Obesity and Insulin Resistance Induce Early Development of Diastolic Dysfunction in Young Female Mice Fed a Western Diet

Abstract

Cardiovascular disease (CVD), including heart failure, constitutes the main source of morbidity and mortality in men and women with diabetes. Although healthy young women are protected against CVD, postmenopausal and diabetic women lose this CVD protection. Obesity, insulin resistance, and diabetes promote heart failure in females, and diastolic dysfunction is the earliest manifestation of this heart failure. To examine the mechanisms promoting diastolic dysfunction in insulin-resistant females, this investigation evaluated the impact of 8 weeks of a high-fructose/high-fat Western diet (WD) on insulin sensitivity and cardiac structure and function in young C57BL6/J female versus male mice. Insulin sensitivity was determined by hyperinsulinemic-euglycemic clamps and two-dimensional echocardiograms were used to evaluate cardiac function. Both males and females developed systemic insulin resistance after 8 weeks of a WD. However, only the females developed diastolic dysfunction. The diastolic dysfunction promoted by the WD was accompanied by increases in collagen 1, a marker of stiffness, increased oxidative stress, reduced insulin metabolic signaling, and increased mitochondria and cardiac microvascular alterations as determined by electron microscopy. Aldosterone (a promoter of cardiac stiffness) levels were higher in females compared with males but were not affected by the WD in either gender. These data suggest a predisposition toward developing early diastolic heart failure in females exposed to a WD. These data are consistent with the notion that higher aldosterone levels, in concert with insulin resistance, may promote myocardial stiffness and diastolic dysfunction in response to overnutrition in females.

Regional variation in arterial stiffening and dysfunction in Western diet-induced obesity

“…Although not specifically examined in this study, it is likely that reduced NO bioavailability owing to increased oxidative stress contributes to WD-induced femoral vasodilator dysfunction. We have previously reported increased oxidative stress in this model of WD feeding (28,33). Impaired endothelial function may underlie the structural remodeling of the femoral artery, since endothelium-derived substances (i.e., NO) modulate structural components of the vascular wall.…”

Catabolism of (2E)-4-Hydroxy-2-nonenal via ω- and ω-1-Oxidation Stimulated by Ketogenic Diet

“…The dramatic increase ofand -1-hydroxylation of HNE in KG liver correlates well with observations of lower [HNE] compared with the other diets. HF-HC diet (Western diet) induces obesity and diabetes (39). KG diet with extremely high fat composition has been used worldwide for refractory childhood epilepsy (40).…”

Perilipin-2 Deletion Impairs Hepatic Lipid Accumulation by Interfering with Sterol Regulatory Element-binding Protein (SREBP) Activation and Altering the Hepatic Lipidome

“…WD-induced obesity is associated with glucose utilization abnormalities linked to insulin resistance (14). To determine whether protection from obesity by PLIN2 deletion in WD-fed mice also confers protection against abnormalities in glucose utilization, we determined serum glucose responses to intraperitoneal (i.p.)…”