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Overweight and obesity result from an imbalance between caloric intake and energy expenditure, including expenditure from spontaneous physical activity (SPA). Changes in SPA and resulting changes in non-exercise activity thermogenesis (NEAT) likely interact with diet to influence risk for obesity. However, previous research on the relationship between diet, physical activity, and energy expenditure has been mixed. The neuropeptide orexin is a driver of SPA, and orexin neuron activity can be manipulated using DREADDs (Designer Receptors Exclusively Activated by Designer Drugs). We hypothesized that HFD decreases SPA and NEAT, and that DREADD-mediated activation of orexin neuron signaling would abolish this decrease and produce an increase in NEAT instead. To test these ideas, we characterized behaviors to determine the extent to which access to a high-fat diet (HFD) influences the proportion and probability of engaging in food intake and activity. We then measured NEAT following access to HFD and following a DREADD intervention targeting orexin neurons. Two cohorts of orexin-cre male mice were injected with an excitatory DREADD virus into the caudal hypothalamus, where orexin neurons are concentrated. Mice were then housed in continuous metabolic phenotyping cages (Sable Promethion). Food intake, indirect calorimetry, and SPA were automatically measured every second. For cohort 1 (n=8), animals were given access to chow, then switched to HFD. For cohort 2 (n=4/group), half of the animals were given access to HFD, the other access to chow. Then, among animals on HFD, orexin neurons were activated following injections of clozapine n-oxide (CNO). Mice on HFD spent significantly less time eating (p<0.01) and more time inactive compared to mice on chow (p<0.01). Following a meal, mice on HFD were significantly more likely to engage in periods of inactivity compared to those on chow (p<0.05). NEAT was decreased in animals on HFD, and was increased to the NEAT level of control animals following activation of orexin neurons with DREADDs. Food intake (kilocalories) was not significantly different between mice on chow and HFD, yet mice on chow expended more energy per unit of SPA, relative to that in mice consuming HFD. These results suggest that HFD consumption reduces SPA and NEAT, and increases inactivity following a meal. Together, the data suggest a change in the efficiency of energy expenditure based upon diet, such that SPA during HFD burns fewer calories compared to SPA on a standard chow diet., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The hypothalamic neuropeptides orexin A and B (hypocretin 1 and 2) are important homeostatic mediators of central control of energy metabolism and maintenance of sleep/wake states. Dysregulation or loss of orexin signaling has been linked to narcolepsy, obesity, and age-related disorders. In this review, we present an overview of our current understanding of orexin function, focusing on sleep disorders, energy balance, and aging, in both rodents and humans. We first discuss animal models used in studies of obesity and sleep, including loss of function using transgenic or viral-mediated approaches, gain of function models using exogenous delivery of orexin receptor agonist, and naturally-occurring models in which orexin responsiveness varies by individual. We next explore rodent models of orexin in aging, presenting evidence that orexin loss contributes to age-related changes in sleep and energy balance. In the next section, we focus on clinical importance of orexin in human obesity, sleep, and aging. We include discussion of orexin loss in narcolepsy and potential importance of orexin in insomnia, correlations between animal and human studies of age-related decline, and evidence for orexin involvement in age-related changes in cognitive performance. Finally, we present a summary of recent studies of orexin in neurodegenerative disease. We conclude that orexin acts as an integrative homeostatic signal influencing numerous brain regions, and that this pivotal role results in potential dysregulation of multiple physiological processes when orexin signaling is disrupted or lost., (Published by Elsevier B.V.)

Anorexia nervosa (AN) is a chronic eating disorder affecting females and males, defined by body weight loss, higher physical activity levels and restricted food intake. Currently, the commonalities and differences between genders in etiology of AN are not well understood. Animal models of AN, such as activity-based anorexia (ABA), can be helpful in identifying factors determining individual susceptibility to AN. In ABA, rodents are given an access to a running wheel while food restricted, resulting in paradoxical increased physical activity levels and weight loss. Recent studies suggest that different behavioral traits, including voluntary exercise, can predict individual weight loss in ABA. A higher inherent drive for movement may promote development and severity of AN, but this hypothesis remains untested. In rodents and humans, drive for movement is defined as spontaneous physical activity (SPA), which is time spent in low-intensity, non-volitional movements. In this paper, we show that a profile of body weight history and behavioral traits, including SPA, can predict individual weight loss caused by ABA in male and female rats with high accuracy. Analysis of the influence of SPA on ABA susceptibility in males and females rats suggests that either high or low levels of SPA increase the probability of high weight loss in ABA, but with larger effects in males compared to females. These results suggest that the same behavioral profile can identify individuals at-risk of AN for both male and female populations and that SPA has predictive value for susceptibility to AN., (Copyright © 2014 Elsevier Inc. All rights reserved.)

