Version 2 2023-03-15, 15:23Version 2 2023-03-15, 15:23
Version 1 2021-01-06, 21:26Version 1 2021-01-06, 21:26
figure
posted on 2023-03-15, 15:23authored byAda AdminAda Admin, Regine Å. Jersin, Divya Sri Priyanka Tallapragada, André Madsen, Linn Skartveit, Even Fjære, Adrian McCann, Laurence Lawrence-Archer, Aron Willems, Jan-Inge Bjune, Mona S. Bjune, Villy Våge, Hans Jørgen Nielsen, Håvard Luong Thorsen, Bjørn Gunnar Nedrebø, Christian Busch, Vidar M. Steen, Matthias Blüher, Peter Jacobson, Per-Arne Svensson, Johan Fernø, Mikael Rydén, Peter Arner, Ottar Nygård, Melina Claussnitzer, Ståle Ellingsen, Lise Madsen, Jørn V. Sagen, Gunnar Mellgren, Simon N. Dankel
Elucidation
of mechanisms that govern lipid storage, oxidative stress and insulin
resistance may lead to improved therapeutic options for type 2 diabetes and other
obesity-related diseases. Here, we find that adipose expression of the small neutral amino acid transporter
SLC7A10, also known as alanine-serine-cysteine transporter 1 (ASC-1), shows
strong inverse correlates with visceral adiposity, insulin resistance and
adipocyte hypertrophy across multiple cohorts. Concordantly, loss of Slc7a10
function in zebrafish in vivo accelerates diet-induced body weight gain
and adipocyte enlargement. Mechanistically, SLC7A10 inhibition in human and
murine adipocytes decreases adipocyte serine uptake and total glutathione
levels and promotes reactive oxygen species (ROS) generation. Conversely,
SLC7A10 overexpression decreases ROS generation and increases mitochondrial
respiratory capacity. RNA-sequencing revealed consistent changes in gene
expression between human adipocytes and zebrafish visceral adipose tissue
following loss of SLC7A10, e.g., upregulation of SCD (lipid storage) and
downregulation of CPT1A (lipid oxidation). Interestingly, ROS scavenger
reduced lipid accumulation and attenuated the lipid-storing effect of SLC7A10
inhibition. These data uncover adipocyte SLC7A10 as a novel important regulator
of adipocyte resilience to nutrient and oxidative stress, in part by enhancing
glutathione levels and mitochondrial respiration, conducive to decreased ROS generation,
lipid accumulation, adipocyte hypertrophy, insulin resistance and type 2
diabetes.
Funding
Bergens Forskningsstiftelse Diabetesforbundet KG Jebsen Center for Diabetes Research x Norges Forskningsråd 245979/F50 263124 / F20 Novo Nordisk Fonden Samarbeidsorganet Helse-Vest