Described herein are methods and compositions for the prevention or treatment of obesity and obesity-related disorders. The methods and compositions are based, inter alia, on the observations that OPN3 is the most highly expressed opsin in the hypothalamus, a key site for the regulation of energy homeostasis. Indeed, OPN3 expression was highest in regions associated with energy homeostasis, namely the paraventricular nucleus and arcuate nucleus of the hypothalamus. OPN3 was shown to interact and form a complex with MC3R and MC4R, and to modulate MC3R- and MC4R-mediated signaling in the hypothalamus. Accordingly, the methods involve the regulation of melanocortin receptors by downregulating opsin 3 (OPN3) protein expression, OPN3 gene expression, and/or OPN3 activation in the hypothalamus.