Endothelial AMPKα1/PRKAA1 exacerbates inflammation in HFD-fed mice

Qiuhua Yang, Qian Ma, Jiean Xu, Zhiping Liu, Xiaoxiao Mao, Yaqi Zhou, Yongfeng Cai, Qingen Da, Mei Hong, Neal Lee Weintraub, David J. Fulton, Eric J. Belin de Chantemèle, Yuqing Huo

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
JournalBritish Journal of Pharmacology
DOIs
StateAccepted/In press - 2021

ASJC Scopus subject areas

  • Pharmacology

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