Molecular Genetic Studies

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Destruction of orexin neurons in human narcolepsy is accompanied not only by abnormal sleep/wake regulation but also by metabolic alterations (22,23). The finding of decreased caloric intake (24) combined with an increased body mass index (23) in narcolepsy suggests that narcolepsy patients have a feeding abnormality with reduced energy expenditure or low metabolic rate. Because narcolepsy is caused by orexin deficiency, the altered energy home-ostasis in human narcolepsy patients suggests roles of orexin in regulation of energy home-ostasis (22,23). Consistently, orexin neuron-ablated mice show hypophagia and late-onset obesity (25). Complex disruptions of energy homeostasis in orexin/ataxin-3 transgenic mice are indicated by hypophagia (Fig. 3), obesity, and inactivity relative to control litter mates (25,26). Orexin knockout mice were also showed to be hypophagic (27). The decreases in food intake observed in orexin knockout or orexin neuron-ablated mice suggest the physiological roles of orexins in support of feeding behavior.

Studies from orexin knockout mice, orexin neuron-ablated mice, and narcolepsy patients showed that chronic deficiency of orexins could result in obesity despite hypophagia (23,25,27). Although we have found that the development of obesity observed in orexin-deficient mice

Fig. 4. A schematic drawing of the mechanisms by which orexins induce food intake. Orexin neurons activate neuropeptide Y (NPY) ergic neurons and inhibit pro-opiomelanocortin (POMC) neurons in the arcuate nucleus to increase food intake. Orexin neurons also regulate monoaminergic/cholinergic nuclei in the brainstem to maintain arousal and support motivation for reinforcing feeding behavior.

Fig. 4. A schematic drawing of the mechanisms by which orexins induce food intake. Orexin neurons activate neuropeptide Y (NPY) ergic neurons and inhibit pro-opiomelanocortin (POMC) neurons in the arcuate nucleus to increase food intake. Orexin neurons also regulate monoaminergic/cholinergic nuclei in the brainstem to maintain arousal and support motivation for reinforcing feeding behavior.

is dependent of genetic background (our unpublished observation), these observations suggest altered energy homeostasis in orexin-deficient narcolepsy. On the other hand, acute pharmacological blockade of orexin-1 receptor (OXjR) results in hypophagia and decreased body weight (10). This paradoxical phenomenon might suggest that receptor blockade is necessary for developing obesity. In fact, we observed that OX1R knockout mice do not develop obesity (our unpublished observation). It is also possible that chronic disruption of orexin signaling by gene targeting and acute or semichronic blockade of orexin receptor might have different impacts on the orexin-mediated feeding pathway and an orexin-mediated increase in metabolic rate.

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Your Metabolism - What You Need To Know

Your Metabolism - What You Need To Know

If you have heard about metabolism, chances are it is in relation to weight loss. Metabolism is bigger than weight loss, though, as you will learn later on. It is about a healthier, better you. If you want to fire up your metabolism and do not have any idea how to do it, you have come to the right place. If you have tried to speed up your metabolism before but do not see visible results, you have also come to the right place.

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