Mutations resulting in defects of the leptin receptor in the hypothalamus may occur. These mutations result in early-onset obesity and hyperphagia despite normal or elevated leptin levels, along with hypogonadotropic hypogonadism, and defective thyrotropin secretion.

Murray et al first reported on a sequence variant within the leptin gene that enhances the intrinsic bioactivity of leptin, but which was associated with reduced weight rather than obesity.  This sequence variant within the leptin gene is also associated with delayed puberty.