Activation of natriuretic peptides and the sympathetic nervous system following Roux-en-Y gastric bypass is associated with gonadal adipose tissues browning

Michael D Neinast; Aaron P Frank; Juliet F Zechner; Quanlin Li; Lavanya Vishvanath; Biff F Palmer; Vincent Aguirre; Rana K Gupta; Deborah J Clegg

doi:10.1016/j.molmet.2015.02.006

Activation of natriuretic peptides and the sympathetic nervous system following Roux-en-Y gastric bypass is associated with gonadal adipose tissues browning

Mol Metab. 2015 Mar 3;4(5):427-36. doi: 10.1016/j.molmet.2015.02.006. eCollection 2015 May.

Authors

Michael D Neinast¹, Aaron P Frank², Juliet F Zechner¹, Quanlin Li³, Lavanya Vishvanath¹, Biff F Palmer¹, Vincent Aguirre¹, Rana K Gupta¹, Deborah J Clegg²

Affiliations

¹ Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
² Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA ; Biomedical Research Division, Diabetes and Obesity Research Institute, Department of Biomedical Science, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
³ Biostatistic and Bioinformatics Core, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

Abstract

Objective: Roux-en-Y gastric bypass (RYGB) is an effective method of weight loss and remediation of type-2 diabetes; however, the mechanisms leading to these improvements are unclear. Additionally, adipocytes within white adipose tissue (WAT) depots can manifest characteristics of brown adipocytes. These 'BRITE/beige' adipocytes express uncoupling protein 1 (UCP1) and are associated with improvements in glucose homeostasis and protection from obesity. Interestingly, atrial and B-type natriuretic peptides (NPs) promote BRITE/beige adipocyte enrichment of WAT depots, an effect known as "browning." Here, we investigate the effect of RYGB surgery on NP, NP receptors, and browning in the gonadal adipose tissues of female mice. We propose that such changes may lead to improvements in metabolic homeostasis commonly observed following RYGB.

Methods: Wild type, female, C57/Bl6 mice were fed a 60% fat diet ad libitum for six months. Mice were divided into three groups: Sham operated (SO), Roux-en-Y gastric bypass (RYGB), and Weight matched, sham operated (WM-SO). Mice were sacrificed six weeks following surgery and evaluated for differences in body weight, glucose homeostasis, adipocyte morphology, and adipose tissue gene expression.

Results: RYGB and calorie restriction induced similar weight loss and improved glucose metabolism without decreasing food intake. β3-adrenergic receptor expression increased in gonadal adipose tissue, in addition to Nppb (BNP), and NP receptors, Npr1, and Npr2. The ratio of Npr1:Npr3 and Npr2:Npr3 increased in RYGB, but not WM-SO groups. Ucp1 protein and mRNA, as well as additional markers of BRITE/beige adipose tissue and lipolytic genes increased in RYGB mice to a greater extent than calorie-restricted mice.

Conclusions: Upregulation of Nppb, Npr1, Npr2, and β3-adrenergic receptors in gonadal adipose tissue following RYGB was associated with increased markers of browning. This browning of gonadal adipose tissue may underpin the positive effect of RYGB on metabolic parameters and may in part be mediated through upregulation of natriuretic peptides.

Keywords: Atrial natriuretic peptide (ANP); B-type natriuretic peptide (BNP); Browning; High fat diet (HFD); Natriuretic peptide receptor; Roux-en-Y gastric bypass (RYGB).

Grants and funding

P01 DK088761/DK/NIDDK NIH HHS/United States