DPP-4 inhibition improves NALFD and the associated cardiac diastolic dysfunction in a mouse model of western diet induced obesity

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SAT 723-745-Lipids: Fatty Liver Disease & Lipodystrophies
Basic/Clinical
Saturday, June 15, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SAT-730
Annayya Aroor*1, Ravi Nistala1, Adam T Whaley-Connell2, Vincent DeMarco1 and James R Sowers1
1University of Missouri, Columbia, MO, 2Harry S Truman Memorial Veterans Hospital, Columbia, MO
Background and significance  Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease, with a prevalence of 20-33% of the Western population.  In overweight and obese persons with insulin (INS) resistance, cardiac diastolic dysfunction often develops concurrently with NAFLD.  Recently, DPP-4 inhibition has been shown to improve hepatic steatosis, but its effects on diastolic dysfunction in the presence of NAFLD have not been reported.

Methods We fed C57BL/6  male mice with a western diet (WD) (high fat and fructose) for 16 weeks and  measured INS resistance (HOMA-IR), cardiac diastolic dysfunction  (echocardiography), plasma alanine amino transaminase (ALT) levels, hepatic triglycerides, and  plasma DPP-4 activity.   We further investigated the effect of the DPP-4 inhibitor MK0626 on these parameters in mice on a WD.

Results   Compared to mice on a regular chow diet, both INS resistance and diastolic dysfunction were present after 8 weeks on a WD.  After 16 weeks of WD, there was a progression in the level of diastolic dysfunction which was accompanied by progressive increases in liver and body weight. The increase in liver weight was accompanied by an increase in plasma DPP-4 activity, hepatic triglycerides, and plasma ALT levels. DPP-4 inhibition treatment begun concurrently with the WD (4weeks of age) substantially reduced plasma DPP-4 activity and improved INS resistance. This was accompanied by improvement in diastolic dysfunction, serum ALT, hepatic triglyceride levels, and plasma DPP-4 activity and levels.

Conclusion  We have developed a clinically translational mouse model (WD) of obesity and INS resistance which is accompanied by NAFLD and cardiac diastolic dysfunction which is improved by administration of a DPP-4 inhibitor.

Disclosure: RN: Principal Investigator, Merck & Co.. JRS: Advisory Group Member, Merck & Co.. Nothing to Disclose: AA, ATW, VD

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

Sources of Research Support: Supported by NIH R01HL73101, NIH R01 HL107910 (JRS) and AG040638 (AWC) and VA Merit (JRS) CDA-2 (AWC), and Merck IIT (RN).