Chapter 5 - Orexins, feeding, and energy balance
Introduction
Although currently best known for their effects on sleep and arousal, when discovered in 1998, the orexin peptides were identified as regulators of feeding behavior, which also explains their name (orexis is the Greek word for appetite) (Sakurai et al., 1998). Their sleep regulatory influence was only recognized later. Screening of high-resolution high-performance liquid chromatography (HPLC) fractions in an intracellular-calcium-influx assay on multiple cells expressing individual orphan G-protein-coupled receptors resulted in the isolation of two peptides, coined orexin A and B (Sakurai et al., 1998). In the same year, an analysis of mRNAs, whose expression was restricted to or enriched in the rat hypothalamus, resulted in the isolation of a nucleotide sequence encoding a 130 residue protein called preprohypocretin (HCRT). Sequence analysis indicated that prepro-HCRT yields two peptides, HCRT-1 and HCRT-2 (deLecea et al., 1998). Chemical analyses subsequently confirmed that orexin A and B were identical to HCRT-1 and HCRT-2. Positional cloning to identify the autosomal recessive mutation that is responsible for narcolepsy in a well-established canine model revealed that the orexin peptides were the endogenous ligands of the mutated receptor that was causing narcolepsy in these dogs (Lin et al., 1999). It was subsequently discovered that, in humans, narcolepsy is accompanied by a specific destruction of orexin neurons in the hypothalamus (Peyron et al., 2000).
The neuropeptides orexin A and orexin B are expressed by a specific population of neurons in the lateral hypothalamic (LH) area (Elias et al., 1998). This region of the brain is implicated in feeding, arousal, and motivated behavior (Sakurai et al., 1998). Orexin A and B are derived from a precursor peptide, the product of the prepro-orexin gene (Sakurai et al., 1998). Two G-protein-coupled receptors, the orexin receptor type 1 (OxR1) and the orexin receptor type 2 (OxR2), respond to orexins (Sakurai et al., 1998). OxR1 and OxR2 are distributed widely but differentially throughout the brain (Vanitallie, 2006).
Lack of orexin results in narcolepsy, but later work confirmed that it also induces hypophagia. Antagonism of orexin A receptors is characterized by reduced food intake and weight reduction in rodents (Smart et al., 2002). Despite the reduced food intake, the narcoleptic patients with orexin deficiency and the animal model with genetic ablation of the orexin neurons tend to be obese (Hara et al., 2001, Kok et al., 2003). These findings indicate that the link between orexin and energy homeostasis involves an effect of orexin on appetite (Cai et al., 2001, Sakurai et al., 1998) as well as additional mechanisms implicated in the control of energy metabolism. Indeed, when orexins are administered centrally in rodents, they are reported to increase not only arousal and food intake but also blood glucose levels, sympathetic tone, plasma corticosterone levels, metabolic rate, and locomotor activity (Vanitallie, 2006, Yamanaka et al., 2003).
In this chapter, we focus on the role of orexin in the control of feeding behavior and energy homeostasis. First, we provide a detailed overview of the anatomical distribution of the orexin neurons and their projections with a focus on their relation with control of feeding behavior. Subsequently, we discuss the effects of orexin on glucose homeostasis and the connections of the orexin system with the autonomic nervous system.
Section snippets
Projections
Orexin neurons have widespread projections not only to the cerebral cortex, that is, perirhinal, sensory, and motor cortex, but also to the olfactory bulbs, the hippocampus, the amygdala, the septum, the diagonal band of Broca, the bed nucleus of the stria terminalis, the thalamus, the locus coeruleus (LC), the central gray, the dorsal raphe, the dorsal motor nucleus of the vagus nerve, and the cerebellum. Within the hypothalamus, the orexin neurons project to the ventral and dorsal parts of
Activity of orexin neurons
Hypothalamic neurons maintain body energy balance by sensing energy status and initiating adjustments in food intake and energy expenditure. Four populations of neurons are engaged in sensing glucose in the hypothalamus: (1) glucose-excited neurons, which increase their firing rate when extracellular glucose levels increase; (2) glucose-inhibited neurons, which decrease their firing rate when glucose levels increase; (3) low glucose-sensing neurons, which increase their firing rate when
Orexin neurons and regulation of food intake
Orexin mRNA expression was shown to increase during fasting (Sakurai et al., 1998) and when faced with a negative energy balance, such as during food restriction, obese mice, too, show elevated orexin mRNA expression (Yamanaka et al., 2003). A transcription factor Foxa2 is likely to mediate this phenomenon by translocating into the nucleus, binding to the orexin promoter and subsequently stimulating transcription of the orexin gene in response to fasting (Silva et al., 2009). Orexin neurons
Orexin and regulation of energy homeostasis
Recently, it has become clear that, in addition to its effects on food intake, the hypothalamic orexin system is a key player in the control of glucose metabolism. Orexin deficiency results in an age-related development of impaired glucose tolerance and insulin resistance in both male and female mice (Tsuneki et al., 2008). In line with this observation, insulin signaling through Akt/protein kinase B was markedly reduced in skeletal muscle and liver tissue of middle aged (9 months old), but not
Effects of orexin on autonomic nervous system
ICV administration of orexin not only stimulates food intake but also sympathetic outflow and body temperature (Monda et al., 2004, Yoshimichi et al., 2001), heart rate, blood pressure, and renal sympathetic nerve activity (Shirasaka et al., 1999). Since a lack of orexin signaling leads to a decrease in body temperature and physical activity, it may be hypothesized that reduced orexin signaling will result in reduced energy expenditure and ultimately in obesity, despite hypophagia (Taylor and
Concluding remarks
The expanding body of literature on this subject highlights the extensive implications of the orexin system in the regulation of food intake and energy balance (Fig. 1). Both peripheral (glucose, leptin, and ghrelin sensing) and central (i.e., SCN and ARC for example) inputs allow orexin neurons to receive information about the wakefulness and energy states of the body. The orexin system then relays its information to a number of relevant brain areas through its broad range of neural
Acknowledgments
This work was supported by Top Institute Pharma grant (project T2-105) to A. K. and a Rubicon grant to C.-X. Y.
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