FP33-2 Follistain like 3 overespression improves insulin sensitivity in diet induced obese female mice

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: FP33-Insulin Signaling & Inflammation
Monday, June 17, 2013: 10:45 AM-11:15 AM
Presentation Start Time: 10:50 AM
Room 303 (Moscone Center)

Poster Board MON-843
Claus Brandt*1, Rasmus Hvass Hansen2, Bente Klarlund Pedersen3 and Pernille Hojman4
1Centre of Inflammation and Metabolism, Department of Infectious Diseases and CMRC, Rigshospitalet, Faculty of Health Science, University of Copenhagen, Denmark, Copenhagen, Denmark, 2Research Group, Dept. of Radiology, Copenhagen University Hospital, Herlev, Copenhagen, Denmark, 3Rigshospitalet, copenhagen, Denmark, 4The Centre of Inflammation and Metabolism, Department of Infectious Diseases and CMRC, Rigshospitalet, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
Introduction and aim.

Myostatin a TGF beta super family member secreted primarily from skeletal muscle is a negative regulator of skeletal muscle mass. Recently, myostatin been implicated in the pathogenesis of type 2 diabetes. Elevated levels of myostatin protein have been found in muscle from diabetic and obese subjects. In mice injection of recombinant myostatin in mice decreased akt phosphorylation in response to insulin. Follistatin like 3 (fstl3) binds and inhibits the function of myostatin in both human and mice serum. Like myostatin Fstl3 has been found to be released from skeletal muscle. Similar myostatin, changes in Fstl3 has been linked to glucose metabolism in humans. Low plasma levels of fstl3 was associated with glucose intolerance and the development of gestational diabetes mellitus.

Therefore the aim of this study was to investigate the effect of an increase in the endogen myostatin inhibitor fstl3 on metabolic function in a mouse model of diet induced obesity.


We overexpressed fstl3 in female mice muscles using DNA electrotransfer to generate a mouse model with increased circulating levels of fstl3.  MR scan was used to quantify fat volume, fat distribution and liver fat. Insulin and glucose tolerance test was used to access metabolic function. Tissue was dissected and frozen for protein and mRNA analysis.


DNA electrotransfer increased fstl3 in the circulation ~ 3 times and lasted for  12 weeks. Overexpression of follistatin like 3 did not alter body weight or food intake. However, a 18 % reduction in fat volume and lower lever lipid was observed with MR. Muscle mass did increase only in the transfected muscle not nearby untransfected muscles. At 5 and 10 weeks, fstl3 mice on a high fat diet tended to have lower fasting glucose and insulin. There was no effect of fstl3 overexpression in mice on a regular chow diet. The glucose lowering effect of exogenous insulin was significantly higher in fstl3 mice on a high fat diet, and this was associated with increased Akt phoshorylation in skeletal muscle, but not adipose tissue or liver.  Interestingly glucose tolerance was not affected by the elevated fstl3 on either diet. After 12 weeks AMPK phosphorylation (Thr172) was increased in transfected muscle on either diet.


A modest elevation in circulating fstl3 resulted in lower fat accumulation in female mice fed a high fat diet for 12 weeks. This resulted in lower glucose levels and increased Akt phosphorylation when the mice were injected with insulin. This effect was largely independent of muscle mass, but related to an increase in AMPK phosphorylation in skeletal muscle.

Nothing to Disclose: CB, RH, BKP, PH

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: The Centre of Inflammation and Metabolism (CIM) is supported by a grant from the Danish National Research Foundation (# 02-512-55). This study was further supported by the Danish Council for Independent Research – Medical Sciences, the Commission of the European Communities (Grant Agreement no. 223576 - MYOAGE) CIM is part of the UNIK Project: Food, Fitness & Pharma for Health and Disease, supported by the Danish Ministry of Science, Technology, and Innovation. CIM is a member of DD2 - the Danish Center for Strategic Research in Type 2 Diabetes (the Danish Council for Strategic Research, grant no. 09-067009 and 09-075724). The Copenhagen Muscle Research Centre is supported by a grant from the Capital Region of Denmark