustrates the importance of this evolutionary-conserved energy signaling cascade in the control of this complex and fundamental biological process.

View Article: PubMed Central - PubMed

Affiliation: Diabetes and Obesity Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer Barcelona, Spain ; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas Barcelona, Spain ; Department of Endocrinology and Nutrition, Hospital Clínic, School of Medicine, University of Barcelona Barcelona, Spain.

ABSTRACT
In 2004, two seminal papers focused on the role of AMP-activated protein kinase (AMPK) in the hypothalamus opened new avenues of research in the field of the central regulation of energy homeostasis. Over the following 8 years, hundreds of studies have firmly established hypothalamic AMPK as a key sensor and integrator of hormonal and nutritional signals with neurochemical and neurophysiological responses to regulate whole-body energy balance. In this review article we aim to discuss the most recent findings in this particular area of research, highlighting the function of hypothalamic AMPK in appetite, thermogenesis, and peripheral glucose metabolism. The diversity of mechanisms by which hypothalamic AMPK regulates energy homeostasis illustrates the importance of this evolutionary-conserved energy signaling cascade in the control of this complex and fundamental biological process.

No MeSH data available.