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Daily Intra-Paraventricular Orexin-A Treatment Induces Weight Loss in Rats
Abstract
The neuropeptide orexin (hypocretin) increases energy expenditure partially through increasing spontaneous physical activity. The ability of exogenous orexin to alter body weight has never been established, however. We sought to determine whether orexin-A microinjected into the paraventricular nucleus of the hypothalamus (PVN) induced weight loss in rats. Chronic guide cannulae were implanted into rats, aimed at the PVN. Rats were given daily microinjections of orexin (0.5 nmol) or vehicle into the PVN for 6 days; food intake and body weight were measured daily. In a separate group of rats, we injected orexin-A and vehicle intra-PVN and measured daily activity levels. Daily orexin treatment induced weight loss: orexin-A-treated rats lost significantly more weight than their vehicle-injected counterparts without a significant difference in food intake. Rats were significantly more active after intra-PVN orexin compared to vehicle. These results support the concept that orexinergic agents have the potential to produce negative energy balance through increasing physical activity. This presents a promising, untapped potential resource for weight loss.
... M. Kotz et al., 2002;Nishino et al., 2001). In addition, central injection of orexin or brain orexin overexpression decreases body weight gain in animals (Funato et al., 2009;Novak & Levine, 2009;Perez-Leighton et al., 2012). Obesity resistant rats have greater orexin receptor gene expression and orexin behavioral sensitivity Teske et al., 2006;Teske et al., 2008); are more physically active; and have consolidated sleep (Mavanji et al., 2010;Teske et al., 2006), indicating a protective effect of orexin against obesity. ...
... M. Kotz, 2006;C. M. Kotz et al., 2002;Mavanji et al., 2015;Novak et al., 2006;Novak & Levine, 2009;Teske et al., 2010;Teske et al., 2006;Teske et al., 2013;Thorpe & Kotz, 2005) enhances SPA and EE. Moreover, micro-infusion of orexin into several brain regions increased EMG activity and muscle tone Mileykovskiy et al., 2002Mileykovskiy et al., , 2005Peever et al., 2003;Teske & Mavanji, 2012). ...
... The orexin neurons project densely to the PVN of the hypothalamus (de Lecea et al., 1998), and 6 days of daily intra-PVN orexin treatment induced loss of body weight, without affecting feeding behavior. Furthermore, intra-PVN orexin enhanced physical activity compared with control treatment, indicating that orexin in PVN promotes physical activity, and hence negative energy balance (Novak & Levine, 2009). Another study showed that intra-PVN orexin reduced palatable snack intake in mice (Alvarez et al., 2018). ...
The lateral hypothalamus is critical for the control of ingestive behavior and spontaneous physical activity (SPA), as lesion or stimulation of this region alters these behaviors. Evidence points to lateral hypothalamic orexin neurons as modulators of feeding and SPA. These neurons affect a broad range of systems, and project to multiple brain regions such as the dorsal raphe nucleus, which contains serotoninergic neurons (DRN) important to energy homeostasis. Physical activity is comprised of intentional exercise and SPA. These are opposite ends of a continuum of physical activity intensity and structure. Non‐goal‐oriented behaviors, such as fidgeting, standing, and ambulating, constitute SPA in humans, and reflect a propensity for activity separate from intentional activity, such as high‐intensity voluntary exercise. In animals, SPA is activity not influenced by rewards such as food or a running wheel. Spontaneous physical activity in humans and animals burns calories and could theoretically be manipulated pharmacologically to expend calories and protect against obesity. The DRN neurons receive orexin inputs, and project heavily onto cortical and subcortical areas involved in movement, feeding and energy expenditure (EE). This review discusses the function of hypothalamic orexin in energy‐homeostasis, the interaction with DRN serotonin neurons, and the role of this orexin‐serotonin axis in regulating food intake, SPA, and EE. In addition, we discuss possible brain areas involved in orexin–serotonin cross‐talk; the role of serotonin receptors, transporters and uptake‐inhibitors in the pathogenesis and treatment of obesity; animal models of obesity with impaired serotonin‐function; single‐nucleotide polymorphisms in the serotonin system and obesity; and future directions in the orexin–serotonin field.
This article is categorized under: Metabolic Diseases > Molecular and Cellular Physiology
... The opioid DYN and orexin peptides interact to regulate different behaviors in several brain sites, such as cocaine self-administration in the ventral tegmental area (Chemelli et al., 1999;Hara et al., 2001Hara et al., , 2005Eriksson et al., 2004;Li and van den Pol, 2006;Muschamp et al., 2014). In PVN, orexin and opioid DYN peptides can separately increase chow intake and SPA (Gosnell et al., 1986b;Kiwaki et al., 2004;Novak and Levine, 2009) and co-injection of DYN-A 2-17 and orexin-A in PVN in mice potentiates their individual effects on chow intake (Gac et al., 2016), suggesting that orexin-A and DYN-A 2-17 might share similar mechanisms of action within PVN. In this brain site, orexin-A increases activity of CRF neurons (Kuru et al., 2000;Follwell and Ferguson, 2002;Sakamoto et al., 2004) and their activation can induce local CRF release (Imaki et al., 1996;Mansi et al., 1996;Dabrowska et al., 2013). ...
... Additional experiments are required to test this hypothesis and whether the effects of DYN-A 2-17 on SPA and exercise habituate as we have observed for food intake. Overall, these data suggest that like orexin-A, DYN-A 2-17 can acutely increase SPA, wheel running, food intake and energy expenditure; yet repeated orexin-A administration into PVN drives a negative energy balance (Russell et al., 2002;Kiwaki et al., 2004;Novak and Levine, 2009) while DYN-A 2-17 cannot. As orexin-A and DYN-A 2-17 can interact to potentiate their individual effects on chow intake (Gac et al., 2016), these data suggest that the physiological role of DYN-A 2-17 is to fine tune the feedingrelated effects of orexin-A, rather than drive behaviors relevant for energy balance. ...
... Finally, it remains to be determined whether CRF signaling in PVN modulates the effects of DYN-A 2-17 on SPA. Orexin-A can increase SPA and energy expenditure by acting in PVN (Kiwaki et al., 2004;Novak and Levine, 2009), which would be consistent with activation of PVN CRF receptors (Mo¨nnikes et al., 1992). In fact, ICV injection of aCRF 9-41 blocks the effects of ICV orexin-A on grooming behavior (Ida et al., 2000b). ...
The dynorphin (DYN) peptide family includes opioid and non-opioid peptides, yet the physiological role of the non-opioid DYN peptides remains poorly understood. Recent evidence shows that administering the non-opioid peptide DYN-A2-17 into the paraventricular hypothalamic nucleus (PVN) simultaneously increased short-term intake of standard rodent chow and spontaneous physical activity (SPA). The present studies aimed to expand upon the mechanisms and role of DYN-A2-17 on food intake and energy expenditure. Injection of DYN-A2-17 in PVN increased SPA, energy expenditure and wheel running in the absence of food. Repeated DYN-A2-17 injection in PVN increased short-term chow intake, but this effect habituated over time and failed to alter cumulative food intake, body weight or adiposity. Pre-treatment with a CRF receptor antagonist into PVN blocked the effects of DYN-A2-17 on food intake while injection of DYN-A2-17 in PVN increased plasma ACTH. Finally, as DYN peptides are co-released with orexin peptides in PVN, we compared the effects of DYN-A2-17 to orexin-A and the opioid peptide DYN-A1-13 on food choice and intake when palatable snacks and chow were available. DYN-A1-13 selectively increased intake of palatable snacks. DYN-A2-17 and orexin-A decreased palatable snack intake while orexin-A also increased chow intake. These findings demonstrate that the non-opioid peptide DYN-A2-17 acutely regulates physical activity, energy expenditure and food intake without long-term effects on energy balance. These data also propose different roles of opioid, non-opioid DYN and orexin peptides on food choice and intake when palatable and non-palatable food options are available.
... Among these brain sites, PVN, rostral LH, TMN, and SNpc show equally high sensitivity to orexin-A-induced SPA in rats, though high activity/low activity (HA/LA) studies (described later in this review) suggest that the SNpc has lower sensitivity to orexin-A as compared to rostral LH . Moreover, repeated injection of orexin-A in PVN and the rostral LH causes either weight loss or prevents obesity induced by high-fat diet intake (Kiwaki, Kotz, Wang, Lanningham-Foster, & Levine, 2004;Kotz et al., 2006;Novak & Levine, 2009;Perez-Leighton, Butterick-Peterson, et al., 2013;Perez-Leighton, Little, Grace, Billington, & Kotz, 2017). Together, this evidence supports the idea that orexin-A can drive SPA by its distributed action across different brain sites. ...
... Importantly, the development of obesity was observed concurrently with the loss of orexin neurons, suggesting that a role of the orexin neurons is to promote a net increase in energy expenditure. This hypothesis is supported by studies showing that chronic intrathecal orexin injections do not result in body weight gain, but rather weight loss (Kiwaki et al., 2004;Kotz et al., 2006;Novak & Levine, 2009;Perez-Leighton, Butterick-Peterson, et al., 2013;Perez-Leighton et al., 2017). An important caveat to this hypothesis was demonstrated in a study showing that mice deficient only in orexin peptides do not become obese (Hara, Yanagisawa, & Sakurai, 2005), suggesting that additional peptides expressed in orexin neurons contribute to promote NEAT. ...
... Among these brain sites, PVN, rostral LH, TMN, and SNpc show equally high sensitivity to orexin-A-induced SPA in rats, though high activity/low activity (HA/LA) studies (described later in this review) suggest that the SNpc has lower sensitivity to orexin-A as compared to rostral LH . Moreover, repeated injection of orexin-A in PVN and the rostral LH causes either weight loss or prevents obesity induced by high-fat diet intake (Kiwaki, Kotz, Wang, Lanningham-Foster, & Levine, 2004;Kotz et al., 2006;Novak & Levine, 2009;Perez-Leighton, Butterick-Peterson, et al., 2013;Perez-Leighton, Little, Grace, Billington, & Kotz, 2017). Together, this evidence supports the idea that orexin-A can drive SPA by its distributed action across different brain sites. ...
... Importantly, the development of obesity was observed concurrently with the loss of orexin neurons, 71 Orexin Drives Energy Expenditure suggesting that a role of the orexin neurons is to promote a net increase in energy expenditure. This hypothesis is supported by studies showing that chronic intrathecal orexin injections do not result in body weight gain, but rather weight loss (Kiwaki et al., 2004;Kotz et al., 2006;Novak & Levine, 2009;Perez-Leighton, Butterick-Peterson, et al., 2013;Perez-Leighton et al., 2017). An important caveat to this hypothesis was demonstrated in a study showing that mice deficient only in orexin peptides do not become obese , suggesting that additional peptides expressed in orexin neurons contribute to promote NEAT. ...
... Identifying specific neural targets may guide development of precise therapeutic interventions to prevent weight gain associated with poor sleep. Based on the ability of central orexin-A stimulation to cause negative energy balance (29,30), lower total EE following orexin receptor blockade (24,25), and lower physical activity and EE following sleep deprivation that increased weight gain (7,8), we hypothesized that sleep deprivation would reduce orexin function in the VLPO, indicated by the inability of orexin-A to stimulate physical activity and EE after sleep deprivation. These data are novel and show that, in contrast to acute sleep deprivation, which was sufficient to reduce the behavioral response and energetic effects of orexin-A in the VLPO, chronic sleep deprivation had a more potent effect and completely blocked the effects of orexin-A. ...
... It is plausible that chronic sleep deprivation modified the feeding response to orexin-A in the VLPO despite the fact that the effect of orexin-A on feeding was null in rats with sufficient sleep (24). Finally, we acknowledge divergent effects of central (29,30) and peripheral (40) orexin-A therapy on weight gain and energy expenditure. Further work is needed to resolve the specific mechanisms within and external to the VLPO that mediate the reduction in physical activity and its associated EE that leads to weight gain following sleep deprivation due to noise exposure. ...
Objective:
Sufficient sleep is required for weight maintenance. Sleep deprivation due to noise exposure stimulates weight gain by increasing hyperphagia and reducing energy expenditure (EE). Yet the mechanistic basis underlying the weight gain response is unclear. Orexin-A promotes arousal and negative energy balance, and orexin terminals project to the ventrolateral preoptic area (VLPO), which is involved in sleep-to-wake transitions. To determine whether sleep deprivation reduces orexin function in VLPO and to test the hypothesis that sleep deprivation would attenuate the orexin-A-stimulated increase in arousal, physical activity (PA), and EE.
Methods:
Electroencephalogram, electromyogram, distance traveled, and EE were determined in male Sprague-Dawley rats following orexin-A injections into VLPO both before and after acute (12-h) and chronic (8 h/d, 9 d) sleep deprivation by noise exposure.
