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.