OR08-5 SRA Gene Knockout Protects Against Diet-Induced Obesity and Improves Glucose Tolerance

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: OR08-Obesity: Novel Mechanisms of Body Weight Regulation
Saturday, June 15, 2013: 11:30 AM-1:00 PM
Presentation Start Time: 12:30 PM
Room 301 (Moscone Center)
Shannon Liu1, Hongzhi Miao1, Liang Sheng1, Thomas L Saunders2, Ormond A MacDougald2, Ronald J Koenig3 and Bin Xu*4
1University of Michigan, 2University of Michigan, Ann Arbor, MI, 3Univ of Michigan Med Ctr, Ann Arbor, MI, 4The Univ of Michigan, Ann Arbor, MI
We have recently shown that the Steroid Receptor RNA Activator (SRA), promotes adipocyte differentiation and improves insulin-stimulated glucose uptake in adipocytes in vitro through multiple mechanisms, such as coactivating transcriptional activity of PPARΥ, promoting S-phase entry during mitotic clonal expansion, increasing phosphorylation of Akt and FOXO1 in response to insulin, and inhibiting expression of adipocyte-related inflammatory genes. To assess SRA function in vivo, we have generated a whole mouse SRA gene knockout (SRA-/-). Here, we show that the SRA gene is an important regulator of fat mass and function. SRA is expressed at higher levels in both brown and white adipose tissues (BAT, WAT) than other organs in wild type mice. SRA-/- mice are resistant to diet-induced obesity, weighing on average 6 g less after 14 weeks on a high fat diet. Body composition analysis showed the whole mouse fat content decreased from 28% (wild type) to 17% (SRA-/-). This lean phenotype of SRA-/- mice is associated with decreased expression of a subset of WAT genes including C/EBPα and FABP4, as well as decreased expression of the inflammatory genes TNFα and CCL2. The SRA-/- mice are more insulin sensitive, as evidenced by reduced fasting insulin despite unchanged blood glucose, as well as lower blood glucoses in response to IP glucose and insulin. In addition, the livers of SRA-/- mice had fewer lipid droplets after high fat feeding, and the expression of lipogenesis-associated genes was decreased. At the end of the high fat feeding, energy expenditure (CLAMS analysis) and food intake showed no significant change. In summary, we have created a whole mouse SRA knockout, and found that these mice are resistant to diet-induced obesity, with decreased fat, decreased expression of a subset of adipocyte genes, and improved insulin sensitivity. These data indicate an important role for SRA in adipose tissue biology in vivo.

Nothing to Disclose: SL, HM, LS, TLS, OAM, RJK, BX

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

Sources of Research Support: This research was supported by a Pilot and Feasibility Grant and the Cell and Molecular Biology Core of the Michigan Diabetes Research and Training Center (NIH Grant 5P60-DK020572) (B.X.)