Hypothalamic Orexin Neurons Regulate Arousal According to Energy Balance in Mice

Yamanaka, Akihiro; Beuckmann, Carsten T.; Willie, Jon T.; Hara, Junko; Tsujino, Natsuko; Mieda, Michihiro; Tominaga, Makoto; Yagami, Ken Ichi; Sugiyama, Fumihiro; Goto, Katsutoshi; Yanagisawa, Masashi; Sakurai, Takeshi

doi:10.1016/s0896-6273(03)00331-3

Cited by 842 publications

(824 citation statements)

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“…Orexin neurons are known to discharge during active waking [41], and the excitability is inhibited by glucose [1,4,6]. In addition, changes in blood glucose levels negatively correlate with expression of the gene encoding prepro-orexin in the mouse hypothalamus [11].…”

Section: Discussionmentioning

confidence: 99%

“…This may explain why the incidence of type 2 diabetes increases in orexin-deficient human narcolepsy without severe obesity. Furthermore, the expression of the gene for preproorexin is downregulated in diabetic ob/ob and db/db mice [47], and the downregulation is shown to be due to hyperglycaemia in these animals [4]. These suggest that diabetic hyperglycaemia reduces the expression of the gene for prepro-orexin in the hypothalamus, and thereby further worsens the insulin resistance.…”

Section: Irmentioning

confidence: 97%

“…Orexin neurons are localised in the posterolateral hypothalamus and project into the entire brain except the cerebellum [1]. Electrophysiological studies on hypothalamic slices have shown that orexin neurons are responsive to peripheral metabolic cues [4,5]. The excitability of orexin neurons was inhibited by glucose and leptin, indicators of high energy levels, whereas ghrelin, a signal for energy depletion, caused a stimulatory effect.…”

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confidence: 99%

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Age-related insulin resistance in hypothalamus and peripheral tissues of orexin knockout mice

et al. 2008

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Aims/hypothesis Orexin/hypocretin is a hypothalamic neuropeptide that regulates motivated behaviours, such as feeding and arousal, and, importantly, is also involved in energy homeostasis. The aim of this study was to reveal the role of orexin in the regulation of insulin sensitivity for glucose metabolism. Methods Orexin knockout mice fasted overnight underwent oral glucose tolerance testing and insulin tolerance testing. The impact of orexin deficiency on insulin signalling was studied by Western blotting to measure levels of Akt phosphorylation and its upstream and downstream molecules in the hypothalamus, muscle and liver in orexin knockout mice. Results We found that orexin deficiency caused the agerelated development of impaired glucose tolerance and insulin resistance in both male mice without obesity and female mice with mild obesity, fed a normal chow diet. When maintained on a high-fat diet, these abnormalities became more pronounced exclusively in female orexin knockout mice that developed severe obesity. Insulin signalling through Akt was disrupted in peripheral tissues of middle-aged (9-month-old) but not young adult (2-to-3-month-old) orexin knockout mice fed a normal chow diet. Moreover, basal levels of hypothalamic Akt phosphorylation were abnormally elevated in orexin knockout mice at every age studied, and insulin stimulation failed to increase the level of phosphorylation. Similar abnormalities were observed with respect to GSK3β phosphorylation in the hypothalamus and peripheral tissues of middle-aged orexin knockout mice. Conclusions/interpretation Our results demonstrate a novel role for orexin in hypothalamic insulin signalling, which is likely to be responsible for preventing the development of peripheral insulin resistance with age.