Results:
Orexin-A in the VLPO significantly increased arousal, PA, total EE, and PA-related EE and reduced sleep and respiratory quotient before sleep deprivation. In contrast to after acute sleep deprivation in which orexin-A failed to stimulate EE during PA only, orexin-A failed to significantly increase arousal, PA, fat oxidation, total EE, and PA-related EE after chronic sleep deprivation.
Conclusions:
Sleep deprivation may reduce sensitivity to endogenous stimuli that enhance EE due to PA and thus stimulate weight gain.
... Overall, these data suggest that orexins could modulate the hypothalamicpituitary-thyroid (HPT) axis. This idea was supported by studies demonstrating that peripheral ORX-A administration in rats inhibits TRH release from the hypothalamus (Mitsuma et al., 1999), resulting in a fall in the levels of thyroid-stimulating hormone (TSH) (Mitsuma et al., 1999;Novak and Levine, 2009). This effect appears to be entirely mediated by the decrease in TRH levels, because both ORX-A and ORX-B failed to inhibit TSH secretion in primary cultures from rat P r o v i s i o n a l pituitary (Samson and Taylor, 2001). ...
... This effect appears to be entirely mediated by the decrease in TRH levels, because both ORX-A and ORX-B failed to inhibit TSH secretion in primary cultures from rat P r o v i s i o n a l pituitary (Samson and Taylor, 2001). It has been suggested that this lack of effect could be based on the slow metabolism of thyroid hormones (Novak and Levine, 2009), which normally show a delay in their secretory responses to modulatory factors . ...
Hypocretin/orexin (ORX) are two hypothalamic neuropeptides discovered in 1998. Since their discovery, they have been one of the most studied neuropeptide systems because of their projecting fields innervating various brain areas. The orexinergic system is tied to sleep-wakefulness cycle, and narcolepsy is a consequence of their system hypofunction. Orexinergic system is also involved in many other autonomic functions such as feeding, thermoregulation, cardiovascular and neuroendocrine regulation. The main aim of this mini review article is to investigate the relationship between ORX and thyroid system regulation. Although knowledge about the ORX system is evolving, its putative effects on hypothalamic-pituitary-thyroid (HPT) axis still appear unclear. We analyzed some studies about ORX control of HPT axis to know better the relationship between them. The studies that were analyzed suggest Hypocretin/ORX to modulate the thyroid regulation, but the nature (excitatory or inhibitory) of this possible interaction remains actually unclear and needs to be confirmed.
... Some studies have investigated systemic anti-nociceptive effect of orexin-A in different animal models of pain (summarized table in Chiou et al., 2010) (26) and most of them used orexin-A at doses from 0.1 nmol to 1 nmol for ICV (5 µl) or intrathecal (IT, 10 µl) injection. Moreover, a similar amount of orexin-A (0.5 nmol) was microinjected (ICV) for examining the effects of this agent on food intake and body weight (27). ...
... Although, they applied orexin-A into a paraventricular nucleus at a different dose, their results are similar to ours. It has been reported that orexins increase the food intake (27) and also affect the spontaneous physical activity and wakefulness; therefore, a weight loss due to negative energy balance may be expected (29). ...
Objectives:
Reduction of pharmacological effectiveness or tolerance appears following repeated administration of many analgesic drugs. We investigated tolerance to anti-nociceptive effects of orexin-A, an endogenous potent analgesic peptide using the hot-plate test.
Materials and methods:
Orexin-A was microinjected ICV (intracerebroventricular) with an interval of 12 hr for 7 continuous days and its anti-nociceptive responses were measured on days 1, 4 and 7 using the hot-plate test following the first day of administration. Orexin-A was used at a dose of 100 pmol to induce analgesic effects.
Results:
ICV administration of orexin-A produced an effective anti-nociception on the first day of experiment as measured by hot-plate 5, 15, and 30 min after the injection, in comparison with both baselines (hot-plate test one day before the beginning of orexin-A administration and control, saline-administrated group). However, repeated administration of orexin-A on the following days revealed a significant reduction in this analgesic effect during day 4 to day 7. However, to rule out any associative tolerance resulting from learning related to experimental procedures and/or environmental cues, a single injection of orexin-A was administrated to animals of control group (which were receiving saline during 7 days of experiments) and the analgesic effect was observed.
Conclusion:
These results, for the first time, indicated the appearance of tolerance to anti-nociceptive effects of orexin-A, following repeated administrations of this agent.
... Animals in which there is progressive loss of orexin neurons display more severe obesity phenotypes than mice who are only deficient in prepro-orexin, indicating that multiple factors and signaling systems coalesce in orexin neurons to regulate body weight (Hara et al., 2005). To complement genetic ablation approaches, pharmacological studies of repeated orexin A injection into the brain result in body weight loss and protection against obesity (Novak and Levine, 2010;Perez-Leighton et al., 2012;Teske et al., 2013). Indeed, selective activation of orexin neurons in the LH via Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) stimulates SPA, food intake, and energy expenditure (Inutsuka et al., 2014). ...
... Data from our laboratory and others show that a major effect of orexin A signaling is to promote SPA and NEAT Inutsuka et al., 2014). Increased SPA and NEAT are observed following injection of the orexin peptides directly into the rostral LH, hypothalamic paraventricular nucleus, nucleus accumbens, locus coeruleus, dorsal raphe nucleus, tuberomammillary nucleus, and substantia nigra (Kotz et al., 2002Kiwaki et al., 2004;Thorpe and Kotz, 2005;Novak and Levine, 2010;Perez-Leighton et al., 2012;Teske et al., 2013). Of these sites, our work suggests that orexin A in the rostral LH has the greatest effect on SPA. ...
There is a rising medical need for novel therapeutic targets of physical activity. Physical activity spans from spontaneous, low intensity movements to voluntary, high-intensity exercise. Regulation of spontaneous and voluntary movement is distributed over many brain areas and neural substrates, but the specific cellular and molecular mechanisms responsible for mediating overall activity levels are not well understood. The hypothalamus plays a central role in the control of physical activity, which is executed through coordination of multiple signaling systems, including the orexin neuropeptides. Orexin producing neurons integrate physiological and metabolic information to coordinate multiple behavioral states and modulate physical activity in response to the environment. This review is organized around three questions: (1) How do orexin peptides modulate physical activity? (2) What are the effects of aging and lifestyle choices on physical activity? (3) What are the effects of aging on hypothalamic function and the orexin peptides? Discussion of these questions will provide a summary of the current state of knowledge regarding hypothalamic orexin regulation of physical activity during aging and provide a platform on which to develop improved clinical outcomes in age-associated obesity and metabolic syndromes.
... This hypothesis is supported by studies showing that chronic orexin intrathecal injections do not result in body weight gain. 66,67 Further support comes from a mouse model, in which the pre-proorexin gene is under the control of the b-actin/cytomegalovirus (CAG) promoter (CAG-OX), leading to overexpression of the orexin peptides. 68 Consistent with the role of orexin in promoting energy expenditure, the CAG-OX mice show resistance to obesity induced by consumption of a high-fat diet. ...
... For example, both OXR subtypes are expressed in PVN (Figure 1) and daily intra-PVN injections of OXA in male rats decreased body weight under a standard diet. 66 Because OXA can activate both OX1R and OX2R, this suggests that both OXR subtypes are involved in the obesity-protective effects of orexin signaling, at least through PVN. However, to confirm this hypothesis, experiments using OXR antagonists in PVN are needed. ...
The orexin peptides and their two receptors are involved in multiple physiological processes, including energy homeostasis, arousal, stress and reward. Higher signaling of the orexin peptides at the orexin receptors (OXR) protects against obesity, but it is less clear how their activation in different brain regions contributes to this behavioral output. This review summarizes the evidence available for a role of central OXR in energy homeostasis and their contribution to obesity. A detailed analysis of anatomical, cellular and behavioral evidence shows that modulation of energy homeostasis by the OXR is largely dependent upon anatomical and cellular context. It also shows that obesity resistance provided by activation of the OXR is distributed across multiple brain sites with site-specific actions. We suggest that understanding the role of the OXR in the development of obesity requires considering both specific mechanisms within brain regions and interactions of orexinergic input between multiple sites.International Journal of Obesity advance online publication, 6 March 2012; doi:10.1038/ijo.2012.30.
... Orexin-A injected into various brain sites increases feeding [8], spontaneous physical activity (SPA) and thermogenesis [9][10][11][12][13][14] and orexin neuron ablation is associated with late-onset obesity and reduced locomotion, despite hypophagia [15][16][17][18]. Importantly, our earlier studies show that orexin injection stimulates SPA and associated non-exercise activity thermogenesis (NEAT) with a sustained promotion of total energy expenditure (TEE) [19], and orexin neuron activation increases NEAT, reduces obesity [20,21] and decreases body weight gain in animals [22,23]. Orexin can also promote feeding behavior, but this effect is short-lived, with compensatory feeding reduction in later time intervals, resulting in no overall effect on cumulative food intake [24]. ...
Orexin/hypocretin terminals innervate the dorsal raphe nucleus (DRN), which projects to motor control areas important for spontaneous physical activity (SPA) and energy expenditure (EE). Orexin receptors are expressed in the DRN, and obesity-resistant (OR) rats show higher expression of these receptors in the DRN and elevated SPA/EE. We hypothesized that orexin-A in the DRN enhances SPA/EE and that DRN-GABA modulates the effect of orexin-A on SPA/EE. We manipulated orexin tone in the DRN either through direct injection of orexin-A or through the chemogenetic activation of lateral-hypothalamic (LH) orexin neurons. In the orexin neuron activation experiment, fifteen minutes prior to the chemogenetic activation of orexin neurons, the mice received either the GABA-agonist muscimol or antagonist bicuculline injected into the DRN, and SPA/EE was monitored for 24 h. In a separate experiment, orexin-A was injected into the DRN to study the direct effect of DRN orexin on SPA/EE. We found that the activation of orexin neurons elevates SPA/EE, and manipulation of GABA in the DRN does not alter the SPA response to orexin neuron activation. Similarly, intra-DRN orexin-A enhanced SPA and EE in the mice. These results suggest that orexin-A in the DRN facilitates negative energy balance by increasing physical activity-induced EE, and that modulation of DRN orexin-A is a potential strategy to promote SPA and EE.
... Furthermore, physical exercise increases plasma OrxA levels, which stimulates the sympathetic nervous system and energy expenditure, and OrxA seems to be able to promote thermogenesis during physical activity [118,130,[142][143][144]. To support the role of orexins in obesity resistance, several animal studies have demonstrated that OrxA injections into several cerebral areas, such as the rostral LH, paraventricular nucleus, TMN, LC, DRN, nucleus accumbens, and substantia nigra, improve SPA and NEAT [132,[145][146][147][148][149][150][151][152], while repeated injections of OrxA into LH are associated with reduced fat mass [153]. Orexins also exert a sympathoexcitatory effect, as demonstrated by increased blood pressure and heart rate, increased sympathetic outflow to brown adipose tissue (BAT), and increased plasma epinephrine and noradrenaline release [141,[154][155][156]. ...
Orexins, or hypocretins, are excitatory neuropeptides involved in the regulation of feeding behavior and the sleep and wakefulness states. Since their discovery, several lines of evidence have highlighted that orexin neurons regulate a great range of physiological functions, giving it the definition of a multitasking system. In the present review, we firstly describe the mechanisms underlining the orexin system and their interactions with the central nervous system (CNS). Then, the system’s involvement in goal-directed behaviors, sleep/wakefulness state regulation, feeding behavior and energy homeostasis, reward system, and aging and neurodegenerative diseases are described. Advanced evidence suggests that the orexin system is crucial for regulating many physiological functions and could represent a promising target for therapeutical approaches to obesity, drug addiction, and emotional stress.
... Also, mice that loss orexin-containing neurons acquired obesity despite consuming less food 111 . Furthermore, injection of OXA into the brain led to weight loss and thus played a dampening role in the rise of obesity 112 . In addition, mice deprived of orexins through a knockout or treatment with an ataxin toxin postnatal caused the emergence of obesity in later stages 113 . ...
Coronavirus disease in 2019 (COVID-19) is a pandemic declared by the World Health Organization after its appearance in the Chinese city of Wuhan in late 2019. It has infected more than 30 million people worldwide and led to the death of nearly one million of them. Orexin-A (OXA), a neuropeptide produced by the lateral hypothalamic area and several peripheral tissues, regulates appetite, reproduction, and other physiological functions. There are many symptoms associated with infection with the coronavirus, such as a cytokine storm, narcolepsy, impaired senses of smell and taste, and loss of appetite, usually are associated with high or low levels of OXA in the infected people. Moreover, some chronic diseases such as cancer, diabetes, and obesity, generally referred to as risk factors for the disease, increase the severity of infection or even lead to death and they are associated with either an increase or a decrease in OXA levels. Moreover, some factors, such as a high testosterone level, facilitate the entry of a virus into the cells, which OXA controls. In this review, we described for the first time the potential impact of high or low levels of OXA on the severity of the symptoms of COVID-19 or the death due to this disease.
