Utilizing an endothelial-specific TRPC1 knockout mouse model, this study reveals that TRPC1 deficiency, while not influencing the onset of obesity, exacerbates obesity-associated metabolic complications through the remodeling of the adipose tissue inflammatory microenvironment, impairment of thermogenic function, and disruption of serum metabolomic profiles. Here, TRPC1 is linked to obesity due to melanocortin 4 receptor deficiency.