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Gastric Bypass Surgery Improves the Skeletal Muscle Ceramide/S1P Ratio and Upregulates the AMPK/ SIRT1/ PGC-1α Pathway in Zucker Diabetic Fatty Rats

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Abstract

Purpose

Roux-en-Y gastric bypass (RYGB) is associated with remission of type 2 diabetes. However, the cellular and molecular mechanisms remain unknown. We hypothesized that RYGB would increase peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), sirtuin-1 (SIRT1), AMPK/pAMPK, and citrate synthase (CS) protein expression and decrease insulin resistance and these changes would be mediated by sphingolipids, including ceramides and the sphingolipid metabolite sphingosine-1 phosphate (S1P).

Materials and Methods

Male ZDF rats were randomized to RYGB (n = 7) or sham surgery (n = 7) and harvested after 28 days. Total tissue ceramide, ceramide subspecies (C14:0, C16:0, C18:0, C18:1, C20:0, C24:0, and C24:1), and S1P were quantified in the white gastrocnemius muscle using LC-ESI-MS/MS after separation with HPLC. Total SIRT1, AMPK, PGC-1α, and CS protein expression were measured by Western blot.

Results

Body weight, fasting glucose, insulin, and HOMA-IR decreased significantly after RYGB compared with sham control. These changes were paralleled by lower total ceramide (483.7 ± 32.3 vs. 280.1 ± 38.8 nmol/g wwt), C18:0 ceramide subspecies (P < 0.05), higher S1P (0.83 ± 0.05 vs. 1.54 ± 0.21 nmol/g wwt, P < 0.05), and a lower ceramide/S1P ratio (P < 0.05) in the RYGB versus sham group. AMPK, pAMPK, SIRT1, PGC-1α, and CS protein expression was also higher after RYGB (P < 0.05). The ceramide/S1P ratio correlated with weight loss (r = 0.48, P = 0.08), insulin resistance (r = 0.61, P = 0.02), PGC-1α (r = − 0.51, P < 0.06), CS (r = − 0.63, P = 0.01), and SIRT1 (r = − 0.54, P < 0.04).

Conclusion

Our data demonstrate that sphingolipid balance, and increased AMPK, SIRT1, PGC-1α, and CS protein expression are part of the mechanism that contributes to the remission of diabetes after RYGB surgery.

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Funding

This research was supported by the American Society of Metabolic and Bariatric Surgery, the National Institute of Diabetes and Digestive and Kidney Diseases (DK108089), internal funding from the Cleveland Clinic Research Program Committee (#2010-1009), and the Louisiana Clinical and Translational Science Center (U54 GM104940).

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Authors and Affiliations

  1. Department of Pathobiology, Cleveland Clinic, Lerner Research Institute, Cleveland, OH, USA

    Hazel Huang, Christopher L. Axelrod & John P. Kirwan

  2. Cleveland Clinic, Bariatric and Metabolic Institute, Cleveland, OH, USA

    Ali Aminian, Monique Hassan, Olivia Dan, Philip R. Schauer & Stacy A. Brethauer

  3. Integrated Physiology and Molecular Medicine Laboratory, Pennington Biomedical Research Center, 6400 Perkins Road, L-4030, Baton Rouge, LA, 70808, USA

    Christopher L. Axelrod & John P. Kirwan

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  1. Hazel Huang
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  4. Olivia Dan
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Correspondence to John P. Kirwan.

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Huang, H., Aminian, A., Hassan, M. et al. Gastric Bypass Surgery Improves the Skeletal Muscle Ceramide/S1P Ratio and Upregulates the AMPK/ SIRT1/ PGC-1α Pathway in Zucker Diabetic Fatty Rats. OBES SURG 29, 2158–2165 (2019). https://doi.org/10.1007/s11695-019-03800-z

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