AMPK Activation in Inflammatory and Metabolic Disorders

Adenosine monophosphate-activated protein kinase (AMPK) serves as a central cellular energy sensor that modulates both metabolic homeostasis and inflammatory signalling. Upon activation by increases in the AMP:ATP ratio or by pharmacological agents, AMPK phosphorylates key downstream targets to inhibit anabolic pathways and promote catabolic processes. In inflammatory contexts, AMPK attenuates pro-inflammatory transcription factors such as nuclear factor-κB (NF-κB) and signal transducer and activator of transcription 3 (STAT3), while enhancing anti-inflammatory mediators including interleukin-10. Concomitantly, AMPK rebalances metabolic disturbances by inhibiting the mechanistic target of rapamycin (mTOR) pathway, stimulating fatty acid oxidation and improving insulin sensitivity. These combined actions underpin its protective role in conditions ranging from obesity-linked insulin resistance and atherosclerosis to sepsis and autoimmune arthritis. Therapeutically, small-molecule AMPK activators and dietary interventions targeting AMPK signalling offer promising avenues for the treatment of chronic inflammatory and metabolic disorders on a global scale.

Research from Nature Portfolio

Recent studies have revealed unexpected AMPK-independent anti-inflammatory actions of the prototypical activator AICAR. One investigation demonstrated that AICAR suppresses lipopolysaccharide-induced expression of pro-inflammatory genes in primary human macrophages by preventing recruitment of NF-κB and RNA polymerase II to gene promoters, while also impairing STAT3-dependent induction of interleukin-6 and interleukin-10 targets. A separate report showed that AICAR potently inhibits endoplasmic reticulum stress responses and downstream cytokine production in macrophages exposed to saturated fatty acids and hypoxia. This effect required nucleoside transporter-mediated uptake of AICAR, and mechanistically involved inhibition of IRE1α autophosphorylation alongside activation of its endoribonuclease activity. These findings expand the repertoire of mechanisms through which AICAR modulates inflammation and suggest novel non-canonical pathways for targeting metabolic inflammation.

AMPK Activation in Inflammatory and Metabolic Disorders publication trend

The graph below shows the total number of articles in ampk activation in inflammatory and metabolic disorders across all publications each year (not limited to Nature Index journals).

Technical terms

AMPK (adenosine monophosphate-activated protein kinase): A serine/threonine kinase that senses cellular energy status and regulates metabolic and inflammatory pathways.

NF-κB (nuclear factor-κB): A transcription factor central to the induction of pro-inflammatory genes in immune and non-immune cells.

mTOR (mechanistic target of rapamycin): A kinase that controls growth and anabolic metabolism, inhibited by AMPK to conserve energy.

SIRT1 (sirtuin 1): A NAD+-dependent deacetylase that modulates inflammation and metabolism through transcriptional regulation.

ER stress (endoplasmic reticulum stress): A cellular condition triggered by misfolded proteins that can initiate inflammatory signalling.

STAT3 (signal transducer and activator of transcription 3): A transcription factor activated by cytokines that promotes pro-inflammatory and survival gene expression.

References

1. Ethanol Extract of Rosa laevigata Michx. Fruit Inhibits Inflammatory Responses through NF-κB/MAPK Signaling Pathways via AMPK Activation in RAW 264.7 Macrophages. Molecules (2023).
2. Nrf2-SHP Cascade-Mediated STAT3 Inactivation Contributes to AMPK-Driven Protection Against Endotoxic Inflammation. Frontiers in Immunology (2020).
3. Macrophage α1 AMP-activated Protein Kinase (α1AMPK) Antagonizes Fatty Acid-induced Inflammation through SIRT1*. Journal of Biological Chemistry (2010).
4. AICAR inhibits NFκB DNA binding independently of AMPK to attenuate LPS-triggered inflammatory responses in human macrophages. Scientific Reports (2018).
5. AMPK-independent inhibition of human macrophage ER stress response by AICAR. Scientific Reports (2016).