Background: Roux-en-Y gastric bypass (RYGB) surgery is a therapeutic intervention for morbid obesity and type 2 diabetes (T2D) that improves metabolic regulation. Follistatin (Fst) could be implicated in improved glycemia as it is highly regulated by RYGB. However, it is unknown if metabolic status, such as T2D, alters the Fst response to RYGB. In addition, the effect of RYGB on the Fst target, activin A, is unknown in individuals with obesity and T2D, but is needed to interpret the functional effects of altering Fst. Finally, whether Fst-regulated intracellular signaling contributes to beneficial effects of RYGB is undetermined.

Methods: Circulating Fst and activin A were measured before, 1 week, and 1 year after RYGB surgery in a total of 20 individuals with obesity, 10 with normoglycemia (NGT) and 10 with preoperative T2D. Intracellular signaling downstream of the Activin receptor type IIB (ActRIIB) signaling pathway was analyzed in skeletal muscle and adipose tissue.

Results: The doubling in circulating Fst observed in subjects with NGT 1-week and 1-year post surgery was absent in T2D. After 1 week, RYGB reduced activin A by 27% (p < 0.001) and 20% (p < 0.01) in subjects with NGT and T2D, respectively; a reduction that tended to be maintained in the subjects with T2D at 1-year post-RYGB (-15%; p = 0.0592). RYGB had no effects on skeletal muscle ActRIIB signaling. In contrast, adipose tissue phosphorylation of SMAD2^Ser465/467, p70S6K^Thr389, S6RP^Ser235/236, and 4E-BP1^Thr37/49 was highly regulated, particularly 1-year post-RYGB (p < 0.05).

Conclusions: In subjects with preoperative T2D, RYGB did not increase circulating Fst contrasting subjects with NGT, while the reduction in activin A was maintained. ActRIIB signaling was upregulated in adipose tissue, but not skeletal muscle, following RYGB in both individuals with NGT and T2D. Our results suggest a role of adipose tissue ActRIIB signaling for the beneficial effects of RYGB surgery.