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Amyloid beta 42 alters cardiac metabolism and impairs cardiac function in obesity

ABSTRACT: There are epidemiological associations between obesity and type 2 diabetes, cardiovascular disease and Alzheimer’s disease. While some common aetiological mechanisms are known, the role of amyloid beta 42 (Ab42) in these diverse chronic diseases is obscure. Here we show that adipose tissue releases Ab42, which is increased from adipose tissue of obese mice and is associated with higher plasma Ab42. Increasing circulating Ab42 levels in mice had no effect on systemic glucose homeostasis but had obesity-like effects on the heart, including reduced cardiac glucose clearance and impaired cardiac function. These effects on cardiac function were not observed when circulating Ab40 levels were increased. Administration of an Ab neutralising antibody prevented obesity-induced cardiac dysfunction and hypertrophy. Furthermore, Ab neutralising antibody administration in established obesity prevented further deterioration of cardiac function. Multi-contrast transcriptomic analyses revealed that Ab42 impacted pathways of mitochondrial metabolism and exposure of cardiomyocytes to Ab42 inhibited mitochondrial function. These data reveal a role for systemic Ab42 in the development of cardiac disease in obesity and suggest that therapeutics designed for Alzheimer’s disease could be effective in combating obesity-induced heart failure.

ORGANISM(S): Mus musculus

PROVIDER: GSE213708 | GEO | 2022/09/22

REPOSITORIES: GEO

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Project description:An intrinsic property of the heart is an ability to rapidly and coordinately adjust flux through metabolic pathways in response to physiologic stimuli (termed metabolic flexibility). Cardiac metabolism also fluctuates across the 24-hr day, in association with diurnal sleep-wake and fasting-feeding cycles. Although loss of metabolic flexibility has been proposed to play a causal role in the pathogenesis of cardiac disease, it is currently unknown whether day-night variations in cardiac metabolism are altered during disease states. Here, we tested the hypothesis that diet-induced obesity disrupts cardiac “diurnal metabolic flexibility”, which is normalized by time-of-day-restricted feeding. Chronic high fat feeding (20-wk) induced obesity in mice, abolished diurnal rhythms in whole body metabolic flexibility, and increased markers of adverse cardiac remodeling (hypertrophy, fibrosis, and steatosis). RNAseq analysis revealed that 24-hr rhythms in the cardiac transcriptome were dramatically altered during obesity; only 22% of rhythmic transcripts in control hearts were unaffected by obesity. However, day-night differences in cardiac substrate oxidation were essentially identical in control and high fat fed mice. In contrast, day-night differences in both cardiac triglyceride synthesis and lipidome were abolished during obesity. Next, a subset of obese mice (induced by 18-wks ad libitum high fat feeding) were allowed access to the high fat diet only during the 12-hr dark (active) phase, for a 2-wk period. Dark phase restricted feeding partially restored whole body metabolic flexibility, as well as day-night differences in cardiac triglyceride synthesis and lipidome. Moreover, this intervention partially reversed adverse cardiac remodeling in obese mice. Collectively, these studies reveal diurnal metabolic inflexibility of the heart during obesity specifically for non-oxidative lipid metabolism (but not for substrate oxidation), and that restricting food intake to the active period partially reverses obesity-induced cardiac lipid metabolism abnormalities and adverse remodeling of the heart.

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Amyloid beta 42 alters cardiac metabolism and impairs cardiac function in obesity

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