A short duration of high-fat diet induces insulin resistance and predisposes to adverse left ventricular remodeling after pressure overload

Abstract

Insulin resistance is an increasingly prevalent condition in humans that frequently clusters with disorders characterized by left ventricular (LV) pressure overload, such as systemic hypertension. To investigate the impact of insulin resistance on LV remodeling and functional response to pressure overload, C57BL6 male mice were fed a high-fat (HFD) or a standard diet (SD) for 9 days and then underwent transverse aortic constriction (TAC). LV size and function were assessed in SD- and HFD-fed mice using serial echocardiography before and 7, 21, and 28 days after TAC. Serial echocardiography was also performed on nonoperated SD- and HFD-fed mice over a period of 6 wk. LV perfusion was assessed before and 7 and 28 days after TAC. Nine days of HFD induced systemic and myocardial insulin resistance (assessed by myocardial 18F-fluorodeoxyglucose uptake), and myocardial perfusion response to acetylcholine was impaired. High-fat feeding for 28 days did not change LV size and function in nonbanded mice; however, TAC induced greater hypertrophy, more marked LV systolic and diastolic dysfunction, and decreased survival in HFD-fed compared with SD-fed mice. Compared with SD-fed mice, myocardial perfusion reserve was decreased 7 days after TAC, and capillary density was decreased 28 days after TAC in HFD-fed mice. A short duration of HFD induces insulin resistance in mice. These metabolic changes are accompanied by increased LV remodeling and dysfunction after TAC, highlighting the impact of insulin resistance in the development of pressure-overload-induced heart failure.

Fig. 1.

Systemic insulin sensitivity in standard diet (SD; ○) and high-fat diet (HFD; •) fed mice. A: intraperitoneal glucose tolerance test obtained in 7 SD- and 8 HFD-fed mice. B: intraperitoneal insulin tolerance test obtained in 12 SD- and 9 HFD-fed mice. Values are means ± SE. *P < 0.05 vs. SD.

Fig. 2.

Myocardial ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) uptake on micro-positron emission tomography (micro-PET) before and after HFD. A: representative myocardial ¹⁸F-FDG uptake 45 min after ¹⁸F-FDG injection in a mouse before (Before HFD) and after 9 days of HFD (After HFD). B: myocardial ¹⁸F-FDG uptake 45 min after ¹⁸F-FDG injection in 5 mice before and after 9 days of HFD. Myocardial ¹⁸F-FDG uptake is expressed in percentage of injected dose/ml tissue. Myocardial ¹⁸F-FDG uptake decreased after 9 days of HFD feeding.

Fig. 3.

A and B: cardiomyocyte width (white arrows) measured in a SD- (A) and a HFD-fed (B) mouse, 28 days after transverse aortic constriction (TAC). C and D: capillary density measured in a SD- (C) and a HFD-fed (D) mouse 28 days after TAC. Cardiomyocyte width was greater, and capillary density was decreased, 28 days after TAC in mice fed a HFD. LF, low fat.

Fig. 4.

Survival after TAC in mice fed a SD or HFD. Survival after TAC was decreased in HFD-fed mice compared with SD-fed mice. *P < 0.02.

Fig. 5.

Expression of malonyl CoA decarboxylase before and 7 days after TAC in mice fed a SD or a HFD. *P < 0.05 vs. SD 7 days after TAC.