Identifying safe and effective methods of regulating obesity associated weight gain is problematic. This technology represents a novel method for treating or preventing diet-induced obesity and one or more of its sequelae by inhibiting RP105 (radioprotective protein 105kDa) expression and/or MD-1 expression. Researchers demonstrated that RP105 deficient mice were protected from diet-induced weight gain when on a high fat diet. shRNA or siRNA or a precursor therof against RP105 and/or MD-1 can be used to inhibit expression of RP105 and/or MD-1 and prevent diet-induced obesity. This method represents a novel way to regulate diet-induced weight gain in obesity.