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Section: Discussionmentioning

confidence: 99%

Section: Irmentioning

confidence: 97%

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confidence: 99%

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Age-related insulin resistance in hypothalamus and peripheral tissues of orexin knockout mice

et al. 2008

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“…However, by feeding HFD for 9 weeks, blood glucose level, but not triglycerides level is shown to be increased [22]. It has been reported that most orexin neurons are glucose sensitive, while the activity of isolated orexin neurons is hyperpolarized and their firing frequency is decreased by a high glucose level [23]. Thus, it is suggested that the hyperglycemic state induced by HFD cause the decrease of prepro-orexin mRNA level directly or indirectly in the hypothalamus in our feeding conditions.…”

Section: Discussionmentioning

confidence: 97%

Hypothalamic prepro-orexin mRNA level is inversely correlated to the non-rapid eye movement sleep level in high-fat diet-induced obese mice

Tanno

Terao

Okamatsu‐Ogura

et al. 2013

Obesity Research & Clinical Practice

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Orexins are hypothalamic neuropeptides, which play important roles in the regulation and maintenance of sleep/wakefulness states and energy homeostasis. To evaluate whether alterations in orexin system is associated with the sleep/wakefulness abnormalities observed in obesity, we examined the mRNA expression of prepro-orexin, orexin receptor type 1, (orexin 1r), and orexin receptor type 2 (oxexin 2r) in the hypothalamus in mice fed with a normal diet (ND) and high-fat diet (HFD)-induced obese mice. We also compared their relationships with sleep/wakefulness. Twenty-four, 4-week-old, male C57BL/6J mice were divided randomly into 3 groups, which received the following: (1) ND for 17 weeks; (2) HFD for 17 weeks; and (3) ND for 7 weeks and HFD for a further 10 weeks. The body weights of mice fed the HFD for 10-17 weeks were 112-150% of the average body weight of the ND group. The daily amount of non-rapid eye movement (NREM) sleep increased significantly in HFD-fed mice. These changes were accompanied by increases in the number but decreases in the duration of each NREM sleep episode. In addition, brief awakenings (<20 s epoch) during NREM sleep was nearly 2-fold more frequent. The mRNA level of prepro-orexin in the hypothalamus was significantly reduced in HFD-induced obese 3 mice, whereas the levels of orexin 1r and orexin 2r were unaffected. The daily amount of NREM sleep was negatively correlated with the hypothalamic prepro-orexin mRNA level, so these results suggest that the increased NREM sleep levels in HFD-induced obese mice are attributable to impaired orexin activity.

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“…Food seeking and food intake require vigilant states which require high energy expenditure. Recent evidence suggests that orexin neurons are capable of sensing indicators of energy balance and are activated under negative energy balance, such as decreased extracellular glucose level, reduced leptin level (an anorexigenic protein hormone secreted by adipocytes), and increased ghrelin level (a stomach-derived orexigenic peptide) (Yamanaka et al, 2003;Burdakov et al, 2005). Recently, non-essential amino acids were also reported to activate orexin neurons, which may potentially benefit an animal under prolonged starvation where a rise in extracellular amino acid levels occurs as proteins are broken down for fuel (Karnani et al, 2011).…”

Section: Integrative Physiology Of Orexin Systemmentioning

confidence: 99%

Overview of orexin/hypocretin system

Mieda

Sakurai

2012

Progress in Brain Research

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A series of recent studies has established the orexin/hypocretin system as a critical regulator of sleep/wake states. Its deficiency results in the sleep disorder narcolepsy in humans, dogs, and rodents. These findings have brought about the possibility of novel therapies for sleep disorders including narcolepsy and insomnia. Moreover, accumulating evidence indicates that the orexin/hypocretin system regulates sleep and wakefulness through interactions with neuronal systems that regulate emotion, reward, and energy homeostasis. Here, we briefly summarize the progress of orexin/hypocretin studies and future perspectives.

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Hypothalamic Orexin Neurons Regulate Arousal According to Energy Balance in Mice

Cited by 842 publications

References 64 publications

Age-related insulin resistance in hypothalamus and peripheral tissues of orexin knockout mice

Age-related insulin resistance in hypothalamus and peripheral tissues of orexin knockout mice

Hypothalamic prepro-orexin mRNA level is inversely correlated to the non-rapid eye movement sleep level in high-fat diet-induced obese mice

Overview of orexin/hypocretin system

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