AMPK: An Emerging Drug Target for Diabetes and the Metabolic Syndrome

Abstract

Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) is a key player in regulating energy metabolism, placing it at the center stage in studies of diabetes and related metabolic diseases. Expressed in key metabolically relevant organs, AMPK is activated in response to a variety of stimuli, including cellular stress, exercise, and a wide range of hormones and agents that exert impacts on cellular metabolism. Genetic and pharmacological studies demonstrate that AMPK is required for maintaining glucose homeostasis. Activation of AMPK by pharmacological agents presents a unique challenge, given the complexity of the biology, but holds a considerable potential to reverse the metabolic abnormalities associated with type 2 diabetes.

Rheb activates AMPK and reduces p27Kip1 levels in Tsc2-null cells via mTORC1-independent mechanisms: implications for cell proliferation and tumorigenesis

“…Its primary role is to promote catabolic processes while inhibiting anabolic pathways, thus restoring energy levels. At the molecular level, AMPK is activated by binding to AMP and phosphorylation by LKB1 (Viollet et al, 2009;Zhang et al, 2009). A consequence of AMPK activation is the inhibition of cell growth.…”

La restriction calorique chez les primates

“…Enfin, l'AMPK (adenosine monophosphate-activated protein kinase), une protéine kinase activée par l'AMP, est également au centre des recherches concernant les mimétiques des effets bénéfiques de la restriction calorique, car elle est connue pour être un élément majeur de régulation du métabolisme énergétique cellulaire. Une activation pharmacologique de l'AMPK améliore à la fois la sensibilité au glucose, le métabolisme des lipides et la pression artérielle chez des rongeurs insulinorésistants [45]. De plus, une stimulation de l'AMPK engendre une diminution de la synthèse de certaines protéines, impliquées dans la régulation de la longévité, notamment par une inhibition de la voie de signalisation mTOR [46].…”

Augmenting energy expenditure by mitochondrial uncoupling: a role of AMP-activated protein kinase

“…It is a serine/threonine kinase, which is activated by any metabolic stress, often in response to increased AMP/ATP ratio (Hardie 2008;Zhang et al 2009). AMPK is a heterotrimeric protein with each of its three subunits (a, b, and c, respectively) encoded by different genes, giving rise to a large variety of heterotrimeric combinations in different tissues.…”

“…It thus activates pathways resulting in ATP production while turning off energy-consuming pathways both at a single cell and the whole-body level (Hardie 2008;Zhang et al 2009). Eventually, AMPK contributes to an increase in mitochondrial biogenesis in response to chronic energy depletion (Reznick and Shulman 2006).…”

“…While restricting this review on the effects of ectopic expression of UCP1, the only member of the UCP family with undisputed uncoupling properties (Nedergaard et al 2005), we present evidence that mitochondrial uncoupling in WAT, SM, and liver (1) affects whole-body energy metabolism, glucose homeostasis, and longevity depending in part of the tissue harboring ectopic UCP1 and (2) leads to activation of AMP-activated protein kinase (AMPK), a highly conserved serine/threonine kinase, which plays a key role as a master regulator of cellular energy homeostasis [for reviews, see (Hardie 2008;Zhang et al 2009)]. In spite of a large number of studies focused on the mechanism and physiological role of AMPK, and of the interest in AMPK with respect to the prevention and treatment of metabolic syndrome, the role of AMPK in control of energy expenditure remains controversial.…”