AMPK in Health and Disease Steinberg, Gregory R; Kemp, Bruce E
Physiological reviews,
07/2009, Volume:
89, Issue:
3
Journal Article
Peer reviewed
Protein Chemistry and Metabolism, St. Vincent's Institute of Medical Research, University of Melbourne, Fitzroy, Victoria, Australia
The function and survival of all organisms is dependent on the ...dynamic control of energy metabolism, when energy demand is matched to energy supply. The AMP-activated protein kinase (AMPK) β heterotrimer has emerged as an important integrator of signals that control energy balance through the regulation of multiple biochemical pathways in all eukaryotes. In this review, we begin with the discovery of the AMPK family and discuss the recent structural studies that have revealed the molecular basis for AMP binding to the enzyme's subunit. AMPK's regulation involves autoinhibitory features and phosphorylation of both the catalytic subunit and the β-targeting subunit. We review the role of AMPK at the cellular level through examination of its many substrates and discuss how it controls cellular energy balance. We look at how AMPK integrates stress responses such as exercise as well as nutrient and hormonal signals to control food intake, energy expenditure, and substrate utilization at the whole body level. Lastly, we review the possible role of AMPK in multiple common diseases and the role of the new age of drugs targeting AMPK signaling.
Brown (BAT) and white (WAT) adipose tissues play distinct roles in maintaining whole-body energy homeostasis, and their dysfunction can contribute to non-alcoholic fatty liver disease (NAFLD) and ...type 2 diabetes. The AMP-activated protein kinase (AMPK) is a cellular energy sensor, but its role in regulating BAT and WAT metabolism is unclear. We generated an inducible model for deletion of the two AMPK β subunits in adipocytes (iβ1β2AKO) and found that iβ1β2AKO mice were cold intolerant and resistant to β-adrenergic activation of BAT and beiging of WAT. BAT from iβ1β2AKO mice had impairments in mitochondrial structure, function, and markers of mitophagy. In response to a high-fat diet, iβ1β2AKO mice more rapidly developed liver steatosis as well as glucose and insulin intolerance. Thus, AMPK in adipocytes is vital for maintaining mitochondrial integrity, responding to pharmacological agents and thermal stress, and protecting against nutrient-overload-induced NAFLD and insulin resistance.
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•Adipocyte AMPK is required for cold and β-adrenergic-stimulated thermogenesis•AMPK is required for the browning of white adipose tissue (beige/brite fat)•AMPK is critical for mitophagy and maintaining BAT mitochondrial quality•Adipocyte AMPK is required to prevent NAFLD and insulin resistance
Mottillo et al. find mice lacking AMPK specifically in adipocytes are intolerant to cold and resistant to β-adrenergic stimulation of brown and beige adipose tissues. These defects, independent of lipolysis, are caused by impaired mitophagy, which results in defective BAT mitochondria, non-alcoholic fatty liver disease, and insulin resistance.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract Vitiligo is a hypomelanotic autoimmune skin disease arising from a breakdown in immunological self-tolerance, which leads to aberrant immune responses against melanocytes. Regulatory T cells ...(Tregs) are crucial to the development of self-tolerance and so are major foci in the study of autoimmune pathogenesis of vitiligo. This review will summarise recent findings concerning the role of Tregs in the pathogenesis of vitiligo. In addition, as antigen-specific Tregs are a potential route for the reinstatement of immune tolerance, new strategies that expand or induce de novo generation of Tregs and which are currently being investigated as therapies for other autoimmune diseases, will be discussed. These approaches will highlight the opportunities for Treg cell-based therapeutics in vitiligo.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Abstract
Context
Whereas therapy with immune checkpoint inhibitors (ICIs), such as nivolumab, have substantially improved survival in several types of cancer, increased attention has been given to ...adverse immune events associated with their use, including the development of endocrine autoimmunity.
Objectives
First, to describe a patient with a 2-year history of metastatic small cell lung cancer who had been treated with nivolumab a few months before presentation with the signs and symptoms of severe hypocalcemia and hypoparathyroidism. Second, to investigate the etiology of the patient’s hypoparathyroidism, including the presence of activating autoantibodies against the calcium-sensing receptor (CaSR), as humoral and cellular immune responses against the CaSR have been reported in patients with autoimmune hypoparathyroidism.
Participants
A 61-year-old female was admitted with persistent nausea, vomiting, epigastric pain, constipation, and generalized weakness. Laboratory analyses showed low total serum calcium, ionized calcium, and parathyroid hormone (PTH). The patient was diagnosed with severe hypocalcemia as a result of autoimmune hypoparathyroidism after testing positive for CaSR-activating autoantibodies.
Interventions
She was treated with intravenous calcium gluconate infusions, followed by a transition to oral calcium carbonate, plus calcitriol, which normalized her serum calcium.
Results
Her serum PTH remained low during her hospitalization and initial outpatient follow-up, despite adequate repletion of magnesium.
Conclusions
This case illustrates autoimmune hypoparathyroidism induced by ICI blockade. As ICIs are now used to treat many cancers, clinicians should be aware of the potential risk for hypocalcemia that may be associated with their use.
We studied the etiology of hypocalcemia as a result of hypoparathyroidism in a small cell lung cancer patient on nivolumab therapy and identified calcium-sensing, receptor-activating autoantibodies.
