Catherine M. Kotz

Feeding response to central orexins

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.

The biological control of voluntary exercise, spontaneous physical activity and daily energy expenditure in relation to obesity: human and rodent perspectives

Summary Mammals expend energy in many ways, including basic cellular maintenance and repair, digestion, thermoregulation, locomotion, growth and reproduction. These processes can vary tremendously among species and individuals, potentially leading to large variation in daily energy expenditure (DEE). Locomotor energy costs can be substantial for large-bodied species and those with high-activity lifestyles. For humans in industrialized societies, locomotion necessary for daily activities is often relatively low, so it has been presumed that activity energy expenditure and DEE are lower than in our ancestors. Whether this is true and has contributed to a rise in obesity is controversial. In humans, much attention has centered on spontaneous physical activity (SPA) or non-exercise activity thermogenesis (NEAT), the latter sometimes defined so broadly as to include all energy expended due to activity, exclusive of volitional exercise. Given that most people in Western societies engage in little voluntary exercise, increasing NEAT may be an effective way to maintain DEE and combat overweight and obesity. One way to promote NEAT is to decrease the amount of time spent on sedentary behaviours (e.g. watching television). The effects of voluntary exercise on other components of physical activity are highly variable in humans, partly as a function of age, and have rarely been studied in rodents. However, most rodent studies indicate that food consumption increases in the presence of wheels; therefore, other aspects of physical activity are not reduced enough to compensate for the energetic cost of wheel running. Most rodent studies also show negative effects of wheel access on body fat, especially in males. Sedentary behaviours per se have not been studied in rodents in relation to obesity. Several lines of evidence demonstrate the important role of dopamine, in addition to other neural signaling networks (e.g. the endocannabinoid system), in the control of voluntary exercise. A largely separate literature points to a key role for orexins in SPA and NEAT. Brain reward centers are involved in both types of physical activities and eating behaviours, likely leading to complex interactions. Moreover, voluntary exercise and, possibly, eating can be addictive. A growing body of research considers the relationships between personality traits and physical activity, appetite, obesity and other aspects of physical and mental health. Future studies should explore the neurobiology, endocrinology and genetics of physical activity and sedentary behaviour by examining key brain areas, neurotransmitters and hormones involved in motivation, reward and/or the regulation of energy balance.

Orexin A in the nucleus accumbens stimulates feeding and locomotor activity.

Due to the nature of processing within the accumbens shell (AccSh) and the presence of orexin receptors and varicosities within the AccSh, we hypothesized that orexin A may partly regulate feeding behavior and locomotor activity via signaling in this site. To test this hypothesis, male Sprague-Dawley rats were implanted with guide cannulae directed to the medial portion of the AccSh. Orexin A (0, 100, 500, and 1000 pmol, in 0.5 microl artificial cerebrospinal fluid) was infused into the AccSh and feeding behavior and locomotor activity were monitored. The effect of pretreatment with an orexin 1 receptor antagonist (SB334867A) on orexin A-induced feeding and locomotor activity was assessed. Orexin A augmented feeding in the 0-1 h and 1-2 h post-infusion interval (P = 0.0058 and P = 0.025, respectively) and stimulated locomotor activity in the 30-60 min, 60-90 min, and 90-120 min post-infusion intervals (P <or= 0.0001, P = 0.0056 and P = 0.046, respectively). Orexin A-induced feeding was significantly attenuated by preadministration of SB334867A in the 0-1 h post-infusion time interval (P = 0.03). Orexin A-induced locomotor activity was not affected by SB334867A. These data support the hypothesis that the AccSh is a site of orexin A modulation of feeding behavior and locomotor activity.

Feeding and activity induced by orexin A in the lateral hypothalamus in rats.

Orexin A injected into the lateral hypothalamus (LH) stimulates feeding and activates neurons in brain sites regulating feeding and arousal. The feeding effects of orexin A have been demonstrated during the light cycle, a time when rats are normally resting, and the effect of orexin A on activity after injection into the LH has not been previously measured. Thus, it is unclear whether LH orexin A-induced feeding is secondary to enhanced arousal. To address this, LH-cannulated rats habituated to a running wheel were injected with either orexin A (1000 pmol) or vehicle during light and dark cycles. Food intake and running wheel rotations were measured for 2 h. Spontaneous physical activity (SPA) was also measured during the dark cycle. During the light cycle, orexin A in the LH stimulated feeding in the presence and absence of a running wheel and increased number of running wheel rotations in the presence and absence of food. During the dark cycle, orexin A in the LH induced SPA (+/- presence of food), but had no effect on feeding. These data show that LH orexin A stimulation of feeding is not always coincident with increased activity, suggesting that feeding induced by LH-injected orexin A is not consequent to enhanced arousal.

