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Significance Endoplasmic reticulum (ER) stress plays an important role in obesity and type 2 diabetes mellitus (T2DM), with controversy in mechanisms and regulatory pathways. We found that chronic low-grade ER stress in lean mice promoted hyperglycemia due to enhanced hepatic gluconeogenesis via ubiquitin-specific peptidase14 (USP14) induction, which, in turn, increased the stability of adenosine 3′,5′-cyclic monophosphate–responsive element binding protein to enhance glucagon action and hepatic gluconeogenesis. Overexpression of USP14 in the liver significantly increased hepatic glucose output. Liver-specific knockdown of USP14 abrogated the effects of ER stress on glucose metabolism, improved hyperglycemia and glucose intolerance in obese mice. Our findings show a mechanism underlying ER stress-induced disruption of glucose homeostasis, and present USP14 as a potential therapeutic target against T2DM.

Sustained ER stress promotes hyperglycemia by increasing glucagon action through the deubiquitinating enzyme USP14