UCSF

Proper control of feeding is essential to the fitness of animals. This process involves transformation of homeostatic needs into behavioral control by specialized circuits in the hypothalamus. Agouti-related peptide (AgRP) and proopiomelanocortin (POMC) neurons in the arcuate nucleus (ARC) play dominant roles in this process: they integrate homeostatic information and control feeding. Altogether, 20 years of rigorous research has led to a comprehensive model of the homeostatic control of feeding through the arcuate circuit; this model is described in detail in Chapter 1. Nevertheless, it remains unclear how AgRP and POMC neurons are regulated in vivo.

In the Chapter 2 of this dissertation, we show the first recording of AgRP and POMC neuron activity in vivo during feeding. Contrary to past models, these key feeding neurons do not simply represent the current energy state of the body. Instead they anticipate future homeostatic consequences based on sensory cues associated with food. We discuss the implication of this finding extensively in Chapter 3.

In Chapters 4 and 5, we address two questions: how are homeostatic signals integrated in vivo in the arcuate feeding circuit in the context of the dominant sensory regulation, and how do AgRP neurons drive food intake despite the fact that their activity is reset before food consumption even starts? We show in Chapter 3 that sensory cues, intragastric nutrients and hormones converge onto AgRP neurons to estimate energy balance on different timescales. We then show in Chapter 4 that AgRP neurons promote food intake through a hunger signal that persists for tens of minutes and potentiates the reward value of food.