ESRRA and obesity due to melanocortin 4 receptor deficiency: Both tissues also crosstalk with other tissues to maintain metabolic homeostasis in response to environmental and physiological stresses, such as fasting, CR, exercise, etc. Therefore, disturbances in liver and BAT nutrient- and energy-sensing pathways, such as MTOR and AMPK, can lead to decreased ESRRA expression or activity and contribute to the development of metabolic disorders, such as obesity, non-alcoholic fatty liver disease (NAFLD), steatohepatitis (NASH), insulin resistance, and type 2 diabetes.