The liver produces endogenous glucose to support life during fasting. Counterregulatory hormones, including glucagon, catecholamines, and glucocorticoids, stimulate the expression of gluconeogenic enzymes in the liver, thus driving liver glucose production. In contrast, insulin suppresses hepatic gluconeogenesis, thereby restraining postprandial glucose levels. Hepatic gluconeogenesis aberrantly increases in type 2 diabetes due to an imbalance between insulin and counterregulatory hormone actions, contributing to hyperglycemia and glucose intolerance. N6-methyladenosine (m6A) RNA methylation has emerged as a critical paradigm shaping cell identities and functions. The Mettl3/Mettl14 complex catalyzes m6A on RNA and RNA-binding proteins bind to the m6A motifs and determine the fate of client mRNAs (splicing, trafficking, stability, and/or translation) . However, m6A RNA modification has not been explored in liver gluconeogenesis. Here, we identified Mettl14 as an important positive regulator of hepatic gluconeogenesis. Liver Mettl14 levels were increased in db/db mice and mice with high fat diet (HFD) -induced obesity. Hepatocyte-specific deletion of Mettl14 decreased hepatic glucose production and ameliorated HFD-induced glucose intolerance; conversely, liver-specific overexpression of Mettl14 increased liver glucose production and HFD-induced glucose intolerance. Of note, Mettl14 did not alter liver insulin actions under our experimental conditions. Remarkably, hepatic deficiency of Mettl14 profoundly blunted the ability of glucagon to stimulate gluconeogenesis in mice. Consistently, deletion of Mettl14 largely blocked glucagon-stimulated gluconeogenesis ex vivo in liver slices as well as in primary hepatocyte cultures. In contrast, overexpression of Mettl14 had the opposite effects. Collectively, these data unravel a previously unrecognized glucagon/Mettl14/gluconeogenesis axis that is involved in hyperglycemia and glucose intolerance in diabetes.

Disclosure

Q. Zheng: None. X. Zhong: None. D. Ren: None. L. Rui: None.

Funding

National Institutes of Health (RO1DK127568) , American Heart Association (831585)

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