AMPK Therapy-A Little Goes A Long Way
Abstract
AMP-activated protein kinase (AMPK) is a highly conserved serine/threonine kinase that integrates energetic, nutrient, hormonal, redox, and stress signals to coordinate cellular and whole-body energy homeostasis. Although AMPK was initially characterized primarily as a sensor of changes in cellular AMP/ATP ratios, recent studies have revealed additional layers of regulation involving upstream kinases, post-translational modifications, heterotrimeric isoform composition, subcellular compartmentalization, and tissue-specific signaling. In this review, we provide an updated overview of the molecular mechanisms regulating AMPK activity, its major downstream metabolic and homeostatic pathways, its roles in metabolic, cardiovascular, neurodegenerative, muscular, malignant, and age-associated diseases, and current strategies for pharmacological AMPK modulation. We compare indirect activators, including metformin and naturally derived compounds, with direct small-molecule agonists targeting the allosteric drug and metabolite (ADaM) site, and emerging activators that selectively engage specific AMPK isoforms, tissues, or subcellular pools. We also discuss endogenous AMPK regulators, including microbiota-derived metabolites, and critically evaluate the potential adverse consequences of sustained or systemic AMPK activation. Collectively, current evidence indicates that the therapeutic effects of AMPK activation are highly dependent on tissue, heterotrimer composition, subcellular…
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