AMPK in the brain: its roles in energy balance and neuroprotection

Abstract

AMP-activated protein kinase (AMPK) senses and maintains energy balance in peripheral tissues. When energy is deficient, AMPK activation leads to altered cellular metabolism and gene expression to inhibit anabolic processes, stimulate catabolism, and restore ATP. The CNS integrates diverse central and peripheral signals to maintain homeostasis. CNS AMPK is shown to have important, but complex roles in energy balance. CNS neurons sense their own energy needs, while some also integrate neuro-humoral signals to assess organismal energy balance. In the brain, AMPK is involved in both arenas, coordinating context-specific metabolic responses in many tissues. AMPK plays roles in both physiological (feeding) and pathophysiological (ischemic) states. During the latter, AMPK is highly activated to restore neuronal energy balance, but its over-activation may be deleterious. In this study, we review AMPK regulation and responses to cellular and organismal energy challenges in the CNS. AMP-activated protein kinaseAMP-activated protein kinase is a serine/threonine kinase with a catalytic a subunit and regulatory b and c subunits. AMPK not only senses energy status, but also functions at the tissue and organism levels to promote context-specific responses to physiological signals of metabolic status. AMPK modulates many aspects of cellular metabolism (Fig. 1a). AMPK was first known to be activated by ATP depletion (increased AMP/ATP ratio) and related stimuli (exercise, starvation, hypoxia, cellular pH and redox status, increased creatine/phosphocreatine ratio). However, AMPK is also activated by certain drugs, hormones, and cellular stressors that do not alter AMP/ATP ratio.

Metformin Improves Neurologic Outcome Via AMP‐Activated Protein Kinase–Mediated Autophagy Activation in a Rat Model of Cardiac Arrest and Resuscitation

“…Once activated, AMPK promotes catabolic pathways to generate more ATP, and inhibits anabolic pathways, thus allowing for adaptive changes in growth and metabolism under low energy conditions 23. Emerging evidence indicates that AMPK can be activated by metformin in the brain, exerting a neuroprotective role in response to energy depletion through maintaining cellular energy homeostasis,24, 25, 26 promoting mitochondrial biogenesis,27 and increasing brain‐derived neurotrophic factor expression to promote neuronal survival 28. Recently, autophagy has been proposed as a downstream target of AMPK, and AMPK‐induced autophagy activation protects against ischemic injury to peripheral tissue injury29, 30, 31 as well as ischemic brain injury 32.…”

Ameliorating antipsychotic-induced weight gain by betahistine: Mechanisms and clinical implications

“…Hypothalamic AMPK is also involved in feeding regulation and food intake by regulating the AMPK-ACC-Malonyl-CoA-CPT1 axis (ACC: acetyl-CoA carboxylase; CPT1: carnitine palmitoyltransferase 1) [91][92][93][94]. A study using the CT1-1 cell line reported that the protein level of phosphor-AMPK (pAMPK) is activated by the H 1 R antagonist chlorpheniramine, while it is blocked by histamine [95].…”

Age-related changes in AMP-activated protein kinase after stroke

“…A rise in AMP levels or an increase in the AMP/ATP ratio signals declining energy stores, activating AMPK (see review by Li and McCullough 2010). Although responsive to ATP depletion (increased AMP/ATP ratio), AMPK is also activated by related stimuli such as exercise, starvation, hypoxia, cellular pH, and redox status (Ronnett et al 2009). Ischemic brain injury involves a complex sequence of excitotoxic and oxidative events, including cellular energy depletion, disrupted protein synthesis, and apoptosis, etc.…”