... We have shown that resistance to weight gain in obesity-resistant (OR) rats is associated with increased LH orexin gene expression, orexin sensitivity, physical activity and enhanced sleep quality (Teske et al. 2006;Kotz et al. 2008;Mavanji et al. 2010). We and others have shown reduced weight gain following orexin treatment (Novak and Levine 2009;Perez-Leighton et al. 2012). In addition, we showed that sleep disturbances alter feeding and energy homeostasis (Mavanji et al. 2010(Mavanji et al. , 2013, which could be due to altered LH orexin function. ...
Synchronous neural activity is a feature of normal brain function, and altered synchronization is observed in several neurological diseases. Dysfunction in hypothalamic pathways leads to obesity, suggesting that hypothalamic neural synchrony is critical for energy homeostasis. The lateral hypothalamic orexin neurons are extensively interconnected with other brain structures and are important for energy balance. Earlier studies show that rats with higher orexin sensitivity are obesity resistant. Similarly, topiramate, an anti-epileptic drug, has been shown to reduce weight in humans. Since orexin enhances neuronal excitation, we hypothesized that obesity-resistant rats with higher orexin sensitivity may exhibit enhanced hypothalamic synchronization. We further hypothesized that anti-obesity agents such as orexin and topiramate will enhance hypothalamic synchronization. To test this, we examined neural synchronicity in primary embryonic hypothalamic cell cultures, obtained from embryonic day 18 (E18) obesity-susceptible Sprague–Dawley (SD) and obesity-resistant rats. Hypothalamic tissue was cultured in multielectrode array (MEA), and recordings were performed twice weekly, from 4th to 32nd day in vitro (DIV). Next, we tested the effects of orexin and topiramate application on neural synchronicity of hypothalamic cultures obtained from SD rat embryos. Signals were analyzed for synchronization using cross correlation. Our results showed that (1) obesity-resistant hypothalamus exhibits significantly higher synchronization compared to obesity-sensitive hypothalamus; and (2) orexin and topiramate enhance hypothalamic synchronization. These results support that enhanced orexin sensitivity is associated with greater neural synchronization, and that anti-obesity treatments enhance network synchronization, thus constrain variability in hypothalamic output signals, to extrahypothalamic structures involved in energy homeostasis.
... It is important to acknowledge that the lack of leptin or its insensitivity are linked to pathophysiology of obesity and insulin resistance (Ingalls et al. 1950, Hummel et al. 1966, Girard 1997. Exogenous orexin A attenuates adiposity in rats and mice with diet-induced obesity, further supporting the observations in genetically modified animals (Novak & Levine 2009, Perez-Leighton et al. 2012. ...
Orexin A and B are two neuropeptides which regulate a variety of physiological functions by interacting with central nervous system and peripheral tissues. Biological effects of orexins are mediated through two G-protein coupled receptors (OXR1 and OXR2). In addition to their strong influence on the sleep-wake cycle, there is growing evidence that orexins regulate body weight, glucose homeostasis and insulin sensitivity. Furthermore, orexins promote energy expenditure and protect against obesity by interacting with brown adipocytes. Fat tissue and the endocrine pancreas play pivotal roles in maintaining energy homeostasis. Since both organs are crucially important in the context of pathophysiology of obesity and diabetes, we summarize the current knowledge regarding the role of orexins and their receptors in controlling adipocytes as well as the endocrine pancreatic functions. Particularly, we discuss studies evaluating the effects of orexins in controlling brown and white adipocytes as well as pancreatic alpha, and beta cell functions.
... Surgical removal of these orexin neurons caused narcolepsy and obesity [151], but also decreased spontaneous movements [152][153][154]. Age-related decline in orexin receptor messenger-RNA levels in rats has also been shown to correlate with decreased ambulatory activity [155], while biochemically elevated orexin levels increased daily ambulatory activity [156]. These studies suggest that lower orexin levels may mediate lower incidental activity, energy expenditure, and obesity. ...
Sedentary behaviours—too much sitting as distinct from too little exercise—are emerging as a ubiquitous, modern-day health hazard. Epidemiological evidence is accumulating that indicates greater time spent in sedentary behaviour is associated with increased cardiometabolic risk, even when controlling for the influence of leisure time moderate-to-vigorous physical activity. Based on these observations and preliminary experimental work, it has been proposed that sedentary behaviour influences health risk in part through some distinct mechanisms that act independently of lack of physical activity. However, the observational evidence is well ahead of evidence on physiological responses and potential biological mechanisms that may underlie the observed associations. Here, we summarize and discuss experimental evidence to date on the physiological effects of sedentary behaviours (prolonged sitting), including potential countermeasures aiming to address too much sitting as a health risk. We also highlight future research that is needed to further ascertain the impact of sedentary behaviour on altering physiology.
... Finally, the latter suggests that orexin-A in this brain site may have an independent effect on EE during NREM sleep versus REM sleep. Taken together, our data suggest that orexin-A contributes to negative energy balance by increasing multiple components of total EE in addition to SPA. 42 Next, we tested whether blocking both OXRs reduced the aforementioned effects of orexin-A. The DORA reduced orexin-Astimulated increases in AW, SPA, total EE, resting EE and EE during SPA, AW and NREM sleep. ...
Background:
Identifying whether components of total EE are affected by orexin receptor (OXR1 and OXR2) stimulation or antagonism with dual orexin receptor antagonists (DORAs) has relevance for obesity treatment. Orexin receptor stimulation reduces weight gain by increasing total energy expenditure (EE) and EE during spontaneous physical activity (SPA).
Objective:
The purpose of this study was to determine if a DORA (TCS-1102) in the ventrolateral preoptic area (VLPO) reduced orexin-A-induced arousal, SPA, total EE and EE during sleep, rest, wake and SPA and whether the DORA alone reduced total EE and its components. We hypothesized that: (1) a DORA would reduce orexin-A induced increases in arousal, SPA, components of total EE, reductions in sleep and the EE during sleep and (2) the DORA would reduce basal (non-stimulated) SPA and total EE.
Subjects/methods:
Sleep, wakefulness, SPA, and EE were determined after microinjection of the DORA (TCS-1102) and orexin-A in the VLPO of male Sprague-Dawley rats with a unilateral cannula targeted towards the VLPO. Individual components of total EE were determined based on time-stamped data.
Results:
The DORA reduced orexin-A-induced increases in arousal, SPA, total EE, and EE during SPA, wake, rest and sleep 1-h post-injection (P<0.05). Orexin-A significantly reduced sleep and significantly increased EE during sleep 1-h post-injection (P<0.05). Furthermore, the DORA alone significantly reduced total EE and resting EE 2-h post-injection (P<0.05).
Conclusions:
These data suggest that orexin-A reduces weight gain by stimulating total EE through increases in EE during SPA, rest, and sleep. Residual effects of the DORA alone include decreases in total EE and EE during sleep and rest, which may promote weight gain.International Journal of Obesity accepted article preview online, 10 April 2017. doi:10.1038/ijo.2017.92.
... The orexin peptides modulate behaviors such as SPA, reward, food intake, and the sleep/wake cycle, with orexin-A showing more robust effects in all of these behaviors (41). By promoting SPA and energy expenditure by their action at multiple brain sites (8,9,12,17,26,35), the activity of orexin neurons and peptides is sufficient to reduce susceptibility to diet-induced obesity (5,7,22,27). ...
... A number of animal experiments on orexin noted the association between orexin and SPA. Novak and Levine administered orexin-A microinjection into the paraventricular nucleus (PVN) of the hypothalamus that induced weight loss and more active movement in rats [11], which demonstrated directly that brain orexin linked to SPA and weight control. Teske proved that orexin induced voluntary PA, such as wheel running in rats through orexin receptor1 (OX1R) antagonism [12]. ...
Objective:
To measure the amount of physical activity (PA) among obese adults, investigate the association between plasma orexin-A level and PA patterns, and explore the effect of orexin on the prevention and control of obesity.
Methods:
Interviews were conducted in 218 participants (106 obese; 73 overweight; and 39 normal) who ranged in age between 18 and 70 years using a survey that included sociodemographic variables. The International Physical Activity Questionnaire (IPAQ-long version) was used to measure PA. A total of 178 participants agreed to submit blood sample collections, and plasma orexin-A content was measured by ELISA testing.
Results:
The average level of orexin-A was 85.34 ± 42.85 ng/L in the obese group, 97.38 ± 36.72 ng/L in the overweight group, and 106.56 ± 52.09 ng/L in the control group, which was significantly different (P = 0.03). The concentration of plasma orexin-A correlated with the total PA (P = 0.000), moderate PA (obese = 0.007; overweight: P = 0.000; control: P = 0.000), and walking PA (P = 0.000) in all three groups. Working and domestic PAs were significantly associated with the plasma orexin-A level (P < 0.0001).
Conclusions:
The plasma orexin-A level was associated with PA in obese and overweight people, including many aspects of daily life, such as working, domestic work, and walking especially.
... These controversial clinical and animal studies showed orexin was closely associated with obesity. Orexin was known to increase food intake [51] and chronic intracerebroventricular administration of OX-A to rats increased food intake in daytime [52]. ...
... 9,10 As might be expected from the discharge pattern of orexin neurons, orexin-A administration in the brain enhances wakefulness, 20 SPA, [20][21][22] energy expenditure, 23 and, depending upon brain site, acutely increases feeding. 10,22 Given chronically, orexin-A reduces body weight, 24,25 highlighting that orexin-A predominantly promotes energy expenditure and a net negative energy balance. 14 Taken together, these data suggest that orexin-A coordinates and modulates sleep, eating behavior, and SPA to increase net energy expenditure. ...
The ventrolateral preoptic area (VLPO) and the orexin/ hypocretin neuronal system are key regulators of sleep onset, transitions between vigilance states, and energy homeostasis. Reciprocal projections exist between the VLPO and orexin/ hypocretin neurons. Although the importance of the VLPO to sleep regulation is clear, it is unknown whether VLPO neurons are involved in energy balance. The purpose of these studies was to determine if the VLPO is a site of action for orexin-A, and which orexin receptor subtype(s) would mediate these effects of orexin-A. We hypothesized that orexin-A in the VLPO modulates behaviors (sleep and wakefulness, feeding, spontaneous physical activity [SPA]) to increase energy expenditure.
Sleep, wakefulness, SPA, feeding, and energy expenditure were determined after orexin-A microinjection in the VLPO of male Sprague-Dawley rats with unilateral cannulae targeting the VLPO. We also tested whether pre-treatment with a dual orexin receptor antagonist (DORA, TCS-1102) or an OX2R antagonist (JNJ-10397049) blocked the effects of orexin-A on the sleep/ wake cycle or SPA, respectively.
Orexin-A injected into the VLPO significantly increased wakefulness, SPA, and energy expenditure (SPA-induced and total) and reduced NREM sleep and REM sleep with no effect on food intake. Pretreatment with DORA blocked the increase in wakefulness and the reduction in NREM sleep elicited by orexin-A, and the OX2R antagonist reduced SPA stimulated by orexin-A.
These data show the VLPO is a site of action for orexin-A, which may promote negative energy balance by modulating sleep/wakefulness and stimulating SPA and energy expenditure.
Copyright © 2015 Associated Professional Sleep Societies, LLC. All rights reserved.
... Nonetheless, transgenic overexpression of orexin and the orexin receptor 2 affords protection from obesity when mice are placed on a high fat diet. Novak and Levine (2009) have shown that daily injection of orexin A into the hypothalamic paraventricular nucleus results in weight loss in rats, and recently, Perez-Leighton et al. (2012) showed that daily orexin A injections into the rostral lateral hypothalamus reduces fat mass gain in rats on a high fat diet. These studies demonstrate that enhanced orexin signaling, via increase in peptide or in receptor activation, can protect against weight gain. ...
... For example, our results showing that OX in the PVN acts to initiate ethanol drinking may explain, in part, the specific efficacy of OX antagonists in preventing the reinstatement of ethanol-seeking behavior (Lawrence et al., 2006). Notably, studies have shown that repeated injections of OX, while initially stimulating food intake, subsequently cause a compensatory inhibition that ultimately leaves overall intake unaffected (Novak & Levine, 2009;Yamanaka, Sakurai, Katsumoto, Yanagisawa, & Goto, 1999). In addition, the expression of OX, while stimulated by short bursts of ethanol intake or acute ethanol administration, is suppressed by chronic consumption of ethanol (Morganstern et al., 2010). ...
