Over the last thirty years, researchers have come to appreciate the hugely important role of a tiny group of neurons in the hypothalamus, and their influence on both feeding and sleeping behaviour. Perhaps once dismissed as insignificant, we are now beginning to understand how a relatively miniscule group of cells in the lateral hypothalamus (described shortly) could be linked with everything from wakefulness to addiction to overeating.
To be clear, the hypothalamus is the body’s main control centre. The hypothalamus guides thirst, eating motivation, and sexual behaviour. For this reason, it has occupied a large focus area in obesity related research. In a crude way, obesity is the manifestation of the body’s failure to metabolize energy, which ultimately is guided by hypothalamic signalling. However, in recent years we have come to appreciate that pleasure- not physiological need- is a bigger issue in overeating behavior. Thus, understanding what contributes to hypothalamic guidance of eating is hugely relevant, both to obesity researchers, those interested in the brain and behaviour, and more broadly speaking anyone who suffers with sleeping or eating issues. Critically, this group of neurons may hold an important clue.
So, back to orexin, or the name for this group of neurons. There are only around 20,000 of them compared to the brain’s 80 billion. It has now been established that, despite their tiny numbers, these neurons (and their corresponding neuropeptide) play a key role in a wide variety of vital functions, which range from regulating patterns of sleep and wakefulness, to the experience of pleasure and perception of pain. Their role in obesity also demonstrates the hugely complex interplay of chemical interactions that guide human behaviour and reveal how just a single, tiny, deviation in normal brain activity can result in enormous problems for people in everyday life.
Because the neuropeptide involved was discovered simultaneously by two independent groups it is known as both ‘orexin’ and ‘hypo cretin’. Orexin, a name chosen by a group of molecular biologists based at the Howard Hughes Medical Insitute in Texas, was taken from the Greek ‘orexis’, meaning ‘appetite’. Hypo cretin, the choice of scientists, at Scripps in California, refers to the hypothalamically derived neuropeptide that bears significant similarity to ‘secretin’ produced in the gut. The scientific community currently uses both names interchangeably. Can I cut in for a moment? Both ‘orexin’ and ‘hypocretin’ sound equally awful. In the case of the former, it feels overtly sexual, and in the latter a hyphenated insult. I’m not really sure as scientists we have perfected the art of how to name, market, and therefor sell certain parts of the body. A rose by any other name may smell as sweet, but can this apply to a hormone called orexin…?
Orexin neurons provide a crucial link between energy balance and the coordination of mood, reward, addiction and arousal. Dysregulation of this infinitesimally tiny brain region produces to some terrifying physiological and psychological consequences. These include a tendency to fall sleep in the presence of stress or emotional arousal. Such ‘sleep attacks’, known as narcolepsy and cataplexy, can be as frustrating as they are dangerous. Narcoleptics may put their life in jeopardy falling into immediate deep sleep, resulting in injuries ranging from bruises to serious trauma. To add to their problems, narcoleptics are often overweight despite never overeating. (1) In the laboratory mice whose orexin neurons have been removed (a process called ‘ablation’) exhibit late-onset obesity despite never being allowed to overeat.(2)
While its location in the hypothalamus is indicative of orexin’s role in guiding homeostatically driven hunger, its direct connection with the reward pathway, via the Nucleus Accumbens, suggests it could be involved in both homeostatic and hedonically driven eating. The link between orexin and drug taking further suggest it might be an important focus for minimizing the pleasurable feeling associated with either drug abuse, or overeating hyper palatable food. Further, it responds to peripheral signals such as leptin and glucose. So, in addition to its implication in the reward system (by virtue the reception of signals from the VTA), and its location in the hypothalamus (homeostatic hunger centre) it also responds to signals within the body. Collated, these points suggest orexin would play an important role in contributing to eating behaviour.
One possible way in which the discovery of orexin might enable us to control obesity is through the development of an orexin receptor ‘antagonist’. That is a drug that would block the uptake of the neuropeptide so increasing wakefulness and arousal. The administration of orexin antagonists in mice, for example, has been found to suppress weight gain in mice on a high-fat diet (3). It has been suggested such a drug could also be useful for treating a wide range of conditions from the withdrawal symptoms of drug addiction, to the control of pain and dysfunctional management of excessive stress. (4)
A critical difficulty with creating pharmacological intervention for obesity, or any disorder of hedonic excess, is the complex interaction between hedonic and homeostatic systems. There is not one area of the brain that must be targeted, but several. With the discovery of orexin researchers may be getting closer to appropriate targets that are involved in both homeostatic and pleasure driven sensations implicated in the progress towards compulsive appetitive behaviour.
- Lammers GJ, Pijl H, Iestra J, Langius JA, Buunk G, and Meinders AE (1996) Spontaneous food choice in narcolepsy. Sleep 19:75–76) (REF: Schuld A, Hebebrand J, Geller F, and Pollmacher T (2000) Increased body-mass index in patients with narcolepsy. Lancet 355:1274 –1275.
- Hara J, Beuckmann CT, Nambu T, Willie JT, Chemelli RM, Sinton CM, Sugiyama F, Yagami K, Goto K, Yanagisawa M, et al. (2001) Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity. Neuron 30:345–354.
- Funato H, Tsai AL, Willie JT, Kisanuki Y, Williams SC, Sakurai T, and Yanagisawa M (2009) Enhanced orexin receptor-2 signaling prevents diet-induced obesity and improves leptin sensitivity. Cell Metab 9:64 –76.),
- Kajiyama et al., 2005; Mobarakeh et al., 2005; Xie et al.,2008).