AMP-activated protein kinase: maintaining energy homeostasis at the cellular and whole-body levels

Abstract

The adenosine monophosphate (AMP)-activated protein kinase (AMPK) signaling pathway arose early during evolution of eukaryotic cells, when it appears to have been involved in the response to glucose starvation and perhaps also in monitoring the output of the newly acquired mitochondria. Due to the advent of hormonal regulation of glucose homeostasis, glucose starvation is a less frequent event for mammalian cells than for single-celled eukaryotes. Nevertheless, the AMPK system has been preserved in mammals where, by monitoring cellular AMP:adenosine triphosphate (ATP) and adenosine diphosphate (ADP):ATP ratios and balancing the rates of catabolism and ATP consumption, it maintains energy homeostasis at a cell-autonomous level. In addition, hormones involved in maintaining energy balance at the whole-body level interact with AMPK in the hypothalamus. AMPK is activated by two widely used clinical drugs, metformin and aspirin, and also by many natural products of plants that are either derived from traditional medicines or are promoted as "nutraceuticals."

Keywords: energy balance; ghrelin; leptin; metformin; salicylate; traditional medicine.

Figure 1. Mechanisms for activation of AMPK by AMP.

AMPK is activated by phosphorylation of Thr172 by the upstream kinases LKB1 and CaMKKβ, a modification that is reversed by protein phosphatases (PP). AMP has three effects caused by binding to one or more of three AMP-binding sites on the AMPK-γ subunit: (i) promoting Thr172 phosphorylation by LKB1; (ii) inhibiting Thr172 dephosphorylation; (iii) causing allosteric activation of the phosphorylated kinase. Only mechanism (ii) is mimicked by binding of ADP, but all three are antagonized by binding of ATP.

Figure 2. Mechanism by which AMPK maintains cellular energy homoeostasis in mammalian cells.

Catabolism generates ATP from ADP, whereas energy-requiring cellular processes mainly convert ATP to ADP. If ATP consumption exceeds ATP production, the ADP:ATP ratio rises and this is converted by adenylate kinase into an even larger rise in AMP:ATP ratio, activating AMPK. AMPK attempts to restore energy homeostasis by activating catabolism and inhibiting ATP consumption.

Figure 3. Role of AMPK in the hypothalamus in regulating whole body energy balance.

The diagram summarizes some of the many hormonal controls that control whole body energy balance, emphasizing the central role of AMPK in hypothalamic neurons (see text for details).