Different alcohol drinking patterns, involving either small and frequent drinking bouts or large and long-lasting bouts, are found to differentially affect the risk for developing alcohol-related diseases, suggesting that they have different underlying mechanisms. Such mechanisms may involve orexigenic peptides known to stimulate alcohol intake through their actions in the hypothalamic paraventricular nucleus (PVN). These include orexin (OX), which is expressed in the perifornical lateral hypothalamus, and galanin (GAL) and enkephalin (ENK), which are expressed within as well as outside the PVN. To investigate the possibility that these peptides affect different aspects of consumption, a microstructural analysis of ethanol drinking behavior was performed in male, Sprague-Dawley rats trained to drink 7% ethanol and implanted with guide shafts aimed at the PVN. While housed in specialized cages containing computerized intake monitors (BioDAQ Laboratory Intake Monitoring System, Research Diets Inc., New Brunswick, NJ) that measure bouts of ethanol drinking, these rats were given PVN injections of OX (0.9 nmol), GAL (1.0 nmol), or the ENK analog DAla2-met-enkephalinamide (DALA) (14.2 nmol), as compared to saline vehicle. Results revealed clear differences between the effects of these peptides. While all 3 stimulated ethanol intake, they had distinct effects on patterns of drinking, with OX increasing the number of drinking bouts, GAL increasing the size of the drinking bouts, and DALA increasing both the size and duration of the bouts. In contrast, these peptides had little impact on water or food intake. These results support the idea that different peptides can increase ethanol consumption by promoting distinct aspects of the ethanol drinking response. The stimulatory effect of OX on drinking frequency may be related to its neuronally stimulatory properties, while the stimulatory effect of GAL and ENK on bout size and duration may reflect a suppressive effect of these neuronally inhibitory peptides on the satiety-controlling PVN.
... However, UCP-1 levels, which serves as a marker of BAT thermogenesis (Haynes et al., 2002;Sellayah et al., 2011), were not analyzed to confirm this conclusion. An alternative possibility for the reduced energy expenditure is that ACT-335827 had an inhibitory effect on non-exercise activity thermogenesis, which can be generated by orexin A (Novak et al., 2006;Novak and Levine, 2009). ...
The orexin system regulates feeding, nutrient metabolism and energy homeostasis. Acute pharmacological blockade of orexin receptor 1 (OXR-1) in rodents induces satiety and reduces normal and palatable food intake. Genetic OXR-1 deletion in mice improves hyperglycemia under high-fat (HF) diet conditions. Here we investigated the effects of chronic treatment with the novel selective OXR-1 antagonist ACT-335827 in a rat model of diet-induced obesity (DIO) associated with metabolic syndrome (MetS). Rats were fed either standard chow (SC) or a cafeteria (CAF) diet comprised of intermittent human snacks and a constant free choice between a HF/sweet (HF/S) diet and SC for 13 weeks. Thereafter the SC group was treated with vehicle (for 4 weeks) and the CAF group was divided into a vehicle and an ACT-335827 treatment group. Energy and water intake, food preference, and indicators of MetS (abdominal obesity, glucose homeostasis, plasma lipids, and blood pressure) were monitored. Hippocampus-dependent memory, which can be impaired by DIO, was assessed. CAF diet fed rats treated with ACT-335827 consumed less of the HF/S diet and more of the SC, but did not change their snack or total kcal intake compared to vehicle-treated rats. ACT-335827 increased water intake and the high-density lipoprotein associated cholesterol proportion of total circulating cholesterol. ACT-335827 slightly increased body weight gain (4% vs. controls) and feed efficiency in the absence of hyperphagia. These effects were not associated with significant changes in the elevated fasting glucose and triglyceride (TG) plasma levels, glucose intolerance, elevated blood pressure, and adiposity due to CAF diet consumption. Neither CAF diet consumption alone nor ACT-335827 affected memory. In conclusion, the main metabolic characteristics associated with DIO and MetS in rats remained unaffected by chronic ACT-335827 treatment, suggesting that pharmacological OXR-1 blockade has minimal impact in this model.
... perifornical, and dorsomedial hypothalamus (de Lecea et al., 1998, Sakurai et al., 1998, is crucial for normal energy homeostasis and arousal. Spontaneous physical activity stimulated by central OXA infusion induces weight loss (Novak and Levine, 2009) while mice lacking OXA are obese and have lower physical activity despite lower energy intake compared to wild-type mice (Hara et al., 2001), highlighting the critical energy balance role of OXAstimulated SPA. Central OXA infusion also stimulates arousal and lack of endogenous orexin or orexin receptors disrupts sleep/wake patterns, so it has been suggested that orexinstimulated SPA may be secondary to arousal. ...
Obesity resistance due to elevated orexin signaling is accompanied by high levels of spontaneous physical activity (SPA). The behavioral and neural mechanisms underlying this observation have not been fully worked out. We determined the contribution of hypothalamic orexin receptors (OXRs) to SPA stimulated by orexin A (OXA), whether OXA-stimulated SPA was secondary to arousal and whether voluntary wheel running led to compensations in 24-h SPA. We further tested whether orexin action on dopamine one receptors (DA1R) in the substantia nigra (SN) plays an important role in the generation of SPA. To test this, SPA response was determined in lean and obese rats with cannulae targeted toward the rostral lateral hypothalamus (rLH) or SN. Sleep/wake states were also measured in rats with rLH cannula and electroencephalogram/electromyogram radiotelemetry transmitters. SPA in lean rats was more sensitive to antagonism of the OX1R and in the early response to the orexin 2 agonist. OXA increased arousal equally in lean and obese rodents, which is discordant from the greater SPA response in lean rats. Obesity-resistant rats ran more and wheel running was directly related to 24-h SPA levels. The OX1R antagonist, SB-334867-A, and the DA1R antagonist, SCH3390, in SN more effectively reduced SPA stimulated by OXA in obesity-resistant rats. These data suggest OXA-stimulated SPA is not secondary to enhanced arousal, propensity for SPA parallels inclination to run and that orexin action on dopaminergic neurons in SN may participate in the mediation of SPA and running wheel activity.
... Administration of orexin-A during the light phase has repeatedly been shown to increase activity in control rodents for up to two hours during the normally inactive light phase (Fenzl et al., 2011;Kiwaki et al., 2004;Nakamura et al., 2000;Novak and Levine, 2009;Samson et al., 2010). Our treatment was aimed at restoring normal dark phase activity, not at producing a pharmacologic enhancement of activity during the normally quiescent light phase. ...
Fatigue is the most common symptom related to cytotoxic chemotherapeutic treatment of cancer. Peripheral inflammation associated with cytotoxic chemotherapy is likely a causal factor of fatigue. The neural mechanisms by which cytotoxic chemotherapy associated inflammation induces fatigue behavior are not known. This lack of knowledge hinders development of interventions to reduce or prevent this disabling symptom. Infection induced fatigue/lethargy in rodents is mediated by suppression of hypothalamic orexin activity. Orexin is critical for maintaining wakefulness and motivated behavior. Though there are differences between infection and cytotoxic chemotherapy in some symptoms, both induce peripheral inflammation and fatigue. Based on these similarities we hypothesized that cytotoxic chemotherapy induces fatigue by disrupting orexin neuron activity. We found that a single dose of a cytotoxic chemotherapy cocktail (cyclophosphamide, adriamycin, 5-fluorouracil-CAF) induced fatigue/lethargy in mice and rats as evidenced by a significant decline in voluntary locomotor activity measured by telemetry. CAF induced inflammatory gene expression-IL-1R1 (p<0.001), IL-6 (p<0.01), TNFα (p<0.01), and MCP-1 (p<0.05) -in the rodent hypothalamus 6 to 24 hours after treatment during maximum fatigue/lethargy. CAF decreased orexin neuron activity as reflected by decreased nuclear cFos localization in orexin neurons 24 hours after treatment (p<0.05) and by decreased orexin-A in cerebrospinal fluid 16 hours after treatment (p<0.001). Most importantly, we found that central administration of1 μg orexin-A restored activity in CAF-treated rats (p<0.05). These results demonstrate that cytotoxic chemotherapy induces hypothalamic inflammation and that suppression of hypothalamic orexin neuron activity has a causal role in cytotoxic chemotherapy-induced fatigue in rodents.
... Evidence suggests the impact of orexin A on SPA is more relevant to energy balance than its effects on feeding. First, orexin A therapy elicits weight loss (33) and leaner body composition (36). Also, mice lacking orexin show obesity caused by reduced physical activity de-spite hypophagia (14). ...
Orexin/hypocretin terminals innervate noradrenergic locus coeruleus (LC) neurons that project to the prefrontral cortex, which may influence spontaneous physical activity (SPA) and energy balance. Obesity resistant (OR) rats have higher orexin receptors (OXR) mRNA in the LC and other brain regions, as well as lower adiposity compared to obese rats. These findings led us to hypothesize that orexin activity in the LC is relevant for the OR phenotype. We compared OR rats to Sprague-Dawley rats. We predicted that: 1) brain OXR expression pattern is sufficient to differentiate OR from non-bred Sprague-Dawley rats; 2) non-resting energy expenditure (NREE) and orexin A (OXA) stimulated SPA after injection in LC would be greater in OR rats; and 3) the effect of OXA on SPA would be greater than its effect on feeding. OXR mRNA from 11 brain sites, and the SPA and feeding responses to OXA in the LC were determined. Body composition, basal SPA and EE were determined. Principal component analysis of the OXR expression pattern differentiates OR and Sprague-Dawley rats and suggests OXR mRNA in the LC is important in defining the OR phenotype. In comparison to Sprague-Dawley rats, OR rats had greater SPA and NREE, lower resting EE and adiposity. SPA responsivity to OXA in the LC was greater in OR rats compared to Sprague-Dawley rats. OXA in the LC did not stimulate feeding in OR or Sprague-Dawley rats. These data suggest that the LC is a prominent site modulating OXA-stimulated SPA, which promotes lower adiposity and higher non-resting EE.
... The orexins have important roles in energy balance and obesity [4,5,[8][9][10][11][12][13]. Evidence from genetic models suggests that orexins promote energy expenditure [14][15][16]. ...
The orexins are neuropeptides with critical functions in the central nervous system. These neuropeptides have important roles in energy balance and obesity, and therefore on the accumulation of adipose tissue. Rodents lacking orexins, typically through genetic knockouts, experience increased weight gain and accumulation of adipose tissue. Evidence indicates the lack of orexin increases adiposity as a result of decreased energy expenditure, principally through a reduction of physical activity. Different lines of evidence suggest other mechanisms are likely also in play, and neural influences on both white and brown adipose tissue remain to be fully and functionally defined. In addition, the orexin peptides and their receptors are expressed in adipose tissue, with little available information as to their significance. This review summarizes our current understanding of how the orexin peptides affect adipose tissue. We provide a brief introduction to the physiology of orexins and their effects on white and brown adipose tissue in the context of energy balance. We conclude this review by integrating this information in the context of the known physiology of the orexins. This article is part of a Special Issue entitled: Modulation of Adipose Tissue in Health and Disease.
... Orexin was known to increase food intake [109] and chronic intracerebroventricular administration of orexin-A to rats increased food intake in daytime [132]. Accordingly, it was seemingly paradoxical that orexin-A, as a matter of fact, acts to decrease body weight in this study [87]. Orexin was able to increase food intake, however, it also robustly increased the physical activity levels and energy expenditure at the same time. ...
Obstructive sleep apnea (OSA) is a complicated disease with an unrecognized mechanism. Obesity, sex, age, and smoking have been found to be independent correlates of OSA. Orexin (also named hypocretin) mainly secreted by lateral hypothalamus neurons, has a wide array of biological functions like regulating sleep, energy-levels and breathingl. Several clinical studies found ties between orexin and OSA. Because of the close correlation between orexin and obesity, sex, age and smoking (which are the key risk factors for OSA patients), we hypothesize that orexin may play a key role in the pathogenesis of OSA.
... Despite the fact that orexin significantly increases food intake in the daytime, continuous intracerebroventricular administration has no effect on body weight [51] and daily intraparaventricular orexin treatment even induces weight loss [62] in rats. on the other hand, in orexin-or orexin receptorknockout mice, body weight is increased [23,41,63] . ...
The neuropeptide orexin is synthesized by neurons exclusively located in the hypothalamus. However, these neurons send axons over virtually the entire brain and spinal cord and therefore constitute a unique central orexinergic system. it is well known that central orexin plays a crucial role in the regulation of various basic non-somatic and somatic physiological functions, including feeding, energy homeostasis, the sleep/wake cycle, reward, addiction, and neuroendocrine, as well as motor control. Moreover, the absence of orexin results in narcolepsy-cataplexy, a simultaneous somatic and non-somatic dysfunction. in this review, we summarize these central functions of the orexinergic system and associated diseases, and suggest that this system may hold a key position in somatic-non-somatic integration.