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., (Published by Elsevier Ltd.)

An acute injection of brain-derived neurotrophic factor (BDNF) in the hypothalamic ventromedial nucleus (VMN) decreases body weight by reducing feeding and increasing energy expenditure (EE) in animals on standard laboratory chow. Animals have divergent responses to high-fat diet (HFD) exposure, with some developing obesity and others remaining lean. In the current study, we tested the hypothesis that BDNF in the VMN reduces HFD-induced obesity. Seventy-two 10-week old rats were allowed HFD ad libitum for 8 weeks and then prepared with bilateral VMN cannulae. Animals were then divided into tertiles based on their fat mass rank: high, intermediate, and low (H, I, and L). Each group was further divided into two subgroups: BDNF (1 μg) or control (artificial cerebrospinal fluid, aCSF); they were then injected every other day for 20 days according to subgroup. Energy intake, body weight, and body composition were measured. Other metabolic indexes were measured before and after treatment. In parallel, another 12 rats were fed control diet (CD), VMN-cannulated, and injected with aCSF. HFD exposure induced obesity in the H group, with a significant increase in energy intake, body weight, fat mass, liver size, and serum glucose, insulin, and leptin. BDNF significantly reduced body weight and fat mass in all phenotypes, while it reduced energy intake only in the I group. However, BDNF increased EE, spontaneous physical activity, and fat oxidation in the H group, suggesting that BDNF-induced EE elevation contributed to reduction of body weight and fat mass. Chronic VMN BDNF reduced insulin elevation and/or reversed hyperleptinemia. These data suggest that the VMN is an important site of action for BDNF reduction of HFD-induced obesity., (Published by Elsevier Ltd.)

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.

Spontaneous physical activity is activity that is non-volitional, or subconscious, such as fidgeting and shifting in one's seat, and time spent moving (standing and ambulating). Recent evidence indicates that spontaneous physical activity, and the resulting thermogenesis (non-exercise activity thermogenesis) may be regulated by brain systems. A large number of brain areas, with their associated neurotransmitter populations and connectivity, participate in the regulation of feeding behavior by acting as energy sensing and modulating centers. Although less well characterized, it is likely that a multitude of neurotransmitters and brain areas act to mediate spontaneous physical activity. These two behaviors, feeding and spontaneous physical activity, affect energy intake and expenditure and thus are important to body weight. Interestingly, often the two behaviors are affected simultaneously; when feeding is affected, so too is spontaneous physical activity, and both food intake and physical activity (whether spontaneous or volitional) influence activity of brain areas important to both. Several brain areas and neuropeptides are important to feeding and spontaneous physical activity. The lateral hypothalamus is one area that appears important to both behaviors, as stimulation or lesion of this region produces alterations in feeding behavior and spontaneous physical activity. Orexin neurons, with their central location in the lateral hypothalamus, widespread projections and connectivity to other brain areas important to energy homeostasis, are well situated to perform an integrative function. This review focuses on how hypothalamic orexins participate in both feeding and spontaneous physical activity, and provides potential models for the integration of signals important to both.

A retrospective chart review characterizing changes in 17 male and 10 female Parkinson's disease (PD) patients undergoing deep brain stimulation (DBS) surgery indicated that 6 mo before surgery, patients lost a mean of 5.1 lbs, whereas in the 6 mo after surgery, subjects gained a mean of 10.1 lbs; 22% gained more than 14 lbs. In 10 patients followed an additional 6 mo, weight gain continued. This weight gain may be associated with decreased energy expenditure due to subsidence of chronic tremor. The magnitude of gain underscores the need for proactive management of body weight in PD patients undergoing DBS.