HNF4A and Insulin resistance: Specifically, the whole-body overexpression of human PGC-1α increases the expression of HNF4α and gluconeogenic enzymes PEPCK and G6P in the liver, and causes hepatic insulin resistance, while insulin sensitivity is improved in muscle.573 Likewise, short-term CR and endurance training differently affect energy metabolism and mitochondrial biogenesis in the cardiac and skeletal muscle.370,740 In one aspect, this emphasizes the necessity of conducting tissue-specific deficiency or overexpression models.