Targeting AgRP neurons to maintain energy balance: Lessons from animal models

The current obesity epidemic is a major worldwide health and economic burden. In the modern environment, an increase in the intake of high-fat and high-sugar foods plays a crucial role in the development of obesity by disrupting the mechanisms governing food intake and energy balance. Food intake and whole-body energy balance are regulated by the central nervous system through a sophisticated neuronal network located mostly in the hypothalamus. In particular, the hypothalamic arcuate nucleus (ARC) is a fundamental center that senses hormonal and nutrient-related signals informing about the energy state of the organism. The ARC contains two small, defined populations of neurons with opposite functions: anorexigenic proopiomelanocortin (POMC)-expressing neurons and orexigenic Agouti-related protein (AgRP)-expressing neurons. AgRP neurons, which also co-produce neuropeptide Y (NPY) and γ-Aminobutyric acid (GABA), are involved in an increase in hunger and a decrease in energy expenditure. In this review, we summarize the key findings from the most common animal models targeting AgRP neurons and the tools used to discern the role of this specific neuronal population in the control of peripheral metabolism, appetite, feeding-related behavior, and other complex behaviors. We also discuss how knowledge gained from these studies has revealed new pathways and key proteins that could be potential therapeutic targets to reduce appetite and food addictions in obesity and other diseases.