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Bariatric Surgery

Effects of Roux-en-Y gastric bypass on circulating follistatin, activin A, and peripheral ActRIIB signaling in humans with obesity and type 2 diabetes

International Journal of Obesity volume 45, pages 316–325 (2021)Cite this article

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Abstract

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 SMAD2Ser465/467, p70S6KThr389, S6RPSer235/236, and 4E-BP1Thr37/49 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.

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Fig. 1: T2D abrogates regulation of circulating follistatin by Roux-en-Y gastric bypass in subjects with obesity.
Fig. 2: Follistatin acutely positively correlates with glucagon/c-peptide (CPEP) ratio and glucagon/insulin ratio after Roux-en-Y gastric bypass.
Fig. 3: Roux-en-Y gastric bypass has no effect on ActRIIB signaling in skeletal muscle.
Fig. 4: Adipose tissue-ActRIIB signaling is highly responsive to effects elicited Roux-en-Y gastric bypass, particulary after 1 year.

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Acknowledgements

We acknowledge the skilled technical assistance of Betina Bolmgren, Dorte E. Steenberg, and Peter H. Albers (Molecular Physiology Group, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Denmark; Diabetes Research Unit, Novo Nordisk A/S, Maaloev, Denmark). We also wish to thank all the subjects participating in this study.

Funding

This work was carried out as a part of the program of the UNIK: Food, Fitness & Pharma for Health and Disease (see www.foodfitnesspharma.ku.dk). The UNIK project was supported by the Danish Ministry of Science, Technology and Innovation, the Danish Council for Independent Research Medical Sciences (FSS), the Novo Nordisk Foundation, and the Strategic Counsel for the Capital Area of Copenhagen (Denmark). The study was further supported by the Novo Nordisk Foundation (grant NNF16OC0023418 and NNF18OC0032082 to LS).

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Authors and Affiliations

  1. Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark

    Tang Cam Phung Pham, Jørgen Frank Pind Wojtaszewski, Erik Arne Richter & Lykke Sylow

  2. Department of Endocrinology, Hvidovre Hospital, Hvidovre, Denmark

    Kirstine Nyvold Bojsen-Møller & Sten Madsbad

  3. Novo Nordisk Foundation Centre for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark

    Kirstine Nyvold Bojsen-Møller

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Correspondence to Lykke Sylow.

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Clinical experiments were approved by the Ethics Committee of Copenhagen and complied with the ethical guidelines of the Declaration of Helsinki II 2000.

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Pham, T.C.P., Bojsen-Møller, K.N., Madsbad, S. et al. Effects of Roux-en-Y gastric bypass on circulating follistatin, activin A, and peripheral ActRIIB signaling in humans with obesity and type 2 diabetes. Int J Obes 45, 316–325 (2021). https://doi.org/10.1038/s41366-020-00664-7

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