Inactivating hepatic follistatin alleviates hyperglycemia

Abstract

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.

Follistatins in glucose regulation in healthy and obese individuals

“…As recently reported, FST inactivation improves glucose tolerance in hyperglycaemic mice, and FST levels decreased in parallel with HbA1c in 10 morbidly obese individuals with T2D after RYGB . In our study, we observed a significant reduction in FST after both RYGB and VSG, but not after AGB.…”

“…Follistatins participate in a wide spectrum of physiological processes, ranging from reproductive function to muscle and liver metabolism, as well as glucose and lipid homeostasis . It has been reported recently that knockdown of FST in hyperglycaemic mice improves glucose tolerance by increasing white adipose tissue insulin sensitivity and by reducing hepatic glucose output . In addition, circulating FST concentrations were elevated in patients with type 2 diabetes (T2D) and decrease concomitantly with HbA1c in a limited number of obese individuals with T2D 6 months after Roux‐en‐Y gastric bypass (RYGB) .…”

“…It has been reported recently that FST increases blood glucose levels by promoting hepatic glucose output and insulin resistance in white adipose tissue in mice . Here, we demonstrate that glucose itself is a potent down‐regulator of FST, establishing an endocrine loop between FST and glucose in humans.…”

“…It has been reported recently that knockdown of FST in hyperglycaemic mice improves glucose tolerance by increasing white adipose tissue insulin sensitivity and by reducing hepatic glucose output . In addition, circulating FST concentrations were elevated in patients with type 2 diabetes (T2D) and decrease concomitantly with HbA1c in a limited number of obese individuals with T2D 6 months after Roux‐en‐Y gastric bypass (RYGB) . These findings indicate that, if these data are extended to and confirmed in humans, FST may be an attractive therapeutic target in the treatment of T2D .…”

“…In addition, circulating FST concentrations were elevated in patients with type 2 diabetes (T2D) and decrease concomitantly with HbA1c in a limited number of obese individuals with T2D 6 months after Roux‐en‐Y gastric bypass (RYGB) . These findings indicate that, if these data are extended to and confirmed in humans, FST may be an attractive therapeutic target in the treatment of T2D . FSTL3 is a protein highly homologous to FST that may also participate in the regulation of glucose and lipid homeostasis.…”