A century ago, scientists discovered a hormone released from the frog pituitary gland that regulates the pigmentation of tadpoles. They called it melanocyte stimulating hormone or MSH. Decades later it was discovered that MSH, adrenocorticotropin (ACTH), which stimulates the adrenal glands to secrete cortisol, and the opioid peptide beta-endorphin are all produced from a single prohormone in the hypothalamus as well as in the pituitary gland. MSH has many essential functions in the brain including the control of appetite, energy balance and activity of the sympathetic nervous system. I will discuss how the genetic loss of brain MSH causes a unique obesity syndrome and accompanying metabolic disturbances in humans, mice and Labrador retrievers.