Adenosine monophospate-activated protein kinase (AMPK) is a master sensor and regulator of energy balance in living organisms. Highly conserved in eukaryotes, mammalian AMPK is a heterotrimeric protein, comprising of two catalytic alpha subunits (alpha 1-2), two beta (beta 1-2), and three gamma regulatory subunits (gamma 1-3). The alpha subunits contain the catalytic serine-threonine kinase domain where AMPK is phosphorylated by upstream kinases, specifically at the Threonine 172 (Thr172) site. Mutation of this site results in a loss of function of AMPK (dominant negative). Tissues from AMPK-deficient mice provide evidence that the catalytic alpha2 subunit, not alpha1, is the major subunit involved in glucose uptake in muscle, especially in response to AMPK agonists. However, the alpha1 subunit may play some role in glucose uptake in response to twitch contraction. In fact, most models of AMPK deficiency possess mutations to the alpha2 catalytic subunit due to its more pronounced phenotype. The AMPK beta subunits contain a glycogen binding domain (GBD), allowing for localization of AMPK to glycogen, which may regulate its activity. The gamma subunits contain four tandem repeats of a sequence motif, otherwise known as the CBS or Bateman domains. These motifs contain regulatory AMP- and ATP- binding sites, which bind these nucleotides in a cooperative manner.
AMPK affects a number of metabolic processes in different mammalian tissues, such as the liver, pancreas, muscle, heart, adipose tissues, and the central nervous system (CNS). AMPK generally stimulates energy production by increasing catabolic pathways and conversely inhibiting anabolic pathways. AMPK also produces both translational and transcriptional effects through phosphorylation of its targets or through nuclear localization. Recent research has implicated a role for AMPK in adaptive metabolic reprogramming through transcriptional regulation. Abnormalities in AMPK function have been implicated in a number of metabolic diseases. In Type II diabetes and obesity, increasing AMPK activity through exercise or pharmacologically through metformin, AICAR, or TZD treatments, have been shown to be beneficial, especially due to its effect on increasing glucose uptake, fatty acid oxidation, and even autophagy in peripheral tissues. AMPK dysregulation in the brain has also been linked to abnormal autonomic nervous system function and feeding behavior. AMPK alpha2 knockout mice demonstrate several metabolic defects, such as insulin resistance, as well as increased adiposity and adipocyte hypertrophy following a high calorie diet, suggesting that the lack of the AMPK alpha2 subunit may be a factor contributing to the development of obesity.
The importance of AMPK signaling is also recognized in the field of aging. Caloric restriction, which has been linked to increase lifespan of yeast, mice, worms, and primates, has been found to increase AMPK activity. Sirtuin1 (sirt1), a histone deacetylase implicated in longevity, also interacts with AMPK signaling pathways. Furthermore, several studies have linked FOXO3A to AMPK activation. FOXO3A is an important downstream molecule in the insulin growth factor (IGF) signaling pathway implicated in longevity. More recently, AMPK has been shown to phosphorylate the CREB coactivator CRTC, which leads to the nuclear exclusion of CRTC and increased lifespan in Caenorhabditis elegans (C. elegans). AMPK also induces autophagy through direct phosphorylation of UNC-51-Like Kinase-1 (ULK1). Induction of autophagy has been associated with the beneficial effects endowed by caloric restriction and exercise to aging.
Reference:Maria A. G. Lim. THE CONTRIBUTION OF METABOLIC DYSFUNCTION TO GENETIC MODELS OF MOTOR NEURON DISEASE