AMPK inhibition in health and disease

Abstract

All living organisms depend on dynamic mechanisms that repeatedly reassess the status of amassed energy, in order to adapt energy supply to demand. The AMP-activated protein kinase (AMPK) alphabetagamma heterotrimer has emerged as an important integrator of signals managing energy balance. Control of AMPK activity involves allosteric AMP and ATP regulation, auto-inhibitory features and phosphorylation of its catalytic (alpha) and regulatory (beta and gamma) subunits. AMPK has a prominent role not only as a peripheral sensor but also in the central nervous system as a multifunctional metabolic regulator. AMPK represents an ideal second messenger for reporting cellular energy state. For this reason, activated AMPK acts as a protective response to energy stress in numerous systems. However, AMPK inhibition also actively participates in the control of whole body energy homeostasis. In this review, we discuss recent findings that support the role and function of AMPK inhibition under physiological and pathological states.

Figure 1. Domain organization of the catalytic α and regulatory β and γ subunits of AMPK

Residues phosphorylated by AMPKK (LKB1, CaMKKβ, TAK1), PKA and Akt are shown within the α subunit.

Figure 2. Regulation of AMPK activation by phosphorylation/dephosphorylation

Phosphorylation of AMPK at Thr-172 is regulated by the upstream protein kinases LKB1, CaMKKβ and possibly TAK1. Dephosphorylation of AMPK at Thr172 is modulated by protein phosphatases PP2A and PP2C. Multiple effectors (nutrients, hormones and cytokines) regulating AMPK phosphorylation and activity are listed.

Figure 3. Regulation of AMPK activity by inflammatory signals

Activation of TLR4 by endotoxin and free fatty acid (FFA) regulates AMPK phosphorylation status through the action of protein phosphatase (PP).