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SGK1 Is a Potential New Target to Prevent Obesity-related Atrial Fibrillation

Key findings

  • Massachusetts General Hospital researchers previously found that cardiac expression of serum glucocorticoid kinase 1 (SGK1) increases the risk of lethal ventricular arrhythmias
  • This murine study examined whether obesity induces pathologic SGK1 signaling, comprehensively assessed the effects of obesity on atrial gene expression, and investigated whether genetic inhibition of SGK1 protects against atrial fibrillation
  • In a mouse model of diet-induced obesity, the researchers demonstrated alterations in atrial gene expression, with enrichment of multiple SGK1-related pathways, and confirmed upregulation of SGK1 signaling in obese atria
  • There was a marked difference between lean and obese mice in the inducibility of atrial arrhythmias and electrical properties of the atria. Genetic SGK1 inhibition reversed obesity-related changes in atrial electrophysiology, structural remodeling and inflammation
  • Pharmacologic targeting of SGK1 for its therapeutic potential in obesity-related atrial fibrillation is warranted

Obesity has become a prominent—and potentially preventable or reversible—risk factor for atrial fibrillation (AF). The mechanistic relationship is unclear, though, so no specific therapy exists.

Researchers at Massachusetts General Hospital previously reported in Circulation that cardiac expression of serum glucocorticoid kinase 1 (SGK1) increases the risk of lethal ventricular arrhythmias. SGK1 directly modulates cardiac electrophysiology through effects on the sodium current, and intriguingly it is presumed to be involved in multiple obesity-related pathways.

Saumya Das, MD, PhD, co-director of the Resynchronization and Advanced Cardiac Therapeutics Program and investigator in the Cardiovascular Research Center, David Milan, MD, and lead author Aneesh Bapat, MD, a cardiac electrophysiologist in the Center, and colleagues now report in JCI Insight that SGK1 is a promising therapeutic target for obesity-related AF.


Most experiments in this study involved using a high-fat diet to create a mouse model of obesity-related AF. For electrophysiology analyses, the researchers used a transgenic mouse model that overexpresses a dominant negative form of SGK1 in cardiomyocytes.

Principal Results

The key observations were that:

  • Diet-induced obesity increased both atrial and ventricular SGK1 transcription and signaling
  • Obesity resulted in the activation of SGK1-related pathways in atrial tissue, including increased insulin, mineralocorticoid, and mTOR signaling
  • There was a marked difference between lean and obese mice in inducibility of atrial arrhythmias
  • Inter-atrial differences in action potential characteristics and impulse propagation were brought on by obesity and were reversed with genetic SGK1 inhibition
  • SGK1 inhibition protected against the expression of several pro-fibrotic factors, such as collagen; this is important because substantial evidence suggests a role for obesity-induced structural remodeling in the pathogenesis of AF

Future Work

Based on these results, targeting SGK1 should be further investigated for its therapeutic potential in obesity-related AF. Mass General researchers have work underway to assess the role of SGK1 inhibition in other AF-related stressors known to activate SGK1 signaling, such as hypertension. Future studies to determine the effects of pharmacologic SGK1 inhibition on AF risk reduction are being planned.

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