AMPK signalling in health and disease

Abstract

In eukaryotic cells AMP-activated protein kinase (AMPK) plays a major role in regulating cellular energy balance. AMPK responds to changes in intracellular adenine nucleotide levels, being activated by an increase in AMP/ADP relative to ATP. Activation of AMPK increases the rate of catabolic (ATP-generating) pathways and decreases the rate of anabolic (ATP-utilising) pathways. In addition to its role in maintaining intracellular energy balance, AMPK regulates whole body energy metabolism. Given its key role in controlling energy homeostasis, AMPK has attracted widespread interest as a potential therapeutic target for metabolic diseases, including type 2 diabetes and, more recently, cancer. Here I review the regulation of AMPK and its potential as a target for therapeutic intervention in human disease. IntroductionThe hydrolysis of ATP to ADP provides the energy for driving virtually all of the processes associated with living cells. Maintaining an adequate supply of energy is an essential requirement for survival [1]. At a single cell level this means keeping ATP, the immediate source of energy, at a relatively high concentration -in the millimolar range in most eukaryotic cells. The concentration of ATP within most eukaryotic cells is kept at a remarkably constant level, despite wide fluctuations in the demand for ATP [2]. In order to achieve this, cells require systems to monitor changes in ATP levels, and to couple these changes to a transponder that leads to functional outputs to restore ATP levels. One such system that has been identified is the AMP-activated protein kinase (AMPK) and orthologues of AMPK are found in virtually all eukaryotes. A major function of AMPK is to monitor changes in the level of ATP and to couple this to phosphorylation of downstream substrates leading to an increase in the rate of ATP-producing pathways and/or a decrease in the rate of ATP-utilising pathways. Dysregulation of energy homeostasis is thought to be an important factor in driving changes in a wide range of human diseases, such as type 2 diabetes, obesity and cancer. The central role of AMPK in maintaining energy homeostasis has made it an attractive target for drugs aimed at preventing and/or treating metabolic diseases, including cancer [3][4][5]. In this review, I will focus on recent developments regarding the regulation of AMPK that directly impact on its therapeutic utility. I will also discuss some potential caveats arising from studies examining the role of AMPK in vivo using mouse models.

Central insulin dysregulation and energy dyshomeostasis in two mouse models of Alzheimer's disease

“…Energy homeostasis is an additional dimension to the cellular and physiological dysfunction related to insulin resistance and T2D (Carling, 2017; Porte, 2006; Saha et al, 2010). AMPK is a key cellular sensor of energy reserves and a significant diabetes therapeutic target to increase insulin sensitivity (Misra, 2008; Misra and Chakrabarti, 2007; Musi, 2006).…”

Mannose Alters Gut Microbiome, Prevents Diet-Induced Obesity, and Improves Host Metabolism

“…Mannose did not alter the rate of triglyceride synthesis (HFD: 1,880 ± 116.2 mg/dL/hr; HFD+M: 1,957 ± 144.5 mg/dL/hr; n = 8) or VLDL clearance (HFD: 72.29 ± 13.29 ng/mL/min; HFD+M: 86.43 ± 12.02 ng/mL/min; n = 7). AMPK activation is important for nutrient sensing, cellular glucose uptake, and energy homeostasis (Carling, 2017; Hardie et al, 2012). We measured the phosphorylated form, AMPKα[pT172], in mouse liver and muscle tissue.…”

Genotoxic Damage Activates the AMPK-α1 Isoform in the Nucleus via Ca2+/CaMKK2 Signaling to Enhance Tumor Cell Survival

“…Because increases in the cellular ADP:ATP ratio (signifying energy deficit) are always accompanied by even larger increases in the AMP:ATP ratio, these three effects allow AMPK to act as an ultrasensitive sensor of cellular energy status. The CaMKK2-AMPK pathway appears to be activated solely by increases in intracellular Ca 2þ to cells of Ca 2þ ionophores, such as A23187, or by hormones or cytokines that increase intracellular Ca 2þ (4)(5)(6). Each AMPK subunit exists as multiple isoforms (a1/a2, b1/b2, g1/g2/g3) encoded by multiple genes (PRKAA1/2, PRKAB1/2, PRKAG1/2/3).…”

“…The AMP-activated protein kinase (AMPK) is a sensor of cellular energy status expressed in essentially all eukaryotic cells, which occurs universally as heterotrimeric complexes comprising catalytic a subunits and regulatory b and g subunits (4)(5)(6). AMPK is activated by phosphorylation of a conserved threonine residue within the activation loop of the kinase domain on the a subunit, usually referred to as Thr172.…”