Unsuppressed hepatic glucose production (HGP) contributes significantly to glucose intolerance and diabetes, which can be modeled by genetic inactivation of hepatic insulin receptor substrate (Irs) 1 and Irs2 (LDKO-mice). We previously showed that glucose intolerance in LDKO-mice is resolved by hepatic inactivation of the transcription factor FoxO1 (i.e., LTKO-mice)—even though the liver remains insensitive to insulin. Here, we report that insulin sensitivity in the white adipose tissue (WAT) of LDKO-mice is also impaired, but is restored in LTKO-mice in conjunction with normal suppression of HGP by insulin. To establish the mechanism by which WAT insulin signaling and HGP were regulated by hepatic FoxO1, we identified putative hepatokines—including excess follistatin (Fst)—that were dysregulated in LDKO-mice but normalized in LTKO-mice. Knockdown of hepatic Fst in the LDKO-liver restored glucose tolerance, WAT insulin signaling, and the suppression of HGP by insulin; however, expression of Fst in the liver of healthy LTKO-mice had the opposite effect. Of potential clinical significance, knockdown of Fst also improved glucose tolerance in high-fat fed obese mice, and serum FST was reduced in parallel with glycated hemoglobin in obese individuals with diabetes who underwent therapeutic gastric bypass surgery. We conclude that follistatin is a pathological hepatokine that might be targeted for diabetes therapy during hepatic insulin resistance.

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HIGHLIGHTSd b-catenin activation drives adrenal hyperplasia by blocking cellular differentiation d Upregulation of Pde2a, an inhibitor of cAMP/PKA, is a potential mechanism for the block d Hyperplasia is exacerbated by trophic factor stimulation leading to organomegaly