Unraveling the actions of AMP-activated protein kinase in metabolic diseases: Systemic to molecular insights

Abstract

Summary AMP-activated protein kinase (AMPK) plays a critical role both in sensing and regulating cellular energy state. In experimental animals, its activation has been shown to reduce the risk of obesity and diabetes-related co-morbidities such as insulin resistance, the metabolic syndrome and atherosclerotic cardiovascular disease. However, in humans, AMPK activation alone often does not completely resolve these conditions. Thus, an improved understanding of AMPK action and regulation in metabolic and other diseases is needed. Herein, we provide a brief description of the enzymatic regulation of AMPK and review its role in maintaining energy homeostasis. We then discuss tissue-specific actions of AMPK that become distorted during such conditions as obesity, type 2 diabetes and certain cancers. Finally, we explore recent findings regarding the interactions of AMPK with mTORC1 and the lysosome and discuss how changes in these relationships during overnutrition may lead to AMPK dysfunction. A more thorough understanding of AMPK's molecular interactions during diseases of overnutrition may provide key insights for the development of AMPK-based combinatorial treatments for metabolic disease.

Deconvoluting AMP-activated protein kinase (AMPK) adenine nucleotide binding and sensing

“…AMPK plays critical roles in numerous aspects of physiology ( 4 , 5 , 35 ) and is an important target for the treatment of metabolic diseases, including diabetes and obesity ( 1 , 7 ), as well as cancer ( 2 , 6 , 36 ) and heart disease ( 37 ). In addition, AMPK activation mimics many of the beneficial effects of exercise and caloric restriction ( 38 – 41 ).…”

“…ATP homeostasis is critically important for cellular functions and is maintained at a tight concentration range by the regulatory protein kinase AMP-activated protein kinase (AMPK), 2 a therapeutic target for metabolic diseases and cancer ( 1 – 7 ). Because of this tight range, AMPK senses the energy state of the cell largely as ratio of AMP to ATP, which changes much more dramatically than ATP levels under energy stress, whereas ADP levels change relatively more modestly.…”

Macrophage functions in lean and obese adipose tissue

“…IL-6 is a cytokine that has either pro-inflammatory or anti-inflammatory properties depending on whether it binds to its membrane receptor (leading to activation of the JAK pathway) or to its soluble receptor 77 . Macrophage AMPK activity maintains M2 polarization, mitochondrial function, and inhibits the NLRP3 inflammasome, an intracellular structure that promotes the generation of inflammatory cytokines 78,79 . Further, the AMPK activator metformin significantly attenuated monocyte-to-macrophage differentiation and inhibited plaque formation in ApoE knockout mice 80 .…”

Knockdown of GSK3β increases basal autophagy and AMPK signalling in nutrient-laden human aortic endothelial cells

“…Alternatively, GSK3β-induced damage to the lysosome may contribute to the decreased AMPK activity that we previously observed in our excess nutrient-exposed HAECs [ 1 ]. AMPK can be activated at the lysosome [ 40 , 68 ], and inhibition of lysosome acidification has been shown to suppress AMPK activity in several cancer cell lines [ 69 ]. These speculations require further inquiry, as it is unknown how AMPK and the lysosome interact under excess nutrient conditions and whether this interaction involves GSK3β.…”

“…One potential way to improve the efficacy of GSK3β inhibitors in metabolic disease (and potentially prompt future clinical trials) could be to include them in combination therapies. For example, combining a therapy that inhibits GSK3β (to increase autophagy) with one that activates AMPK (to reduce inflammation and oxidative stress) may improve the prognosis for diabetic cardiovascular complications [ 68 ].…”