TY - JOUR

T1 - Over-expression of Follistatin-like 3 attenuates fat accumulation and improves insulin sensitivity in mice

AU - Brandt, Claus

AU - Hansen, Rasmus Hvass

AU - Hansen, Jakob Bondo

AU - Olsen, Caroline Holkmann

AU - Galle, Pia

AU - Mandrup-Poulsen, Thomas

AU - Gehl, Julie

AU - Pedersen, Bente Klarlund

AU - Hojman, Pernille

N1 - Copyright © 2015 Elsevier Inc. All rights reserved.

PY - 2015/2

Y1 - 2015/2

N2 - OBJECTIVE: Follistatin-like 3 (fstl3), a natural inhibitor of members of the TGF-β family, increases during resistance training in human plasma. Fstl3 primarily binds myostatin and activin A, and thereby inhibits their functions. We hypothesize that blocking myostatin and activin A signalling through systemic fstl3 over-expression protects against diet-induced obesity and insulin resistance.METHODS: Fstl3 was over-expressed by DNA electrotransfer in tibialis anterior, quadriceps and gastrocnemius muscles in female C57BL/C mice, and the mice were subsequently randomized to chow or high-fat feeding. Body weight, food intake, fat accumulation by MR scanning, and glucose, insulin and glucagon tolerance were evaluated, as was the response in body weight and metabolic parameters to 24h fasting. Effects of fstl3 on pancreatic insulin and glucagon content, and pancreatic islet morphology were determined.RESULTS: Fstl3 over-expression reduced fat accumulation during high-fat feeding by 16%, and liver fat by 50%, as determined by MRI. No changes in body weight were observed, while the weight of the transfected muscles increased by 10%. No transcriptional changes were found in the subcutaneous adipose tissue. Fstl3 mice displayed improved insulin sensitivity and muscle insulin signalling. In contrast, glucose tolerance was impaired in high-fat fed fstl3 mice, which was explained by increased hepatic glucagon sensitivity and glucose output, as well as a decrease in the pancreatic insulin/glucagon ratio. Accordingly, fstl3 transfection improved counter-regulation to 24h fasting.CONCLUSION: Fstl3 over-expression regulates insulin and glucagon sensitivities through increased muscular insulin action, as well as increased hepatic glucagon sensitivity and pancreatic glucagon content.

AB - OBJECTIVE: Follistatin-like 3 (fstl3), a natural inhibitor of members of the TGF-β family, increases during resistance training in human plasma. Fstl3 primarily binds myostatin and activin A, and thereby inhibits their functions. We hypothesize that blocking myostatin and activin A signalling through systemic fstl3 over-expression protects against diet-induced obesity and insulin resistance.METHODS: Fstl3 was over-expressed by DNA electrotransfer in tibialis anterior, quadriceps and gastrocnemius muscles in female C57BL/C mice, and the mice were subsequently randomized to chow or high-fat feeding. Body weight, food intake, fat accumulation by MR scanning, and glucose, insulin and glucagon tolerance were evaluated, as was the response in body weight and metabolic parameters to 24h fasting. Effects of fstl3 on pancreatic insulin and glucagon content, and pancreatic islet morphology were determined.RESULTS: Fstl3 over-expression reduced fat accumulation during high-fat feeding by 16%, and liver fat by 50%, as determined by MRI. No changes in body weight were observed, while the weight of the transfected muscles increased by 10%. No transcriptional changes were found in the subcutaneous adipose tissue. Fstl3 mice displayed improved insulin sensitivity and muscle insulin signalling. In contrast, glucose tolerance was impaired in high-fat fed fstl3 mice, which was explained by increased hepatic glucagon sensitivity and glucose output, as well as a decrease in the pancreatic insulin/glucagon ratio. Accordingly, fstl3 transfection improved counter-regulation to 24h fasting.CONCLUSION: Fstl3 over-expression regulates insulin and glucagon sensitivities through increased muscular insulin action, as well as increased hepatic glucagon sensitivity and pancreatic glucagon content.

KW - Activins

KW - Adiposity

KW - Animals

KW - Diet, High-Fat

KW - Female

KW - Glucagon

KW - Glucose Intolerance

KW - Insulin

KW - Insulin Resistance

KW - Islets of Langerhans

KW - Liver

KW - Mice, Inbred C57BL

KW - Muscle Development

KW - Muscle, Skeletal

KW - Myostatin

KW - Proteins

KW - Random Allocation

KW - Recombinant Proteins

KW - Signal Transduction

KW - Subcutaneous Fat

KW - Up-Regulation

U2 - 10.1016/j.metabol.2014.10.007

DO - 10.1016/j.metabol.2014.10.007

M3 - Journal article

C2 - 25456456

VL - 64

SP - 283

EP - 295

JO - Metabolism

JF - Metabolism

SN - 0026-0495

IS - 2

ER -