Regulation of the activin-follistatin hormonal system in relation to glucometabolic status in mice, in healthy humans and in obese individuals undergoing bariatric surgery

Objective Activins and their inhibitors, follistatins, control muscle growth and are being developed therapeutically against obesity and T2D. We aimed to investigate the tissue-expression profile of the activins-follistatins in diet-induced obesity(DIO)-prone C57BL/6J and DIO-resistant A/J mice and to assess whether activins, similarly to our recent report for follistatin, are regulated by glucose or lipids and predict the metabolic improvement after bariatric surgery (BS) in humans.

Methods The expression of genes encoding activins, follistatins and their receptors were measured in white (WAT), brown (BAT) adipose tissue and skeletal muscle at 0, 3-4 and 8-10 weeks of high-fat diet (HFD) vs chow in C57BL/6J and A/J mice. Circulating activins were measured in a) healthy humans (n=32) during a 6h-oral and iv glucose and lipid intake, b) morbidly obese people undergoing gastric banding, Roux-en-Y bypass or sleeve gastrectomy in two clinical studies (n=14 and n=27).

Results Follistatin mRNA levels in WAT, BAT and muscle are 80-90% lower in A/J compared to C57BL/6J mice. In C57BL/6J, HFD increases the mRNA expression of follistatin and follistatin-like 3 and decreases of INHBA (encoding activin A) in WAT, whereas it increases the expression of INHBB (encoding activin B) in WAT and BAT. In humans, glucose intake downregulates circulating activin A,B and AB. Three months after BS, activin AB (~25%) and its ratio to follistatin increases and predicts the weight loss and improvement in insulin sensitivity six months postoperatively.

Conclusion The expression and circulation of activins-follistatins are related to glucometabolic status and predict metabolic outcomes prospectively after BS.

Interessenskonflikt

Funding: The current study was funded by NIH K24DK081913 of Christos S. Mantzoros. Nikolaos Perakakis was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) –389891681 (PE 2431/2-1).

Conflict of interest: Christos S. M is advisor of Ansh Labs LLC

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Publication History

Article published online:
06 May 2021