AMP-activated protein kinase (AMPK) is a crucial cellular energy sensor that maintains energy homeostasis by regulating ATP production and conservation. AMPK is activated by falling energy status, promoting ATP production through increased activity or expression of catabolic proteins while conserving ATP by down-regulating anabolic pathways. It also regulates metabolic energy balance at the whole-body level, influencing feeding behavior and circadian rhythms. AMPK's regulatory mechanisms involve sensing changes in the AMP:ATP and ADP:ATP ratios, as well as other signals. The enzyme exists as a heterotrimer comprising a catalytic α subunit and regulatory β and γ subunits. AMPK activation involves allosteric activation by AMP and phosphorylation by upstream kinases like LKB1. Recent studies have identified non-canonical activation mechanisms involving reactive oxygen species (ROS) and genotoxic treatments. AMPK regulates glucose and fatty acid uptake, catabolic pathways, mitochondrial biogenesis, and mitophagy. It also conserves ATP by inhibiting anabolic pathways and modulating the cell cycle and neuronal membrane excitability. AMPK plays a key role in controlling appetite, glucose sensing, and circadian rhythms, contributing to energy balance and metabolic health.AMP-activated protein kinase (AMPK) is a crucial cellular energy sensor that maintains energy homeostasis by regulating ATP production and conservation. AMPK is activated by falling energy status, promoting ATP production through increased activity or expression of catabolic proteins while conserving ATP by down-regulating anabolic pathways. It also regulates metabolic energy balance at the whole-body level, influencing feeding behavior and circadian rhythms. AMPK's regulatory mechanisms involve sensing changes in the AMP:ATP and ADP:ATP ratios, as well as other signals. The enzyme exists as a heterotrimer comprising a catalytic α subunit and regulatory β and γ subunits. AMPK activation involves allosteric activation by AMP and phosphorylation by upstream kinases like LKB1. Recent studies have identified non-canonical activation mechanisms involving reactive oxygen species (ROS) and genotoxic treatments. AMPK regulates glucose and fatty acid uptake, catabolic pathways, mitochondrial biogenesis, and mitophagy. It also conserves ATP by inhibiting anabolic pathways and modulating the cell cycle and neuronal membrane excitability. AMPK plays a key role in controlling appetite, glucose sensing, and circadian rhythms, contributing to energy balance and metabolic health.