... Therefore, we suggest that there is no theoretical necessity for adaptations of orexin signaling to follow a linear trend within a single brain site. This highlights the need to investigate the effects DIO on orexin signaling adaptations in other brain sites that regulate SPA, including PVN, NAC, and SN (22,26,37). ...
There is significant variability in diet-induced obesity (DIO) among humans and rodents, which has been associated with differences in intrinsic spontaneous physical activity (SPA). The orexin neuropeptides positively modulate SPA through multiple brain sites, but the effects of DIO on orexin's activity are not well understood. In this study, we tested the hypothesis that DIO sensitivity is mediated by decreased SPA and changes in the function of the orexins. As a DIO model, we used male Sprague-Dawley rats fed a high-fat (HF; 45% kcal from fat) or a low-fat (LF; 10% kcal from fat) diet for 10 wk. We measured SPA before and after HF or LF feeding and expression of orexin receptors by real-time PCR after dietary treatments. We tested DIO effects on orexin signaling by measuring SPA after injection of orexin A in the rostral lateral hypothalamus (RLH) before and after 10 wk of HF feeding. Finally, we tested whether daily orexin A RLH injections prevent DIO caused by HF feeding. Our results show that resistance to DIO is associated with an increase in SPA, SPA after injection of orexin A in RLH, and orexin receptor expression in sites that mediate orexin's effect on SPA, including RLH. We show that daily injections of orexin peptide in RLH prevent DIO without altering food intake. We estimate that the energetic cost of SPA after orexin A RLH injection accounts for approximately 61% of the extra caloric intake associated with HF intake, suggesting additional effects of orexins. In summary, our results suggest that variability in DIO sensitivity is mediated through adaptations in the activity of the orexin peptides and their receptors.
... We and others have shown that in contrast to OP rats, which display lower SPA levels after high-fat diet consumption, OR rats maintain high basal SPA levels and have greater OXA-induced SPA after high fat diet feeding.97 Most importantly, we also showed that rLH-OXA increases energy expenditure,93 and others found that daily OXA treatment reduces body weight by increasing SPA.98 These findings support the hypothesis that elevated energy expenditure due to SPA-promoting agents such as OXA and defense from SPA-dampening treatments protects against excessive adiposity gain in OR rats. ...
Resistance to obesity is becoming an exception rather than the norm, and understanding mechanisms that lead some to remain lean in spite of an obesigenic environment is critical if we are to find new ways to reverse this trend. Levels of energy intake and physical activity both contribute to body weight management, but it is challenging for most to adopt major long-term changes in either factor. Physical activity outside of formal exercise, also referred to as activity of daily living, and in stricter form, spontaneous physical activity (SPA), may be an attractive modifiable variable for obesity prevention. In this review, we discuss individual variability in SPA and NEAT (nonexercise thermogenesis, or the energy expended by SPA) and its relationship to obesity resistance. The hypothalamic neuropeptide orexin (hypocretin) may play a key role in regulating SPA and NEAT. We discuss how elevated orexin signaling capacity, in the context of a brain network modulating SPA, may play a major role in defining individual variability in SPA and NEAT. Greater activation of this SPA network leads to a lower propensity for fat mass gain and therefore may be an attractive target for obesity prevention and therapy.
... While the magnitude of OXA-induced physical activity varies with respect to the location of the microinjection (Kotz et al., 2008), the overall stimulatory effect remains consistent. Thus far, OXA infusion into the following brain sites has been shown to reliably stimulate physical activity: lateral hypothalamus, hypothalamic paraventricular nucleus, substantia nigra, tuberomammillary nucleus, dorsal raphe, nucleus accumbens, medial preoptic area, and locus coeruleus (Espana et al., 2001;Kiwaki et al., 2004;Kotz et al., 2002Kotz et al., , 2006Kotz et al., , 2008Novak and Levine, 2009;Novak et al., 2006;Teske et al., 2006Teske et al., , 2010Thorpe and Kotz, 2005). Likewise, OXA infused into the medial preoptic area and medial septum elicits grooming (Espana et al., 2001). ...
The orexins/hypocretins are endogenous, modulatory and multifunctional neuropeptides with prominent influence on several physiological processes. The influence of orexins on energy expenditure is highlighted with focus on orexin action on individual components of energy expenditure. As orexin stabilizes and maintains normal states of arousal and the sleep/wake cycle, we also highlight orexin mediation of sleep and how sleep interacts with energy expenditure.
... Narcoleptics also presented with EDS, sleep onset REM periods, cataplexy, and fragmented sleep, which further supported a role for orexin in sleep/wake regulation. In contrast to orexin deficiency, orexin over expression consolidated sleep wake states and prevented weight gain in mice (Funato et al., 2009) and daily orexin treatment decreased weight gain in rats (Novak and Levine, 2009). Orexin also stimulated spontaneous physical activity and energy expenditure (Hagan et al., 1999; Lubkin and Stricker-Krongrad, 1998). ...
The rapid rise in obesity prevalence in the modern world parallels a significant reduction in restorative sleep (Agras et al., 2004; Dixon et al., 2007, 2001; Gangwisch and Heymsfield, 2004; Gupta et al., 2002; Sekine et al., 2002; Vioque et al., 2000; Wolk et al., 2003). Reduced sleep time and quality increases the risk for obesity, but the underlying mechanisms remain unclear (Gangwisch et al., 2005; Hicks et al., 1986; Imaki et al., 2002; Jennings et al., 2007; Moreno et al., 2006). A majority of the theories linking human sleep disturbances and obesity rely on self-reported sleep. However, studies with objective measurements of sleep/wake parameters suggest a U-shaped relationship between sleep and obesity. Studies in animal models are needed to improve our understanding of the association between sleep disturbances and obesity. Genetic and experimenter-induced models mimicking characteristics of human obesity are now available and these animal models will be useful in understanding whether sleep disturbances determine propensity for obesity, or result from obesity. These models exhibit weight gain profiles consistently different from control animals. Thus a careful evaluation of animal models will provide insight into the relationship between sleep disturbances and obesity in humans. In this review we first briefly consider the fundamentals of sleep and key sleep disturbances, such as sleep fragmentation and excessive daytime sleepiness (EDS), observed in obese individuals. Then we consider sleep deprivation studies and the role of circadian alterations in obesity. We describe sleep/wake changes in various rodent models of obesity and obesity resistance. Finally, we discuss possible mechanisms linking sleep disturbances with obesity.
... The effects of orexin on physical activity, including increases in locomotion, rearing, grooming, and burrowing activities, require muscular contraction and thus expend energy. Consistent with this idea, acute intra-PVH OXA dose-dependently increases physical activity and energy expenditure in rodents Kiwaki et al. 2004), and chronic OXA increases physical activity and reduces body weight (Novak and Levine 2009). ...
In this chapter, we review the feeding and energy expenditure effects of orexin (also known as hypocretin) and neuromedin. Orexins are multifunctional neuropeptides that affect energy balance by participating in regulation of appetite, arousal, and spontaneous physical activity. Central orexin signaling for all functions originates in the lateral hypothalamus-perifornical area and is likely functionally differentiated based on site of action and on interacting neural influences. The effect of orexin on feeding is likely related to arousal in some ways but is nonetheless a separate neural process that depends on interactions with other feeding-related neuropeptides. In a pattern distinct from other neuropeptides, orexin stimulates both feeding and energy expenditure. Orexin increases in energy expenditure are mainly by increasing spontaneous physical activity, and this energy expenditure effect is more potent than the effect on feeding. Global orexin manipulations, such as in transgenic models, produce energy balance changes consistent with a dominant energy expenditure effect of orexin. Neuromedins are gut-brain peptides that reduce appetite. There are gut sources of neuromedin, but likely the key appetite-related neuromedin-producing neurons are in the hypothalamus and parallel other key anorectic neuropeptide expression in the arcuate to paraventricular hypothalamic projection. As with other hypothalamic feeding-related peptides, hindbrain sites are likely also important sources and targets of neuromedin anorectic action. Neuromedin increases physical activity in addition to reducing appetite, thus producing a consistent negative energy balance effect. Together with the other various neuropeptides, neurotransmitters, neuromodulators, and neurohormones, neuromedin and orexin act in the appetite network to produce changes in food intake and energy expenditure, which ultimately influences the regulation of body weight.
... Therefore, our findings of a persistent increase in OX and MCH expression in HFC animals, even after two weeks on a low-fat chow diet, suggest that these animals have endogenous differences in the PFLH peptides that contribute to their increase in consummatory behavior when given access to a meal high in fat content. In light of recent evidence suggesting that OX may protect against weight gain (Funato et al., 2009), possibly by increasing activity levels in animals (Novak and Levine, 2009), our results of increased OX and also MCH peptide expression, which is accompanied by higher activity levels in HFC animals that go on to consume more high-fat diet, may reflect a protective mechanism that helps to maintain homeostatic energy levels. ...
The goal of this study is to examine the expression pattern of orexigenic peptides, orexin (OX) and melanin-concentrating hormone (MCH), in the perifornical lateral hypothalamus (PFLH) in subpopulations of Sprague-Dawley rats differing in their propensity to overconsume a high-fat diet. Immediately after an initial 5-day screening test that predicts long-term consumption, rats identified as high-fat consumers (HFC), ingesting 35% more calories of a high-fat relative to low-fat chow diet, had significantly elevated mRNA expression of OX in the perifornical but not lateral hypothalamic area and of MCH mRNA in both areas, when compared to control rats that consume similar amounts of these diets. This same OX and MCH expression pattern was seen in HFC rats maintained for two weeks on a low-fat chow diet, indicating that increased expression of these orexigenic peptides, occurring independently of the high-fat diet, may be an inherent characteristic of these rats. These HFC rats were also more active and slightly more anxious than controls, as measured by line crossings and time spent in the periphery or middle segments of an open field. Together, these results demonstrate that animals prone to overeating a high-fat diet show a baseline increase in orexigenic peptide expression in the PFLH along with higher behavioral arousal, which together may contribute to their increased consummatory behavior.
... These differential effects of acute and chronic ethanol on mRNA expression are consistent with previous results obtained with injection studies. Whereas acute injection of OX into the LH has a stimulatory effect on ethanol intake (Schneider et al., 2007) and food intake (Haynes et al., 1999;Sakurai, 1999;Sweet et al., 1999), the effect of chronic injection of OX on feeding diminishes or is reversed to a suppression (Novak and Levine, 2009;Rossi et al., 1997;Yamanaka et al., 1999). Together, these studies suggest that OX may function within a negative feedback circuit, in contrast to the proposed positive feedback system regulating GAL and ENK in the PVN (Chang et al., 2007;Leibowitz et al., 2003). ...
Background:
Recent reports support the involvement of hypothalamic orexigenic peptides in stimulating ethanol intake. Our previous studies have examined the effects of ethanol on hypothalamic peptide systems of the paraventricular nucleus (PVN) and identified a positive feedback loop in which PVN peptides, such as enkephalin and galanin, stimulate ethanol intake and ethanol, in turn, stimulates the expression of these peptides. Recently, orexin (OX), a peptide produced mainly by cells in the perifornical lateral hypothalamus (PFLH), has been shown to play an important role in mediating the rewarding aspects of ethanol intake. However, there is little evidence showing the effects that ethanol itself may have on the OX peptide system. In order to understand the feedback relationship between ethanol and the OX system, the current investigation was designed to measure OX gene expression in the PFLH following acute as well as chronic ethanol intake.
Methods:
In the first experiment, Sprague-Dawley rats were trained to voluntarily consume a 2 or 9% concentration of ethanol, and the expression of OX mRNA in the PFLH was measured using quantitative real-time polymerase chain reaction (qRT-PCR). The second set of experiments tested the impact of acute oral gavage of 0.75 and 2.5 g/kg ethanol solution on OX expression in the PFLH using qRT-PCR, as well as radiolabeled in situ hybridization. Further tests using digoxigenin-labeled in situ hybridization and immunofluorescence histochemistry allowed us to more clearly distinguish the effects of acute ethanol on OX cells in the lateral hypothalamic (LH) versus perifornical (PF) regions.
Results:
The results showed chronic consumption of ethanol versus water to dose-dependently reduce OX mRNA in the PFLH, with a larger effect observed in rats consuming 2.5 g/kg/d (-70%) or 1.0 g/kg/d (-50%) compared to animals consuming 0.75 g/kg/d (-40%). In contrast to chronic intake, acute oral ethanol compared to water significantly enhanced OX expression in the PFLH, and this effect occurred at the lower (0.75 g/kg) but not higher (2.5 g/kg) dose of ethanol. Additional analyses of the OX cells in the LH versus PF regions identified the former as the primary site of ethanol's stimulatory effect on the OX system. In the LH but not the PF, acute ethanol increased the density of OX-expressing and OX-immunoreactive neurons. The increase in gene expression was detected only at the lower dose of ethanol (0.75 g/kg), whereas the increase in OX peptide was seen only at the higher dose of ethanol (2.5 g/kg).
