Intestinal-specific ERβ knockout mice and ChIP-seq data demonstrate that ERβ in the colon is a regulator of both Bmal1 and Npas2. This study opens up new insights, where ERβ exhibits beneficial action against deleterious effects of diet-induced obesity on colon microenvironment. This evidence concerns the gene NPAS2 and obesity due to melanocortin 4 receptor deficiency.