Impaired Adipocyte SLC7A10 Promotes Lipid Storage in Association With Insulin Resistance and Altered BCAA Metabolism

Author:

Jersin Regine Å12ORCID,Sri Priyanka Tallapragada Divya12,Skartveit Linn12,Bjune Mona S12,Muniandy Maheswary3,Lee-Ødegård Sindre4,Heinonen Sini3,Alvarez Marcus5,Birkeland Kåre Inge4,André Drevon Christian6,Pajukanta Päivi578,McCann Adrian9,Pietiläinen Kirsi H310,Claussnitzer Melina1112,Mellgren Gunnar12,Dankel Simon N12ORCID

Affiliation:

1. Mohn Nutrition Research Laboratory, Department of Clinical Science, University of Bergen , N-5021 Bergen , Norway

2. Hormone Laboratory, Department of Medical Biochemistry and Pharmacology, Haukeland University Hospital , N-5021 Bergen , Norway

3. Obesity Research Unit, Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki , FIN-00014 Helsinki , Finland

4. Department of Transplantation Medicine, The University of Oslo, Institute of Clinical Medicine, and Oslo University Hospital , N-0372 Oslo , Norway

5. Department of Human Genetics, David Geffen School of Medicine at UCLA , Los Angeles, CA 90095 , USA

6. Department of Nutrition, The University of Oslo, Institute of Basic Medical Sciences , N-0372 Oslo , Norway

7. Bioinformatics Interdepartmental Program, UCLA , Los Angeles, CA 90095 , USA

8. Institute for Precision Health, David Geffen School of Medicine at UCLA , Los Angeles, CA 90095 , USA

9. Bevital A/S, Laboratoriebygget, Haukeland University Hospital , N-5021 Bergen , Norway

10. Obesity Center, Endocrinology, Abdominal Center, Helsinki University Hospital and University of Helsinki , FIN-00014 Helsinki , Finland

11. Broad Institute of MIT and Harvard , Cambridge, MA 02142 , USA

12. Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School , Boston, MA 02215 , USA

Abstract

Abstract Context The neutral amino acid transporter SLC7A10/ASC-1 is an adipocyte-expressed gene with reduced expression in insulin resistance and obesity. Inhibition of SLC7A10 in adipocytes was shown to increase lipid accumulation despite decreasing insulin-stimulated uptake of glucose, a key substrate for de novo lipogenesis. These data imply that alternative lipogenic substrates to glucose fuel continued lipid accumulation during insulin resistance in obesity. Objective We examined whether increased lipid accumulation during insulin resistance in adipocytes may involve alter flux of lipogenic amino acids dependent on SLC7A10 expression and activity, and whether this is reflected by extracellular and circulating concentrations of marker metabolites. Methods In adipocyte cultures with impaired SLC7A10, we performed RNA sequencing and relevant functional assays. By targeted metabolite analyses (GC-MS/MS), flux of all amino acids and selected metabolites were measured in human and mouse adipose cultures. Additionally, SLC7A10 mRNA levels in human subcutaneous adipose tissue (SAT) were correlated to candidate metabolites and adiposity phenotypes in 2 independent cohorts. Results SLC7A10 impairment altered expression of genes related to metabolic processes, including branched-chain amino acid (BCAA) catabolism, lipogenesis, and glyceroneogenesis. In 3T3-L1 adipocytes, SLC7A10 inhibition increased fatty acid uptake and cellular content of glycerol and cholesterol. SLC7A10 impairment in SAT cultures altered uptake of aspartate and glutamate, and increased net uptake of BCAAs, while increasing the net release of the valine catabolite 3- hydroxyisobutyrate (3-HIB). In human cohorts, SLC7A10 mRNA correlated inversely with total fat mass, circulating triacylglycerols, BCAAs, and 3-HIB. Conclusion Reduced SLC7A10 activity strongly affects flux of BCAAs in adipocytes, which may fuel continued lipogenesis during insulin resistance, and be reflected in increased circulating levels of the valine-derived catabolite 3-HIB.

Funder

Research Council of Norway

Western Norway Regional Health Authority

Norwegian Diabetes Association

Trond Mohn Foundation

NovoNordisk Scandinavia AS

Academy of Finland

Finnish Medical Foundation

Gyllenberg Foundation

Novo Nordisk Foundation

Finnish Diabetes Research Foundation

University of Helsinki

Government Research Funds

Helsinki University Hospital

University of Oslo

Southeastern Regional Health Authorities

Anders Jahre's

Foundation

NutriTech

Freia Medical Research Foundation

The Johan Throne-Holst Foundation

Publisher

The Endocrine Society

Subject

Biochemistry (medical),Clinical Biochemistry,Endocrinology,Biochemistry,Endocrinology, Diabetes and Metabolism

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