Conclusion:
These results lead us to propose that OX neurons, while responsive to negative feedback signals from chronic ethanol consumption, are stimulated by acute ethanol administration, most potently in the LH where OX may trigger central reward mechanisms that promote further ethanol consumption.
... Intra-arcuate injections of orexin-A in anesthetized rats increased oxygen consumption (V O 2 ) and body temperature (60). On the other hand, daily intra-PVN injection of orexin-A increased locomotor activity with no change in food intake (38). In agreement with these orexin effects, besides hyperphagia, weight loss and increased energy expenditure have been shown in rats undergoing prolonged sleep deprivation by different procedures (3,22). ...
Several pieces of evidence support that sleep duration plays a role in body weight control. Nevertheless, it has been assumed that, after the identification of orexins (hypocretins), the molecular basis of the interaction between sleep and energy homeostasis has been provided. However, no study has verified the relationship between neuropeptide Y (NPY) and orexin changes during hyperphagia induced by sleep deprivation. In the current study we aimed to establish the time course of changes in metabolite, endocrine, and hypothalamic neuropeptide expression of Wistar rats sleep deprived by the platform method for a distinct period (from 24 to 96 h) or sleep restricted for 21 days (SR-21d). Despite changes in the stress hormones, we found no changes in food intake and body weight in the SR-21d group. However, sleep-deprived rats had a 25-35% increase in their food intake from 72 h accompanied by slight weight loss. Such changes were associated with increased hypothalamus mRNA levels of prepro-orexin (PPO) at 24 h followed by NPY at 48 h of sleep deprivation. Conversely, sleep recovery reduced the expression of both PPO and NPY, which rapidly brought the animals to a hypophagic condition. Our data also support that sleep deprivation rapidly increases energy expenditure and therefore leads to a negative energy balance and a reduction in liver glycogen and serum triacylglycerol levels despite the hyperphagia. Interestingly, such changes were associated with increased serum levels of glucagon, corticosterone, and norepinephrine, but no effects on leptin, insulin, or ghrelin were observed. In conclusion, orexin activation accounts for the myriad changes induced by sleep deprivation, especially the hyperphagia induced under stress and a negative energy balance.
Ingested nutrients are proposed to control mammalian behavior by modulating the activity of hypothalamic orexin/hypocretin neurons (HONs). Previous in vitro studies showed that nutrients ubiquitous in mammalian diets, such as non-essential amino acids (AAs) and glucose, modulate HONs in distinct ways. Glucose inhibits HONs, whereas non-essential (but not essential) AAs activate HONs. The latter effect is of particular interest because its purpose is unknown. Here, we show that ingestion of a dietary-relevant mix of non-essential AAs activates HONs and shifts behavior from eating to exploration. These effects persisted despite ablation of a key neural gut → brain communication pathway, the cholecystokinin-sensitive vagal afferents. The behavioral shift induced by the ingested non-essential AAs was recapitulated by targeted HON optostimulation and abolished in mice lacking HONs. Furthermore, lick microstructure analysis indicated that intragastric non-essential AAs and HON optostimulation each reduce the size, but not the frequency, of consumption bouts, thus implicating food palatability modulation as a mechanism for the eating suppression. Collectively, these results suggest that a key purpose of HON activation by ingested, non-essential AAs is to suppress eating and re-initiate food seeking. We propose and discuss possible evolutionary advantages of this, such as optimizing the limited stomach capacity for ingestion of essential nutrients.
The present study was aimed to investigate the effects of orexin-A and orexin-1 receptor (OX1R) antagonist injected into the fourth ventricle of rats on food-intake and spontaneous physical activity (SPA). Obese rat model was induced by high fat diet. Different doses of orexin-A or SB334867, an OX1R antagonist, were injected into the fourth ventricle of obese and normal rats respectively. SPA and food intake were monitored for 4 h after injection in both light and dark environment. In the light measurement cycle, different doses of orexin-A significantly stimulated feeding and SPA in all injected rats, and the animals' responses showed a dose-dependent manner (P < 0.05-0.01), and compared with those of normal rats, the orexin-A induced food intake and SPA were more pronounced in obese rats. In the dark measurement cycle, different doses of orexin-A had no obvious effect on food intake and SPA in both normal and obese rats (P > 0.05). In the light cycle, different doses of SB334867 significantly decreased food intake and SPA in all rats during 0-2 h and 2-4 h after injection (P < 0.05), but the food intake and SPA in obese rats were significantly greater than those of normal rats. In the dark cycle, different doses of SB334867 showed no obvious effect on food intake and SPA of normal and obese rats (P > 0.05). These results suggest that fourth cerebral ventricle nuclei may be one target for orexin-A and light condition may play an important role in orexin-A and OX1R physiological functional processes.
On 26–28 April 2013, the American Diabetes Association convened an international group of experts in Washington, DC, for a research symposium titled “Biologic Responses to Weight Loss and Weight Regain.” The speakers addressed the following topics: 1 ) developmental processes and the prevention of weight gain, 2 ) behavioral management approaches to weight loss, 3 ) distinctions between the physiological mechanisms of weight loss and weight maintenance and the implications for treatment, 4 ) the role of exercise in weight loss and maintenance, 5 ) the physiological mechanisms and effectiveness of bariatric surgery, and 6 ) pharmacological approaches to weight loss and maintenance. Both scientific and clinical perspectives were provided. The meeting concluded with an open session in which all the participants discussed emerging areas of investigation as well as unmet research needs. This discussion resulted in a series of recommendations for future research directions (Table 1). This Perspective article consists of summaries of the symposium sessions, by topic.
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Table 1
Recommendations for research questions regarding biologic responses to weight loss and weight regain
The rapid increase in the prevalence of childhood obesity has drawn attention to early life influences that may, in part, explain the increased susceptibility to weight gain for individuals and populations. This session featured investigators examining gestational factors and events early in intra- and extrauterine development that may predispose individuals to obesity later in life, such as the programming of the body weight “set point.” These investigations may uncover developmental stages where behavioral or clinical interventions could be implemented to prevent or minimize excessive weight gain.
A propensity toward obesity may begin in utero. Over 40 studies have found a U-shaped relationship between birth weight and the risk for a variety of illnesses, including obesity, type 2 diabetes, and cardiovascular disease, with both high and low birth weights associated with greater risk. Susan Ozanne …
Unlabelled:
Orexin-A has been shown to modulate pain sensation and increase appetite. Rheumatoid arthritis (RA) is characterized by joint destruction, deformity, hyperalgesia, and weight reduction.
Aim:
Evaluate the possible effect of orexin-A on hyperalgesic and cachectic manifestations in an adjuvant-induced arthritis (AIA) rat model.
Methods:
Forty adult male Wistar rats were distributed among 4 groups; I, normal controls; II, rats with AIA induced by intradermal injection of Mycobacterium butyricum, but with no other treatment; III, AIA rats treated daily with an intravenous injection of orexin-A for 8 days; and IV, AIA rats treated orally with dexamethasone for 8 days. The parameters we assessed were pain-associated behavior, body mass, hind paw volume, serum levels of nerve growth factor (NGF) and neuropeptide Y (NPY).
Results:
Orexin-A caused a significant reduction in pain sensation and NGF levels, and increased body mass and the levels of NPY, whereas treatment with dexamethasone led to significant reductions in paw swelling and pain sensation.
Conclusion:
Orexin-A has hypoalgesic properties and increases body mass, whereas dexamethasone has a potent anti-inflammatory effect. Therefore, the combination of orexin-A and dexamethasone should have a greater effect with respect to attenuating the manifestations and complications associated with RA.
Nutrition plays a dominant role in human adaptation. Biological traits conferring these adaptations are of considerable significance. Within an obesogenic environment, there is considerable variation among individuals in their susceptibility to weight gain. Some individuals rapidly gain weight, whereas others remain lean without any conscious effort, suggesting that obesity pathogenesis may not be centered on just the primal feeding behavior. The ability of certain individuals to subconsciously resist obesity reveals adaptive calorie-burning mechanisms that may promote fitness. Here, we review a fat-burning mechanism that is turned on by the brain hormone orexin during high-caloric food consumption. Remarkably, the same hormone also induces feeding, and its levels correlate with lean body mass in both rodents and humans. Intriguingly, loss of orexin prevents thermogenic energy expenditure while inducing obesity in the face of hypophagia. Thus, orexin is a unique neuropeptide that promotes both feeding and energy expenditure, conferring resistance to weight gain. Mechanisms that safely augment orexin signaling may have potential in antiobesity therapeutics.
Orexin A regulates food intake, energy metabolism and gastrointestinal function; it also increases glucose uptake and inhibits lipolysis, suggesting a role for orexin A in glucose and lipid metabolism. In this study, the effects of orexin A on glucose transporter 4 (GLUT4) mRNA level and lipid content were explored in 3T3-L1 preadipocytes and adipocytes. Orexin receptor 1 (OX1R) protein expression was determined in the adipose tissue of normal and obese rats. In addition, 3T3-L1 preadipocytes and differentiated 3T3-L1 adipocytes were incubated with different concentrations of orexin A (10(-9)-10(-7)M), without or with OX1Rspecific antagonist, then the peroxisome proliferator-activated receptor-γ2 (PPARγ2) mRNA expression was analyzed. Differentiated 3T3-L1 adipocytes were exposed to orexin A, without or with MAPK and OX1R antagonist, after which the GLUT4 and ERK1/2, JNK, and p38 MAPK activation, and triglyceride (TG) content were measured. We observed that OX1R protein expression was decreased in obese rats, and OX1R protein level was negatively correlated with body fat, Lee's index, TG, total cholesterol, and fasting insulin levels. Orexin A enhanced PPARγ2 mRNA expression in a dose-dependent manner in 3T3-L1 preadipocytes through OX1R. In differentiated 3T3-L1 adipocytes, orexin A significantly increased GLUT4 mRNA levels, which was blocked by the ERK1/2, JNK, and p38 MAPK inhibitors as well as OX1R antagonist. Furthermore, orexin A increased cellular TG content via ERK1/2, JNK, and p38 MAPK as well as OX1R. Thus, orexin A increases GLUT4 mRNA expression and lipid accumulation in differentiated 3T3-L1 adipocytes via ERK1/2, JNK, and p38 MAPK signaling. In addition, orexin A increases PPARγ2 mRNA expression in 3T3-L1 preadipocytes. Further studies are necessary to elucidate the impact of orexin A in metabolic disorders and adipocyte differentiation.
To determine if resistance to weight gain is associated with alterations in sleep-wake states and orexin receptor gene expression.
Three-month-old obesity-susceptible Sprague-Dawley (SD) and obesity-resistant (OR) rats were fed standard rodent chow. Sleep-wake cycle was measured by radiotelemetry and orexin receptor profiles in sleep-wake regulatory areas of the brain were quantified by quantitative reverse transcriptase-PCR.
Adult male obesity-susceptible SD and selectively bred OR rats.
Body weight, food intake, energy efficiency, percent time spent in active wake (AW), quiet wake (QW), slow-wave sleep (SWS), rapid eye movement (REM) sleep, number and mean duration of sleep-wake episodes, number of stage transitions, SWS sleep delta power and orexin receptor mRNA levels were measured.
OR rats weighed significantly less and had lower energy efficiency than SD rats. Food intake was not different between SD and OR rats. Time spent in QW was similar between groups, and therefore AW and QW were combined and are referred to as 'wakefulness'. OR rats spent significantly more time in wakefulness and less time in SWS compared with SD rats during the 24-h recording period. Relative to SD rats, OR rats had significantly fewer sleep-wake episodes and the duration of the episodes were prolonged, indicating less fragmented sleep. Furthermore, OR rats had fewer transitions between sleep stages, which indicates that OR rats were behaviorally more stable and had more consolidated sleep than obesity-susceptible SD rats. OR rats showed lower delta power during SWS, indicating a lower sleep drive. Our results showed greater orexin receptor gene expression in sleep regulatory brain areas in OR rats.
These results show that prolonged wakefulness, better sleep quality, lower sleep drive and greater orexin signaling may confer protection against obesity.
