Reduction of Plasma BCAAs following Roux-en-Y Gastric Bypass Surgery Is Primarily Mediated by FGF21

Author:

Shah Harsh1ORCID,Kramer Alyssa1,Mullins Caitlyn A.1ORCID,Mattern Marie1,Gannaban Ritchel B.1ORCID,Townsend R. Leigh2,Campagna Shawn R.3,Morrison Christopher D.2ORCID,Berthoud Hans-Rudolf2,Shin Andrew C.1ORCID

Affiliation:

1. Neurobiology of Nutrition Laboratory, Department of Nutritional Sciences, College of Human Sciences, Texas Tech University, Lubbock, TX 79409, USA

2. Neurobiology of Nutrition & Metabolism Department, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA 70808, USA

3. Department of Chemistry, University of Tennessee, Knoxville, TN 37996, USA

Abstract

Type 2 diabetes (T2D) is a challenging health concern worldwide. A lifestyle intervention to treat T2D is difficult to adhere, and the effectiveness of approved medications such as metformin, thiazolidinediones (TZDs), and sulfonylureas are suboptimal. On the other hand, bariatric procedures such as Roux-en-Y gastric bypass (RYGB) are being recognized for their remarkable ability to achieve diabetes remission, although the underlying mechanism is not clear. Recent evidence points to branched-chain amino acids (BCAAs) as a potential contributor to glucose impairment and insulin resistance. RYGB has been shown to effectively lower plasma BCAAs in insulin-resistant or T2D patients that may help improve glycemic control, but the underlying mechanism for BCAA reduction is not understood. Hence, we attempted to explore the mechanism by which RYGB reduces BCAAs. To this end, we randomized diet-induced obese (DIO) mice into three groups that underwent either sham or RYGB surgery or food restriction to match the weight of RYGB mice. We also included regular chow-diet-fed healthy mice as an additional control group. Here, we show that compared to sham surgery, RYGB in DIO mice markedly lowered serum BCAAs most likely by rescuing BCAA breakdown in both liver and white adipose tissues. Importantly, the restored BCAA metabolism following RYGB was independent of caloric intake. Fasting insulin and HOMA-IR were decreased as expected, and serum valine was strongly associated with insulin resistance. While gut hormones such as glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) are postulated to mediate various surgery-induced metabolic benefits, mice lacking these hormonal signals (GLP-1R/Y2R double KO) were still able to effectively lower plasma BCAAs and improve glucose tolerance, similar to mice with intact GLP-1 and PYY signaling. On the other hand, mice deficient in fibroblast growth factor 21 (FGF21), another candidate hormone implicated in enhanced glucoregulatory action following RYGB, failed to decrease plasma BCAAs and normalize hepatic BCAA degradation following surgery. This is the first study using an animal model to successfully recapitulate the RYGB-led reduction of circulating BCAAs observed in humans. Our findings unmasked a critical role of FGF21 in mediating the rescue of BCAA metabolism following surgery. It would be interesting to explore the possibility of whether RYGB-induced improvement in glucose homeostasis is partly through decreased BCAAs.

Funder

Diabetes Action Research and Education Foundation

National Institutes of Health

Publisher

MDPI AG

Subject

Food Science,Nutrition and Dietetics

Reference80 articles.

1. CDC (2023, March 29). National Diabetes Statistics Report, Available online: https://www.cdc.gov/diabetes/data/statistics-report/index.html.

2. Association between insulin resistance and the development of cardiovascular disease;Ormazabal;Cardiovasc. Diabetol.,2018

3. Insulin Resistance in Kidney Disease: Is There a Distinct Role Separate from That of Diabetes or Obesity?;Sowers;Cardiorenal. Med.,2017

4. Resolving the Paradox of Hepatic Insulin Resistance;Santoleri;Cell. Mol. Gastroenterol. Hepatol.,2019

5. The prevalence of meeting A1C, blood pressure, and LDL goals among people with diabetes, 1988–2010;Fradkin;Diabetes Care,2013

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