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Endothelial AMPKα1/PRKAA1 exacerbates inflammation in HFD-fed mice
Qiuhua Yang1, Qian Ma1,2, Jiean Xu1,2
1Vascular Biology Center, Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, Georgia, USA.
Insights
Endothelial cell-specific knockout of AMP-activated protein kinase α1 (AMPKα1/PRKAA1) unexpectedly improved metabolic syndrome in mice fed a high-fat diet, revealing a pro-inflammatory role for AMPKα1 in endothelial cells.
Area of Science:
- Metabolic Syndrome Research
- Endothelial Cell Biology
- Molecular Metabolism
Background:
- Endothelial cell inflammation driven by excess nutrients is central to high-fat diet (HFD)-induced metabolic syndrome.
- AMP-activated protein kinase α1 (PRKAA1/AMPKα1) is a key energy sensor in endothelial cells, but its role in nutrient-induced inflammation is unknown.
Purpose of the Study:
- To investigate the physiological role of endothelial AMPKα1/PRKAA1 in HFD-induced metabolic syndrome and endothelial cell inflammation.
Main Methods:
- Utilized wild-type and endothelial cell-specific Prkaa1 knockout mice fed an HFD.
- Monitored metabolic parameters (body weight, fat mass, glucose, lipids, insulin sensitivity).
- Assessed inflammation via RT-PCR, flow cytometry, and molecular analyses in cultured endothelial cells.
Main Results:
- EC Prkaa1 deficiency unexpectedly ameliorated HFD-induced metabolic syndrome, reducing body weight, fat mass, and improving glucose/lipid profiles and insulin sensitivity.
- EC Prkaa1 deficiency decreased adipose inflammation and hepatic steatosis.
- Mechanistically, PRKAA1 knockdown in ECs reduced glycolysis and fatty acid oxidation, lowering acetyl-CoA and suppressing inflammatory gene transcription.
Conclusions:
- Endothelial AMPKα1/PRKAA1 exhibits an unexpected pro-inflammatory role in the context of metabolic syndrome.
- Therapeutic targeting of AMPKα1/PRKAA1 for metabolic syndrome requires careful consideration due to its complex activities in endothelial cells.
Background And Purpose:
Excess nutrient-induced endothelial cell inflammation is a hallmark of high fat diet (HFD)-induced metabolic syndrome. Pharmacological activation of the protein kinase AMP-activated α1 (PRKAA1) also known as AMPKα1, shows its beneficial effects in many studies of cardiometabolic disorders. However, AMPKα1, as a major cellular sensor of energy and nutrients in endothelial cells, has not been studied for its physiological role in excess nutrient-induced endothelial cell (EC) inflammation.
Experimental Approach:
Wild-type and EC-specific Prkaa1 knockout mice were fed with an HFD. Body weight, fat mass composition, glucose, and lipid levels were monitored regularly. Insulin sensitivity was analysed systemically and in major metabolic organs/tissues. Inflammation status in metabolic organs/tissues were examined with quantitative RT-PCR and flow cytometry. Additionally, metabolic status, inflammation severity, and signalling in cultured ECs were assayed with multiple approaches at the molecular level.
Key Results:
EC Prkaa1 deficiency unexpectedly alleviated HFD-induced metabolic syndromes including decreased body weight and fat mass, enhanced glucose clearance and insulin sensitivity, and relieved adipose inflammation and hepatic steatosis. Mechanistically, PRKAA1 knockdown in cultured ECs reduced endothelial glycolysis and fatty acid oxidation, decreased levels of acetyl-CoA and suppressed transcription of inflammatory molecules mediated by ATP citrate lyase and histone acetyltransferase p300.
Conclusions And Implications:
This unexpected pro-inflammatory effect of endothelial AMPKα1/PRKAA1 in a metabolic context provides additional insight in AMPKα1/PRKAA1 activities. An in-depth study and thoughtful consideration should be applied when AMPKα1/PRKAA1 is used as a therapeutic target in the treatment of metabolic syndrome.