Though obesity is common, some people remain resistant to weight gain even in an obesogenic environment. The propensity to remain lean may be partly associated with high endurance capacity along with high spontaneous physical activity and the energy expenditure of activity, called non-exercise activity thermogenesis (NEAT). Previous studies have shown that high-capacity running rats (HCR) are lean compared to low-capacity runners (LCR), which are susceptible to cardiovascular disease and metabolic syndrome. Here, we examine the effect of diet on spontaneous activity and NEAT, as well as potential mechanisms underlying these traits, in rats selectively bred for high or low intrinsic aerobic endurance capacity. Compared to LCR, HCR were resistant to the sizeable increases in body mass and fat mass induced by a high-fat diet; HCR also had lower levels of circulating leptin. HCR were consistently more active than LCR, and had lower fuel economy of activity, regardless of diet. Nonetheless, both HCR and LCR showed a similar decrease in daily activity levels after high-fat feeding, as well as decreases in hypothalamic orexin-A content. The HCR were more sensitive to the NEAT-activating effects of intra-paraventricular orexin-A compared to LCR, especially after high-fat feeding. Lastly, levels of cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C) in the skeletal muscle of HCR were consistently higher than LCR, and the high-fat diet decreased skeletal muscle PEPCK-C in both groups of rats. Differences in muscle PEPCK were not secondary to the differing amount of activity. This suggests the possibility that intrinsic differences in physical activity levels may originate at the level of the skeletal muscle, which could alter brain responsiveness to neuropeptides and other factors that regulate spontaneous daily activity and NEAT.
The hypothalamic orexin neuropeptide acutely promotes appetite, yet orexin deficiency in humans and mice is associated with obesity. Prolonged effects of increased orexin signaling upon energy homeostasis have not been fully characterized. Here, we examine the metabolic effects of orexin gain of function utilizing genetic and pharmacologic techniques in mice. Transgenic orexin overexpression confers resistance to high-fat diet-induced obesity and insulin insensitivity by promoting energy expenditure and reducing consumption. Genetic studies indicate that orexin receptor-2 (OX2R), rather than OX1R signaling, predominantly mediates this phenotype. Likewise, prolonged central administration of an OX2R-selective peptide agonist inhibits diet-induced obesity. While orexin overexpression enhances the anorectic-catabolic effects of central leptin administration, obese leptin-deficient mice are completely resistant to the metabolic effects of orexin overexpression or OX2R agonist infusion. We conclude that enhanced orexin-OX2R signaling confers resistance to diet-induced features of the metabolic syndrome through negative energy homeostasis and improved leptin sensitivity.
Humans show considerable interindividual variation in susceptibility to weight gain in response to overeating. The physiological
basis of this variation was investigated by measuring changes in energy storage and expenditure in 16 nonobese volunteers
who were fed 1000 kilocalories per day in excess of weight-maintenance requirements for 8 weeks. Two-thirds of the increases
in total daily energy expenditure was due to increased nonexercise activity thermogenesis (NEAT), which is associated with
fidgeting, maintenance of posture, and other physical activities of daily life. Changes in NEAT accounted for the 10-fold
differences in fat storage that occurred and directly predicted resistance to fat gain with overfeeding (correlation coefficient
= 0.77, probability < 0.001). These results suggest that as humans overeat, activation of NEAT dissipates excess energy to
preserve leanness and that failure to activate NEAT may result in ready fat gain.
Obesity occurs when energy intake exceeds energy expenditure. Humans expend energy through purposeful exercise and through
changes in posture and movement that are associated with the routines of daily life [called nonexercise activity thermogenesis
(NEAT)]. To examine NEAT's role in obesity, we recruited 10 lean and 10 mildly obese sedentary volunteers and measured their
body postures and movements every half-second for 10 days. Obese individuals were seated, on average, 2 hours longer per day
than lean individuals. Posture allocation did not change when the obese individuals lost weight or when lean individuals gained
weight, suggesting that it is biologically determined. If obese individuals adopted the NEAT-enhanced behaviors of their lean
counterparts, they might expend an additional 350 calories (kcal) per day.
Nonexercise activity thermogenesis (NEAT), the most variable component of energy expenditure, can account for differential capacities for human weight gain. Also highly variable, spontaneous physical activity (SPA) may similarly affect weight balance in animals. In the following study, we utilized the rat model of obesity, the diet-induced obese (DIO) rat, as well as the diet-resistant (DR) rat strain, to investigate how access to a high-fat diet alters SPA and the associated energy expenditure (i.e., NEAT). DIO and DR rats showed no differences in the amount of SPA before access to the high-fat diet. After 29 days on a high-fat diet, the DIO rats showed significant decreases in SPA, whereas the DR rats did not. Next, we wanted to determine whether the DIO and DR rats showed differential sensitivity to microinjections of orexin into the paraventricular nucleus of the hypothalamus (PVN). Unilateral guide cannulae were implanted, aimed at the PVN. Orexin A (0, 0.125, 0.25, and 1.0 nmol in 500 nl) was microinjected through the guide cannula into the PVN, then SPA and energy expenditure were measured for 2 h. Using the response to vehicle as a baseline, the DR rats showed significantly greater increase in NEAT compared with the DIO rats. These data indicate that diet-induced obesity is associated with decreases in SPA and a lack of increase in NEAT. A putative mechanism for changes in NEAT that accompany obesity is a decreased sensitivity to the NEAT-activating effects of neuropeptides such as orexin.
Selectively-bred obesity-resistant [diet resistant (DR)] rats weigh less than obesity-prone [diet-induced obese (DIO)] rats, despite comparable daily caloric intake, suggesting phenotypic energy expenditure differences. Human data suggest that obesity is maintained by reduced ambulatory or spontaneous physical activity (SPA). The neuropeptide orexin A robustly stimulates SPA. We hypothesized that DR rats have greater: 1) basal SPA, 2) orexin A-induced SPA, and 3) preproorexin, orexin 1 and 2 receptor (OX1R and OX2R) mRNA, compared with DIO rats. A group of age-matched out-bred Sprague-Dawley rats were used as additional controls for the behavioral studies. DIO, DR, and Sprague-Dawley rats with dorsal-rostral lateral hypothalamic (rLHa) cannulas were injected with orexin A (0, 31.25, 62.5, 125, 250, and 500 pmol/0.5 microl). SPA and food intake were measured for 2 h after injection. Preproorexin, OX1R and OX2R mRNA in the rLHa, and whole hypothalamus were measured by real-time RT-PCR. Orexin A significantly stimulated feeding in all rats. Orexin A-induced SPA was significantly greater in DR and Sprague-Dawley rats than in DIO rats. Two-mo-old DR rats had significantly greater rLHa OX1R and OX2R mRNA than DIO rats but comparable preproorexin levels. Eight-mo-old DR rats had elevated OX1R and OX2R mRNA compared with DIO rats, although this increase was significant for OX2R only at this age. Thus DR rats show elevated basal and orexin A-induced SPA associated with increased OX1R and OX2R gene expression, suggesting that differences in orexin A signaling through OX1R and OX2R may mediate DIO and DR phenotypes.
There is debate over the independent and combined effects of dieting and increased physical activity on improving metabolic risk factors (body composition and fat distribution).
The objective of the study was to conduct a randomized, controlled trial (CALERIE) to test the effect of a 25% energy deficit by diet alone or diet plus exercise for 6 months on body composition and fat distribution.
This was a randomized, controlled trial.
The study was conducted at an institutional research center.
Thirty-five of 36 overweight but otherwise healthy participants (16 males, 19 females) completed the study.
Participants were randomized to either control (healthy weight maintenance diet, n = 11), caloric restriction (CR; 25% reduction in energy intake, n = 12), or caloric restriction plus exercise (CR+EX; 12.5% reduction in energy intake + 12.5% increase in exercise energy expenditure, n = 12) for 6 months.
Changes in body composition by dual-energy x-ray absorptiometry and changes in abdominal fat distribution by multislice computed tomography were measured. Results: The calculated energy deficit across the intervention was not different between CR and CR+EX. Participants lost approximately 10% of body weight (CR: - 8.3 +/- 0.8, CR+EX: - 8.1 +/- 0.8 kg, P = 1.00), approximately 24% of fat mass (CR: - 5.8 +/- 0.6, CR+EX: - 6.4 +/- 0.6 kg, P = 0.99), and 27% of abdominal visceral fat (CR: 0.9 +/- 0.2, CR+EX: 0.8 +/- 0.2 kg, P = 1.00). Both whole-body and abdominal fat distribution were not altered by the intervention.
Exercise plays an equivalent role to CR in terms of energy balance; however, it can also improve aerobic fitness, which has other important cardiovascular and metabolic implications.
Orexins are recently identified neuropeptides, and have been shown to increase food intake when administered intracerebroventricularly. We examined the effects of chronic administration of orexin in rats by continuous intracerebroventricular administration by means of an osmotic minipump. Continuous administration of orexin-A (0.5 nmol/h) for 7 days in rats resulted in a significant increase in food intake in the daytime. Daytime food intake increased to 180% of the control value. However, it resulted in a slight decrease nighttime food intake as compared with vehicle-treated rats. The total amount of food intake per day was almost comparable with that of vehicle-administered rats. The gain of body weight and blood glucose, total cholesterol and free fatty acid levels were normal. Chronic orexin-A treatment did not cause obesity in rats. We observed abnormal behavior during the daytime after starting administration of orexin-A; these rats kept awake during the daytime. Our present observation showed that continuous administration of orexin-A could not overcome the regulation of energy homeostasis and body weight. However, orexin-A might be implicated in short-term, immediate regulation of feeding behavior.
Lesions restricted to the ventromedial nucleus of the hypothalamus were neither necessary nor sufficient for, and did not contribute to, the production of hypothalamic obesity. Hypothalamic lesions and knife cuts that do produce obesity damage the nearby ventral noradrenergic bundle or its terminals.
The hypothalamus plays a central role in the integrated control of feeding and energy homeostasis. We have identified two novel neuropeptides, both derived from the same precursor by proteolytic processing, that bind and activate two closely related (previously) orphan G protein-coupled receptors. These peptides, termed orexin-A and -B, have no significant structural similarities to known families of regulatory peptides. prepro-orexin mRNA and immunoreactive orexin-A are localized in neurons within and around the lateral and posterior hypothalamus in the adult rat brain. When administered centrally to rats, these peptides stimulate food consumption. prepro-orexin mRNA level is up-regulated upon fasting, suggesting a physiological role for the peptides as mediators in the central feedback mechanism that regulates feeding behavior.
Orexin-A and orexin-B (OX peptides) are two putative products of a newly discovered secreted protein encoded by a mRNA restricted to neuronal cell bodies of the lateral hypothalamus (LH). Because the activation of the LH can induce changes in energy balance, we wanted to investigate the actions of OX peptides on energy metabolism in mice. We injected male C57BL/6J mice with different doses (1, 3, and 10 nmol) of orexin-A and orexin-B into the third ventricle (i3vt). A single i3vt injection of orexin-A 3 h into the light period slightly stimulated feeding at the lowest dose only over the following 4 h (11 +/- 09 mg/mouse vs 80 +/- 13 mg/mouse, p < 0.05). Orexin-B showed no effects at any dose. We therefore investigated the effects of 3 nmol orexin-A on energy utilization using indirect calorimetry. Single i3vt injection 3 h after light on, or just before dark onset, or in 4-h fasted mice resulted in increases in the metabolic rate. These effects were associated with decreases or increases in the respiratory quotient regarding the time of injection or the underlying metabolic state of the mice. The present findings provide direct evidence that OX peptides are more likely to be involved in the control of energy metabolism than of food intake in mice.
Orexin A and orexin B were microinjected into the perifornical hypothalamus (PFH), lateral hypothalamus (LH), hypothalamic paraventricular nucleus (PVN), and ventral tegmental area (VTA) of male Sprague-Dawley rats. Orexin B (15 nmol) was also injected into the lateral cerebral ventricle (i.c.v.). Orexin A (>/=500 pmol) stimulated feeding in the PFH and LH, but not in the VTA or PVN. Orexin B stimulated feeding only when injected i.c.v.
Orexin A and B, a recently identified pair of neuropeptides, are produced in perikarya located in the lateral and perifornical hypothalamus (LH and PFH). Immunoreactive fibers from these neurons innervate several nuclei in the hypothalamus. Orexin A and orexin B stimulate feeding when administered intracerebroventricularly to rats. To identify the specific sites of orexin action, orexin A and B were microinjected into a number of hypothalamic and extrahypothalamic sites in rats. Orexin A was found to enhance food intake when injected into four hypothalamic sites, the paraventricular nucleus (PVN), the dorsomedial nucleus (DMN), LH and the perifornical area, but was ineffective in the arcuate nucleus (ARC), the ventromedial nucleus (VMN), and the preoptic area (POA) as well as the central nucleus of the amygdala (CeA) and nucleus of the tractus solitarius (NTS). Orexin B was not effective at any site tested. These findings demonstrate that orexin A receptive sites for stimulation of food intake exist primarily in a narrow band of neural tissue within the hypothalamus that is known to be involved in control of energy homeostasis.
