Developing a head for energy sensing: AMP‐activated protein kinase as a multifunctional metabolic sensor in the brain

Ramamurthy, Santosh; Ronnett, Gabriele V.

doi:10.1113/jphysiol.2006.110122

Cited by 144 publications

(123 citation statements)

References 78 publications

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“…This is the first indication of a tissue-specific function of AMPK in this process and suggests that AMPK may not be as functionally universal in this regard as previously thought. It has been postulated before that AMPK activation in general may have cell-or tissue-specific outcomes (Ramamurthy and Ronnett, 2006). This could be attributable to differential expression and/or activity of its upstream regulators, as well as its downstream effectors mediating such responses.…”

Section: Discussionmentioning

confidence: 99%

Drosophila alicorn Is a Neuronal Maintenance Factor Protecting against Activity-Induced Retinal Degeneration

Spasic¹,

Callaerts²,

Norga³

2008

Journal of Neuroscience

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Exploring mechanisms that govern neuronal responses to metabolic stress is essential for the development of therapeutic strategies aimed at treatment of neuronal injury and disease. AMP-activated protein kinase (AMPK) is a key enzyme regulating cellular energy homeostasis that responds to changes in cellular energy levels by promoting energy-restorative and inhibiting energy-consumptive processes. Recent studies have suggested that AMPK might have a neuroprotective function. However, the existing evidence is contradictory and almost exclusively derived from in vitro studies based on drug treatments and metabolic stress models. To tackle these issues in vivo, we used the Drosophila visual system. In this report, we describe a novel Drosophila mutant, alicorn (alc), encoding the single ␤ regulatory subunit of AMPK. Loss of alc using the eyFlp system causes severe early-onset progressive nonapoptotic neurodegeneration in the retina, the optic lobe, and the antennae, as well as behavioral and neurophysiological defects. Retinal degeneration occurs immediately after normal neuronal differentiation, can be enhanced by exposure to light, and can be prevented by blocking photoreceptor excitation. Furthermore, AMPK is required for proper viability of differentiated photoreceptors by mechanisms unrelated to polarity events that AMPK controls in epithelial tissues. In conclusion, AMPK does not affect photoreceptor development but is crucial to maintaining integrity of mature neurons under conditions of increased activity and provides protection from excitotoxicity.

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Section: Discussionmentioning

confidence: 99%

Drosophila alicorn Is a Neuronal Maintenance Factor Protecting against Activity-Induced Retinal Degeneration

Spasic¹,

Callaerts²,

Norga³

2008

Journal of Neuroscience

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“…Molecular and pharmacological inhibition of NMDA receptors in the hypothalamus is mediated by suppressed AMPK activity and lowers glucose production and increases feeding [101]. Several studies showed that AMPK in the hypothalamus regulates energy metabolism by integrating inputs from hormones, peptides, neurotransmitters, and nutrients [102][103][104]. It is highly likely that glutamate-induced neuronal excitation via NMDA receptors mediates the production of ROS.…”

Section: Pharmacological Aspects Of Redox Regulation In the Feeding Cmentioning

confidence: 99%

Oxidative Stress in the Hypothalamus: the Importance of Calcium Signaling and Mitochondrial ROS in Body Weight Regulation

Gyengési¹,

Paxinos²,

Andrews³

2012

Current Neuropharmacology

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Abstract:A considerable amount of evidence shows that reactive oxygen species (ROS) in the mammalian brain are directly responsible for cell and tissue function and dysfunction. Excessive reactive oxygen species contribute to various conditions including inflammation, diabetes mellitus, neurodegenerative diseases, tumor formation, and mental disorders such as depression. Increased intracellular calcium levels have toxic roles leading to cell death. However, the exact connection between reactive oxygen production and high calcium stress is not yet fully understood. In this review, we focus on the role of reactive oxygen species and calcium stress in hypothalamic arcuate neurons controlling feeding. We revisit the role of NPY and POMC neurons in the regulation of appetite and energy homeostasis, and consider how ROS and intracellular calcium levels affect these neurons. These novel insights give a new direction to research on hypothalamic mechanisms regulating energy homeostasis and may offer novel treatment strategies for obesity and type-2 diabetes.

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“…More recently, it has been suggested that AMPK acts as a general energy sensor and integrator of nutrient and hormonal signals in the CNS (1,12). Hypothalamic AMPKα2 activity is reduced by high glucose levels, the physiological transition from the fasted to the fed state, and by the anorexigenic hormones leptin and insulin (13)(14)(15).…”

Section: Introductionmentioning

confidence: 99%

AMPK is essential for energy homeostasis regulation and glucose sensing by POMC and AgRP neurons

Claret¹,

Smith²,

Batterham³

et al. 2007

J. Clin. Invest.

457

470

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Hypothalamic AMP-activated protein kinase (AMPK) has been suggested to act as a key sensing mechanism, responding to hormones and nutrients in the regulation of energy homeostasis. However, the precise neuronal populations and cellular mechanisms involved are unclear. The effects of long-term manipulation of hypothalamic AMPK on energy balance are also unknown. To directly address such issues, we generated POMCα2KO and AgRPα2KO mice lacking AMPKα2 in proopiomelanocortin-(POMC-) and agouti-related protein-expressing (AgRP-expressing) neurons, key regulators of energy homeostasis. POMCα2KO mice developed obesity due to reduced energy expenditure and dysregulated food intake but remained sensitive to leptin. In contrast, AgRPα2KO mice developed an age-dependent lean phenotype with increased sensitivity to a melanocortin agonist. Electrophysiological studies in AMPKα2-deficient POMC or AgRP neurons revealed normal leptin or insulin action but absent responses to alterations in extracellular glucose levels, showing that glucose-sensing signaling mechanisms in these neurons are distinct from those pathways utilized by leptin or insulin. Taken together with the divergent phenotypes of POMCα2KO and AgRPα2KO mice, our findings suggest that while AMPK plays a key role in hypothalamic function, it does not act as a general sensor and integrator of energy homeostasis in the mediobasal hypothalamus.

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Developing a head for energy sensing: AMP‐activated protein kinase as a multifunctional metabolic sensor in the brain

Cited by 144 publications

References 78 publications

Drosophila alicorn Is a Neuronal Maintenance Factor Protecting against Activity-Induced Retinal Degeneration

Drosophila alicorn Is a Neuronal Maintenance Factor Protecting against Activity-Induced Retinal Degeneration

Oxidative Stress in the Hypothalamus: the Importance of Calcium Signaling and Mitochondrial ROS in Body Weight Regulation

AMPK is essential for energy homeostasis regulation and glucose sensing by POMC and AgRP neurons

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