Mice lacking neutral amino acid transporter B(0)AT1 (Slc6a19) have elevated levels of FGF21 and GLP-1 and improved glycaemic control

Yang Jiang; Adam J Rose; Tjeerd P Sijmonsma; Angelika Bröer; Anja Pfenninger; Stephan Herzig; Dieter Schmoll; Stefan Bröer

doi:10.1016/j.molmet.2015.02.003

Mice lacking neutral amino acid transporter B(0)AT1 (Slc6a19) have elevated levels of FGF21 and GLP-1 and improved glycaemic control

Mol Metab. 2015 Feb 16;4(5):406-17. doi: 10.1016/j.molmet.2015.02.003. eCollection 2015 May.

Authors

Yang Jiang¹, Adam J Rose², Tjeerd P Sijmonsma², Angelika Bröer¹, Anja Pfenninger³, Stephan Herzig², Dieter Schmoll³, Stefan Bröer¹

Affiliations

¹ Research School of Biology, The Australian National University, Canberra, ACT 0200, Australia.
² Joint Research Division Molecular Metabolic Control, German Cancer Research Center, Center for Molecular Biology, Heidelberg University and Heidelberg University Hospital, 69120 Heidelberg, Germany.
³ Sanofi-Aventis Deutschland GmbH, Industriepark Hoechst, Frankfurt am Main 65926, Germany.

Abstract

Objective: Type 2 diabetes arises from insulin resistance of peripheral tissues followed by dysfunction of β-cells in the pancreas due to metabolic stress. Both depletion and supplementation of neutral amino acids have been discussed as strategies to improve insulin sensitivity. Here we characterise mice lacking the intestinal and renal neutral amino acid transporter B(0)AT1 (Slc6a19) as a model to study the consequences of selective depletion of neutral amino acids.

Methods: Metabolic tests, analysis of metabolite levels and signalling pathways were used to characterise mice lacking the intestinal and renal neutral amino acid transporter B(0)AT1 (Slc6a19).

Results: Reduced uptake of neutral amino acids in the intestine and loss of neutral amino acids in the urine causes an overload of amino acids in the lumen of the intestine and reduced systemic amino acid availability. As a result, higher levels of glucagon-like peptide 1 (GLP-1) are produced by the intestine after a meal, while the liver releases the starvation hormone fibroblast growth factor 21 (FGF21). The combination of these hormones generates a metabolic phenotype that is characterised by efficient removal of glucose, particularly by the heart, reduced adipose tissue mass, browning of subcutaneous white adipose tissue, enhanced production of ketone bodies and reduced hepatic glucose output.

Conclusions: Reduced neutral amino acid availability improves glycaemic control. The epithelial neutral amino acid transporter B(0)AT1 could be a suitable target to treat type 2 diabetes.

Keywords: Amino acid metabolism; BAT, brown adipose tissue; BM, body mass; Epithelial transport; IPGTT, intraperitoneal glucose tolerance test; IPITT, intraperitoneal insulin tolerance test; NEFA, non-esterified fatty acids; RER, respiratory exchange ratio; Type 2 diabetes; WAT, white adipose tissue; aWAT, abdominal white adipose tissue; iWAT, inguinal white adipose tissue.