Orexins, hypothalamic neuropeptides, are involved in modulation of food intake and arousal status. To further examine their physiological roles in brain function, the effect of centrally administered orexin-A on body temperature was investigated in rats. Assessed by a telemetry sensor system implanted into the abdominal cavity, infusion of orexin-A into the third cerebroventricle (i3vt) increased body temperature in a dose-responsive manner. Expression of uncoupling protein 1 (UCP1) mRNA in brown adipose tissue (BAT), as a marker for peripheral thermogenesis, failed to increase after the infusion. Expression of UCP3 mRNA in skeletal muscle was up-regulated, whereas UCP2 in white adipose tissue was unchanged after the infusion. The resulting information indicates that orexin neurons regulate body temperature in coordination with arousal status independently of peripheral thermogenesis, which is regulated by BAT UCP1.
Orexins (hypocretins) are a pair of neuropeptides implicated in energy homeostasis and arousal. Recent reports suggest that loss of orexin-containing neurons occurs in human patients with narcolepsy. We generated transgenic mice in which orexin-containing neurons are ablated by orexinergic-specific expression of a truncated Machado-Joseph disease gene product (ataxin-3) with an expanded polyglutamine stretch. These mice showed a phenotype strikingly similar to human narcolepsy, including behavioral arrests, premature entry into rapid eye movement (REM) sleep, poorly consolidated sleep patterns, and a late-onset obesity, despite eating less than nontransgenic littermates. These results provide evidence that orexin-containing neurons play important roles in regulating vigilance states and energy homeostasis. Orexin/ataxin-3 mice provide a valuable model for studying the pathophysiology and treatment of narcolepsy.
Orexin-A and -B are hypothalamic neuropeptides that have been implicated in stimulating food intake and maintaining arousal. Because food intake is closely related to the control of energy homeostasis, we examined the effects of intracerebroventricular administration of orexins on O2 consumption (VO2), an index of energy expenditure, body temperature, skin temperature and heart rate (HR) in urethane-anesthetized rats. VO2 increased significantly after an orexin-A injection, and this increase was accompanied by a significant tachycardiac response. Orexin-B also increased VO2 and HR, although orexin-A was approximately 30 times more potent in eliciting these responses than orexin-B. The effects of orexin-A were dose dependent over the range of 1 pmol(-1) x nmol, whereas an injection of the saline vehicle had no effect. These findings suggest that centrally acting orexin-A functions to increase energy expenditure.
Orexin A, synthesised in the posterolateral hypothalamus, has widespread distribution including the paraventricular nucleus (PVN), which is rich in thyrotropin-releasing hormone (TRH) neurones. Nerve fibres in the PVN synapse on neurones that send polysynaptic projections to brown adipose tissue (BAT), which is important in thermogenesis. A number of observations suggests orexin A may be involved in regulation of metabolism and thermogenesis. We investigated the effect of orexin A injected intracerebroventricularly (ICV) on thyroid-stimulating hormone (TSH) and thyroid hormones in male rats. We then examined the effect of chronic iPVN injections of orexin A on plasma TSH and uncoupling protein-1 (UCP-1) protein in BAT. Orexin A (3 nmol) administered ICV significantly suppressed plasma TSH at 10 and 90 min. Orexin A (0.3 nmol) administered into the PVN twice daily for 3 days significantly increased day-time 2-h food intake, but did not significantly alter nocturnal food intake. Though chronic iPVN orexin A altered diurnal food intake, there was no effect on 24-h food intake or body weight. Furthermore, orexin A administered chronically into the PVN did not alter UCP-1 level in BAT, or plasma hormones relative to saline injected animals. Chronic iPVN orexin A does not appear to influence thermogenesis through activation of UCP-1 or the thyroid axis.
Adrenocorticotropic hormone (ACTH) induces lipolysis in a dose-dependent fashion in rodent adipose tissue and adipocytes in vitro. The role of ACTH on lipolysis in human adipose tissue is less clear, however. In this study, we address the hypothesis that ACTH induces lipolysis in human adipose tissue. We used ex vivo organ culture to examine lipolysis in human and mouse adipose tissue. Adipose tissue fragments suspended in culture medium and human ACTH, isoproterenol (positive control), or insulin (negative control) was added in varying concentrations. Lipolysis was measured using glycerol appearance. ACTH receptor mRNA expression was assessed using reverse-transcription polymerase chain reaction (RT-PCR). In mouse adipose tissue, ACTH induced lipolysis in dose-dependent manner; 100 pmol/l ACTH induced 67+/-19% of isoproterenol-stimulated lipolysis and 500 pmol/l ACTH: 86+/-13%. In contrast, human adipose tissue shared no significant response to 100 pmol/l ACTH; ACTH was associated with 9+/-6% and 500 pmol/l of ACTH, 8+/-6% of isoproterenol-stimulated lipolysis. ACTH receptor mRNA was present in mouse adipose tissue, but undetectable in human adipose tissue. These results suggest lipolysis regulation differs between human and mouse adipose tissue in response to ACTH.
In humans, nonexercise activity thermogenesis (NEAT) increases with positive energy balance. The mediator of the interaction between positive energy balance and physical activity is unknown. In this study, we address the hypothesis that orexin A acts in the hypothalamic paraventricular nucleus (PVN) to increase nonfeeding-associated physical activity. PVN-cannulated rats were injected with either orexin A or vehicle during the light and dark cycle. Spontaneous physical activity (SPA) was measured using arrays of infrared activity sensors and night vision videotaped recording (VTR). O(2) consumption and CO(2) production were measured by indirect calorimetry. Feeding behavior was assessed by VTR. Regardless of the time point of injection, orexin A (1 nmol) was associated with dramatic increases in SPA for 2 h after injection (orexin A: 6.27 +/- 1.95 x 10(3) beam break count, n = 24; vehicle: 1.85 +/- 1.13 x 10(3), n = 38). This increase in SPA was accompanied by compatible increase in O(2) consumption. Duration of feeding was increased only when orexin A was injected in the early light phase and accounted for only 3.5 +/- 2.5% of the increased physical activity. In a dose-response experiment, increases in SPA were correlated with dose of orexin A linearly up to 2 nmol. PVN injections of orexin receptor antagonist SB-334867 were associated with decreases in SPA and attenuated the effects of PVN-injected orexin A. Thus orexin A can act in PVN to increase nonfeeding-associated physical activity, suggesting that this neuropeptide might be a mediator of NEAT.
DNA translocases are molecular motors that move rapidly along DNA using adenosine triphosphate as the source of energy. We directly observed the movement of purified FtsK, an Escherichia coli translocase, on single DNA molecules. The protein moves at 5 kilobases per second and against forces up to 60 piconewtons, and locally reverses direction without dissociation. On three natural substrates, independent of its initial binding position, FtsK efficiently translocates over long distances to the terminal region of the E. coli chromosome, as it does in vivo. Our results imply that FtsK is a bidirectional motor that changes direction in response to short, asymmetric directing DNA sequences.
The brain regulates energy balance and spontaneous physical activity, including both small- and large-motor activities. Neural mediators of spontaneous physical activity are currently undefined, although the amount of time spent in sedentary positions versus standing and ambulating may be important in the energetics of human obesity. Orexin A, a neuropeptide produced in caudal hypothalamic areas and projecting throughout the neuraxis, enhances arousal and spontaneous physical activity. To test the hypothesis that orexin A affects the amount of time spent moving, we injected orexin A (0-1000 pmol) into three orexin projection sites in male Sprague-Dawley rats: hypothalamic paraventricular nucleus, rostral lateral hypothalamic area and substantia nigra pars compacta, and measured spontaneous physical activity. Orexin A affects local GABA release and we co-injected orexin A with a GABA agonist, muscimol, in each brain site. Dopamine signaling is important to substantia nigra function and so we also co-injected a dopamine 1 receptor antagonist (SCH 23390) in the substantia nigra pars compacta. In all brain sites orexin A significantly increased time spent vertical and ambulating. Muscimol significantly and dose-dependently inhibited orexin A effects on time spent moving only when administered to the rostral lateral hypothalamic area. In the substantia nigra pars compacta, SCH 23390 completely blocked orexin A-induced ambulation. These data indicate that orexin A influences time spent moving, in three brain sites utilizing separate signaling mechanisms. That orexin A modulation of spontaneous physical activity occurs in brain areas with multiple roles indicates generalization across brain site, and may reflect a fundamental mechanism for enhancing activity levels. This potential for conferring physical activity stimulation may be useful for inducing shifts in time spent moving, which has important implications for obesity.
Daily patterns of sleep and wakefulness are inextricably linked to the regulation of feeding and energy metabolism. Both are affected by homeostatic as well as circadian drives, and both are tightly linked to thermoregulation. In this chapter, we review the basic drain circuitry that regulates sleep and wakefulness, including the flip-flop switch relationship of the arousal system and the ventrolateral preoptic sleep-promoting neurons. We then examine the role of the orexin/hypocretin neurons, which stabilize the switch while driving both wakefulness and foraging for food. We also review the role of the subparaventricular nucleus and the dorsomedial nucleus of the hypothalamus in circadian integration and modulation of both feeding and wake-sleep patterns.
The problem of obesity was only accepted by the World Health Organization as of major public health importance in 1997 when the criteria for the specification of the metabolic syndrome were also being sought. Then the risk factor analyses of the determinants of global ill health at the start of the millennium showed that an excessive body mass index (BMI) above the optimum of 21 was one of the top 10 contributors. No analyses could be related to abdominal obesity because of the absence of systematic representative surveys of waist circumferences but the ill health attributable to excess weight included the risk factors specified in the metabolic syndrome and showed that the co-morbidities in Asia were far greater than those predicted from simply an excess weight. The recent proposed definition of the metabolic syndrome includes these different criteria specified on an ethnic basis but there is now a need to recognize that abdominal obesity is more common on the developing world and linked to childhood stunting and early deprivation. The importance of intrauterine and postnatal epigenetic and altered organ function needs to be recognized. Thus the co-morbidities associated with weight gain and the development of the metabolic syndrome dominate in the developing world where the majority of the population is proving more susceptible to the effects of weight gain than Caucasians now living in affluent societies. This therefore presents a major challenge in both research and public policy terms.
It is not uncommon for people to spend one-half of their waking day sitting, with relatively idle muscles. The other half of the day includes the often large volume of nonexercise physical activity. Given the increasing pace of technological change in domestic, community, and workplace environments, modern humans may still not have reached the historical pinnacle of physical inactivity, even in cohorts where people already do not perform exercise. Our purpose here is to examine the role of sedentary behaviors, especially sitting, on mortality, cardiovascular disease, type 2 diabetes, metabolic syndrome risk factors, and obesity. Recent observational epidemiological studies strongly suggest that daily sitting time or low nonexercise activity levels may have a significant direct relationship with each of these medical concerns. There is now a need for studies to differentiate between the potentially unique molecular, physiologic, and clinical effects of too much sitting (inactivity physiology) separate from the responses caused by structured exercise (exercise physiology). In theory, this may be in part because nonexercise activity thermogenesis is generally a much greater component of total energy expenditure than exercise or because any type of brief, yet frequent, muscular contraction throughout the day may be necessary to short-circuit unhealthy molecular signals causing metabolic diseases. One of the first series of controlled laboratory studies providing translational evidence for a molecular reason to maintain high levels of daily low-intensity and intermittent activity came from examinations of the cellular regulation of skeletal muscle lipoprotein lipase (LPL) (a protein important for controlling plasma triglyceride catabolism, HDL cholesterol, and other metabolic risk factors). Experimentally reducing normal spontaneous standing and ambulatory time had a much greater effect on LPL regulation than adding vigorous exercise training on top of the normal level of nonexercise activity. Those studies also found that inactivity initiated unique cellular processes that were qualitatively different from the exercise responses. In summary, there is an emergence of inactivity physiology studies. These are beginning to raise a new concern with potentially major clinical and public health significance: the average nonexercising person may become even more metabolically unfit in the coming years if they sit too much, thereby limiting the normally high volume of intermittent nonexercise physical activity in everyday life. Thus, if the inactivity physiology paradigm is proven to be true, the dire concern for the future may rest with growing numbers of people unaware of the potential insidious dangers of sitting too much and who are not taking advantage of the benefits of maintaining nonexercise activity throughout much of the day.
The rise in obesity is associated with a decline in the amount of physical activity in which people engage. The energy expended through everyday non-exercise activity, called non-exercise activity thermogenesis (NEAT), has a considerable potential impact on energy balance and weight gain. Comparatively little attention has been paid to the central mechanisms of energy expenditure and how decreases in NEAT might contribute to obesity. In this review, we first examine the sensory and endocrine mechanisms through which energy availability and energy balance are detected that may influence NEAT. Second, we describe the neural pathways that integrate these signals. Lastly, we consider the effector mechanisms that modulate NEAT through the alteration of activity levels as well as through changes in the energy efficiency of movement. Systems that regulate NEAT according to energy balance may be linked to neural circuits that modulate sleep, addiction and the stress response. The neural and endocrine systems that control NEAT are potential targets for the treatment of obesity.