Abstract
Physical activity promotes metabolic and cardiovascular health benefits that derive in part from the transcriptional responses to exercise that occur within skeletal muscle and other organs. There is interest in discovering a pharmacologic exercise mimetic that could imbue wellness and alleviate disease burden. However, the molecular physiology by which exercise signals the transcriptional response is highly complex, making it challenging to identify a single target for pharmacological mimicry. The current studies evaluated the transcriptome responses in skeletal muscle, heart, liver, and white and brown adipose to novel small molecule activators of AMPK (pan-activators for all AMPK isoforms) compared to that of exercise. A striking level of congruence between exercise and pharmacological AMPK activation was observed across the induced transcriptome of these five tissues. However, differences in acute metabolic response between exercise and pharmacologic AMPK activation were observed, notably for acute glycogen balances and related to the energy expenditure induced by exercise but not pharmacologic AMPK activation. Nevertheless, intervention with repeated daily administration of short-acting activation of AMPK was found to mitigate hyperglycemia and hyperinsulinemia in four rodent models of metabolic disease and without the cardiac glycogen accretion noted with sustained pharmacologic AMPK activation. These findings affirm that activation of AMPK is a key node governing exercise mediated transcription and is an attractive target as an exercise mimetic.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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AMP-Activated Protein Kinases / metabolism*
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Adipose Tissue / metabolism*
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Animals
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Energy Metabolism
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Enzyme Activation / drug effects
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Fatty Acids / metabolism
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Gene Expression Regulation / drug effects
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Glucose / metabolism
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Homeostasis
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Liver / metabolism*
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Mice, Inbred C57BL
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Muscle, Skeletal / metabolism*
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Myocardium / metabolism*
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Oxidation-Reduction
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Physical Conditioning, Animal
Substances
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Fatty Acids
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AMP-Activated Protein Kinases
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Glucose
Grants and funding
This work was fully funded by Merck & Co., Inc., Merck Research Laboratories, Kenilworth, NJ, USA. The strategic goal of Merck & Co., Inc., was to explore the drug development potential of an AMPK activator for the treatment of diabetes mellitus and potentially other metabolic disorders. The studies presented in this manuscript accordingly represent investigations undertaken toward this purpose, to gain preclinical proof of concept that long- and short-acting AMPK activators could influence diabetes mellitus in rodent and murine models of this disorder and further, to gain deeper insight into the mechanisms by which salutary effects were obtained through this mechanism. The investigators listed as authors designed the experiments, carried these out, including analysis and made the decision to prepare and publish the manuscript. Senior leaders within Merck & Co., Inc., specifically within Merck Research Laboratories, did periodically review the progress of the AMPK activator program, and as is customary, assign prioritization to the AMPK program. Additionally, through a standard internal review process, senior leaders within Merck authorized the submission of the manuscript for publication.