Abstract
BACKGROUND: Obesity and hypertension are among the most prevalent comorbidities in heart failure with preserved ejection fraction (HFpEF). In addition to its relationship with hypertension in HFpEF, obesity is also strongly associated with insulin resistance (IR) and type 2 diabetes (T2D). However, the exact cardiac effects underlying this relationship are unknown. We sought to differentiate the cardiac phenotype associated with increased adiposity in the presence or absence of IR in obese HFpEF. We utilized adipose tissue-specific MitoNEET transgenic mice, which develop chronic, metabolically healthy adipose tissue expansion (obese non-insulin resistant, OB-NIR), and compared them with their wild-type, insulin-resistant littermates (OB-IR). METHODS: OB-NIR MitoNEET and OB-IR wildtype mice were fed a high-fat diet for 16 weeks, at which time HFpEF was induced via uninephrectomy, d-aldosterone infusion, and 1.0% sodium chloride drinking water for 4 additional weeks while maintained on the same diet. RESULTS: OB-NIR HFpEF mice exhibited reduced cardiac fibrosis without changes in hypertrophy. This reduction was accompanied by increased cardiac expression of SIRT3. Upregulation of several downstream mitochondrial targets of SIRT3 was also observed. These included mitochondrial fission protein 1 (Fis1), a critical regulator of mitochondrial dynamics, and the antioxidant enzyme heme oxygenase-1 (Hmox1). In contrast, levels of hydroxy-3-methylglutaryl coenzyme A (CoA) synthase 2 (HMGCS2) were decreased, while both 3-hydroxybutyrate dehydrogenase 1 (Bdh1) and succinyl-CoA:3-ketoacid CoA transferase (Oxct1) were elevated. Furthermore, genes involved in the electron transport chain, such as ubiquinol-cytochrome C reductase hinge protein (Uqcrh, Complex III) and mitochondrially encoded cytochrome c oxidase I (Mt-Co1, Complex IV), were upregulated. DISCUSSION: Distinct alterations in cardiac mitochondrial function were observed depending on the presence or absence of IR in obese HFpEF mice. These findings suggest that SIRT3 may play a central role in mediating mitochondrial adaptations in the heart and could represent a promising therapeutic target in HFpEF.