Abstract There are epidemiological associations between obesity and type 2 diabetes, cardiovascular disease and Alzheimer’s disease. The role of amyloid beta 42 (Aβ42) in these diverse chronic diseases is obscure. Here we show that adipose tissue releases Aβ42, which is increased from adipose tissue of male mice with obesity and is associated with higher plasma Aβ42. Increasing circulating Aβ42 levels in male mice without obesity has no effect on systemic glucose homeostasis but has obesity-like effects on the heart, including reduced cardiac glucose clearance and impaired cardiac function. The closely related Aβ40 isoform does not have these same effects on the heart. Administration of an Aβ-neutralising antibody prevents obesity-induced cardiac dysfunction and hypertrophy. Furthermore, Aβ-neutralising antibody administration in established obesity prevents further deterioration of cardiac function. Multi-contrast transcriptomic analyses reveal that Aβ42 impacts pathways of mitochondrial metabolism and exposure of cardiomyocytes to Aβ42 inhibits mitochondrial complex I. These data reveal a role for systemic Aβ42 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.
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