Metabolic Influence on the Hypocretin/Orexin Neurons

Abstract

The reciprocal connection between hypocretin neurons and body energy balance was recognized essentially at the moment of their discovery, when Sakurai et al. showed that (1) intracerebroventricular injection of orexin-A/hypocretin-1 dose dependently increases food intake and (2) prepro-orexin/hypocretin mRNA levels in the lateral hypothalamus are upregulated by fasting [1]. Thus, very early on, the hypocretin system was viewed as a feeding–promoting system activated by falling body energy levels, and this picture is still accurate. However, it is important to note that the net impact of hypocretin cell activity on body weight is probably either insignificant or negative, and not positive as would be expected from a purely feeding-promoting system. This is because hypocretin cell activity also stimulates metabolism, and this “energy-burning” action of hypocretins is presumably greater then their “energy-obtaining” role, since destruction of hypocretin cells leads to late-onset obesity thought to be due to a reduction of energy expenditure [2]. Thus it is more accurate to view the hypocretin system as an orchestrator network that engages multiple processes – wakefulness, hunger, reward-seeking behavior, increased locomotor activity – that help to facilitate successful food seeking. This orchestration is thought to be carried out by diverse projections of hypocretin neurons to wakefulness, reward, breathing, and autonomic centers [3, 4]. This chapter will focus on hypocretin neurons themselves and review evidence supporting the idea that unlike most other neurons in the brain, hypocretin cells act as specialized electrical sensors of ambient nutrient levels, and hence their impact on brain state may critically depend on body energy balance.