Together, our results demonstrate that C29-mediated suppression of the stable and activated ERRα3SA protein enhances whole-body insulin sensitivity as well as provides anti-obesity, anti-hyperglycemia/insulinemia/triglyceridemia, and anti-hepatic steatosis effects in HFD-fed ERRα3SA mice. The gene discussed is INS; the disease is obesity due to melanocortin 4 receptor deficiency.