AMP-Activated Protein Kinase in Metabolic Control and Insulin Signaling

TLDR

AMP-activated protein kinase (AMPK) is a conserved cellular energy sensor composed of α, β, and γ subunits, activated by AMP and regulated by hormones such as insulin, leptin, and adiponectin, and is implicated in whole-body energy balance, exercise benefits, and as a target of metformin. AMPK is activated by increased AMP:ATP ratio through phosphorylation by LKB1, and in certain cells also by CaMKKβ in a Ca²⁺‑dependent, AMP‑independent manner; once activated it promotes catabolic ATP‑generating pathways and suppresses ATP‑consuming biosynthesis and growth. AMPK is a key player in developing treatments for obesity, type 2 diabetes, and metabolic syndrome, and it plays a central role in whole‑body energy balance.

Abstract

The AMP-activated protein kinase (AMPK) system acts as a sensor of cellular energy status that is conserved in all eukaryotic cells. It is activated by increases in the cellular AMP:ATP ratio caused by metabolic stresses that either interfere with ATP production (eg, deprivation for glucose or oxygen) or that accelerate ATP consumption (eg, muscle contraction). Activation in response to increases in AMP involves phosphorylation by an upstream kinase, the tumor suppressor LKB1. In certain cells (eg, neurones, endothelial cells, and lymphocytes), AMPK can also be activated by a Ca 2+ -dependent and AMP-independent process involving phosphorylation by an alternate upstream kinase, CaMKKβ. Once activated, AMPK switches on catabolic pathways that generate ATP, while switching off ATP-consuming processes such as biosynthesis and cell growth and proliferation. The AMPK complex contains 3 subunits, with the α subunit being catalytic, the β subunit containing a glycogen-sensing domain, and the γ subunits containing 2 regulatory sites that bind the activating and inhibitory nucleotides AMP and ATP. Although it may have evolved to respond to metabolic stress at the cellular level, hormones and cytokines such as insulin, leptin, and adiponectin can interact with the system, and it now appears to play a key role in maintaining energy balance at the whole body level. The AMPK system may be partly responsible for the health benefits of exercise and is the target for the antidiabetic drug metformin. It is a key player in the development of new treatments for obesity, type 2 diabetes, and the metabolic syndrome.