Metabolic disorders, such as obesity and type 2 diabetes, are associated with an increased risk of cardiomyopathy. To date, microRNA (miRNAs) functions in cardiac remodeling induced by obesity remain to be elucidated. We found that rats fed a high fat diet (HFD) manifested cardiac fibrosis and LV dysfunction. In the heart of rats fed HFD, the phosphorylation levels of Smad 2 and the expression of fibrotic genes, such as connective tissue growth factor, collagen-1 alpha 1 (Col1 alpha 1), Col3 alpha 1, and Col4 alpha 1, were up-regulated, which accompanied by an increase in Smad 7 protein levels, but not its mRNA levels. Using miRNA microarray analysis, we showed that the miRNA miR-410-5p inhibited the protein expression of Smad 7, thus increasing the phosphorylation levels of Smad 2. Overexpression of miR410-5p promoted cardiac fibrosis in rats fed normal diet, whereas inhibition of miR-410-5p by way of miR-410-5p antimiR suppressed cardiac fibrosis in rats fed HFD. Finally, our data revealed that miR410-5p from the kidney and adipose tissues was probably transferred to heart to induce cardiac fibrosis. Taken together, our study characterizes an endocrine mechanism in which adipose-or kidney-derived circulating miR-410-5p regulates metabolic disorders-mediated cardiac remodeling by activating the TGF beta/Smad signaling in heart.