Recent work has cast a spotlight on the brain as a nutrient-sensing organ that regulates the body's metabolic processes. Here we discuss the physiological and molecular mechanisms of brain lipid sensing and compare these mechanisms to liver lipid sensing. A direct comparison between the lipid-sensing mechanisms in the brain and liver reveals similar biochemical/molecular but opposing physiological mechanisms in operation. We propose that an imbalance between the lipid-sensing mechanisms in the brain and liver may contribute to obesity-associated type 2 diabetes.