The energy sensor AMP-activated protein kinase (AMPK) is activated by metabolic stress and restores ATP levels in cells by switching off anabolic and switching on catabolic pathways. Recent ...discoveries demonstrate that AMPK is activated primarily by rising ADP levels and not, as previously thought, by AMP. AMPK activation is dependent on ADP-controlled phosphorylation of Thr172 on its activation loop, a mechanism of protein regulation that represents an example of an allosterically regulated modification (ARM). AMPK embodies many features of an adenylate charge regulatory system envisaged by Atkinson, where anabolic and catabolic pathway regulation is modulated by adenine nucleotide ratios. Here we discuss the current state of AMPK regulation by adenine nucleotides and we propose that AMPK functions as an adenylate charge-regulated protein kinase.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The last decade was remarkable for neutrino physics. In particular, the phenomenon of neutrino flavor oscillations has been firmly established by a series of independent measurements. All parameters ...of the neutrino mixing are now known, and we have the elements to plan a judicious exploration of new scenarios that are opened by these recent advances. With precise measurements, we can test the three‐neutrino paradigm, neutrino mass hierarchy, and charge conjugation parity (CP) asymmetry in the lepton sector. The future long‐baseline experiments are considered to be a fundamental tool to deepen our knowledge of electroweak interactions. The Deep Underground Neutrino Experiment (DUNE) will detect a broadband neutrino beam from Fermilab in an underground massive liquid argon time‐projection chamber at an L/E of about 103 km GeV−1 to reach good sensitivity for CP‐phase measurements and the determination of the mass hierarchy. The dimensions and the depth of the far detector also create an excellent opportunity to look for rare signals like proton decay to study violation of the baryonic number, as well as supernova neutrino bursts, broadening the scope of the experiment to astrophysics and associated impacts in cosmology. In this paper, we discuss the physics motivations and the main experimental features of the DUNE project required to reach its scientific goals.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The AMP-activated protein kinase (AMPK) activates autophagy, but its role in aging and fasting-induced muscle function has not been defined. Here we report that fasting mice lacking skeletal muscle ...AMPK (AMPK-MKO) results in hypoglycemia and hyperketosis. This is not due to defective fatty acid oxidation, but instead is related to a block in muscle proteolysis that leads to reduced circulating levels of alanine, an essential amino acid required for gluconeogenesis. Markers of muscle autophagy including phosphorylation of Ulk1 Ser555 and Ser757 and aggregation of RFP-LC3 puncta are impaired. Consistent with impaired autophagy, aged AMPK-MKO mice possess a significant myopathy characterized by reduced muscle function, mitochondrial disease, and accumulation of the autophagy/mitophagy proteins p62 and Parkin. These findings establish an essential requirement for skeletal muscle AMPK-mediated autophagy in preserving blood glucose levels during prolonged fasting as well as maintaining muscle integrity and mitochondrial function during aging.
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•Muscle AMPK is required for the induction of autophagy during fasting•AMPK is required for proteolysis to maintain blood glucose during fasting•A loss of AMPK accelerates aging-induced myopathy and mitochondrial dysfunction
Bujak et al. highlight a critical role for the energy sensor AMPK in maintaining glycemia and muscle homeostasis. During fasting, muscle AMPK induces autophagy and muscle protein breakdown to prevent hypoglycemia. With old age, AMPK delays the onset of muscle myopathy and mitochondrial dysfunction.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The autoimmune regulator (AIRE) gene is crucial for establishing central immunological tolerance and preventing autoimmunity. Mutations in AIRE cause a rare autosomal-recessive disease, autoimmune ...polyendocrine syndrome type 1 (APS-1), distinguished by multi-organ autoimmunity. We have identified multiple cases and families with mono-allelic mutations in the first plant homeodomain (PHD1) zinc finger of AIRE that followed dominant inheritance, typically characterized by later onset, milder phenotypes, and reduced penetrance compared to classical APS-1. These missense PHD1 mutations suppressed gene expression driven by wild-type AIRE in a dominant-negative manner, unlike CARD or truncated AIRE mutants that lacked such dominant capacity. Exome array analysis revealed that the PHD1 dominant mutants were found with relatively high frequency (>0.0008) in mixed populations. Our results provide insight into the molecular action of AIRE and demonstrate that disease-causing mutations in the AIRE locus are more common than previously appreciated and cause more variable autoimmune phenotypes.
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•Heterozygous mutations in AIRE cause organ-specific autoimmune disease•Mono-allelic mutations with dominant effects cluster within the PHD1 domain of AIRE•These mutations suppress wild-type AIRE in a dominant-negative manner•Relatively high frequencies of these mutations are found in the population
This paper by Husebye and colleagues directly links heterozygous mutations in the autoimmune regulator (AIRE) gene to organ-specific autoimmunity, including APS-1. The authors show that these mutations cluster within the first PHD domain of AIRE and exert a dominant-negative effect on wild-type AIRE in vitro.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
This book is a practical guide to sensory evaluation methods and techniques in the food, cosmetic and household product industries. It explains the suitability of different testing methods for ...different situations and offers step-by-step instructions on how to perform the various types of tests. Covering a broad range of food and non-food product applications, the book is designed to be used as a practical reference in the testing environment; a training manual for new recruits into sensory science, and a course book for students undertaking industrial training or academic study.
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