Figure 2. Conceptual framework for role of hypothalamic autophagy in food intake and energy balance. (A) During starvation hypothalamic uptake of increased circulating free fatty acids (FFA) leads to induction of neuronal autophagy. The immediate fate of the FFA is triglyceride synthesis within neuronal lipid droplet (LD). Activated autophagy breaks down LDs to generate neuron-intrinsic FFA that increase AgRP expression to promote food intake. (B) Genetic and/or pharmacological inhibition of autophagic degradation of lipids, lipophagy, leads to increased neuronal LDs, and reduced levels of FFA and AgRP in response to starvation. Blocking autophagy in AgRP neurons in vivo increased hypothalamic levels of POMC and its cleavage product α-MSH that contributed to decreased food intake in response to fasting, and increased peripheral energy expenditure.