Neural basis of orexigenic effects of ghrelin acting within lateral hypothalamus

Ghrelin stimulates feeding when administered centrally and peripherally. The lateral hypothalamus (LH) is thought to mediate ghrelin-induced hyperphagia. Thus, we examined central mechanisms underlying feeding generated by LH ghrelin. We determined that 0.3nmol of LH-injected ghrelin was the lowest dose increasing food consumption and it induced Fos immunoreactivity (IR; a marker of neuronal activation) in feeding-related brain areas, including the hypothalamic paraventricular, arcuate, and dorsomedial nuclei, amygdala, and nucleus of the solitary tract. Also, LH ghrelin induced Fos IR in LH orexin neurons. We conclude that the LH, as part of larger central circuitry, integrates orexigenic properties of ghrelin.

Effect of CART in the hypothalamic paraventricular nucleus on feeding and uncoupling protein gene expression.

Cocaine and amphetamine regulated transcript (CART) decreases feeding and body weight after ventricular injection. CART mRNA and peptide are found in the paraventricular nucleus of the hypothalamus (PVN). The purpose of the present study was to determine effects of PVN-injected CART on feeding and thermogenic capacity. PVN-injected CART (55–102, 100 pmol) significantly decreased NPY-induced feeding at 1, 2 and 4 h, but did not significantly affect deprivation-induced feeding. CART induced gene expression of uncoupling protein 1 (UCP1), UCP2, and UCP3 in brown and white adipose tissue and biceps femoris muscle respectively. These results indicate the PVN as a specific site of CART action, and suggest that CART in the PVN may have an important influence on energy metabolism.

Orexin A mediation of time spent moving in rats: neural mechanisms.

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.

Caloric restriction and physical activity in zebrafish (Danio rerio)

Understanding the mechanism of energy flux may be critical for explaining how obesity has emerged as a public health epidemic. It is known that changes in caloric intake predictably alter physical activity levels (PA) in mammals. Here, our goal was to test the hypothesis that fasting induces a biphasic pattern of change in PA by measuring PA before and after long-term food deprivation in zebrafish. Compared to control-fed fish, food-deprived fish showed a significant increase in PA levels during the first 2 days of food deprivation. Subsequently, however, fasted fish showed a significant chronic decrease in PA compared to fish fed at weight-maintenance levels. These data are comparable to those seen with mammals, which also show a biphasic response of PA to caloric restriction. In a separate group of fish, long-term food deprivation, associated with decreases in PA, induced a significant increase in brain preproorexin mRNA levels compared to fed controls. No change in orexin mRNA was seen after 2 days of food deprivation. The finding that orexin mRNA expression is altered only after long-term starvation suggests that orexin may be coupled with the changes in PA seen at this time. Thus, the association between negative energy balance and reductions in PA occurs across genera in biology and is associated with predictable neurological changes in brain gene expression.

Integration of feeding and spontaneous physical activity: role for orexin.

Spontaneous physical activity is activity that is non-volitional, or subconscious, such as fidgeting and shifting in ones 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.

Effects of opioid antagonists naloxone and naltrexone on neuropeptide Y-induced feeding and brown fat thermogenesis in the rat. Neural site of action.

Neuropeptide Y administered intracerebroventricularly and into the paraventricular nucleus of the hypothalamus stimulates feeding and decreases brown adipose tissue thermogenesis. Although specific neuropeptide Y antagonists are not yet available, previous studies had shown that the opioid antagonist naloxone blocked neuropeptide Y-induced feeding when both drugs were injected intracerebroventricularly. We wanted to find out if naloxone injected into specific brain sites would block neuropeptide Y effects on feeding and brown fat thermogenesis. Rats were double injected in specific brain sites with neuropeptide Y and either naloxone or naltrexone (a congener of naloxone). Food intake and brown fat measures were assessed. Naloxone or naltrexone in the paraventricular nucleus weakly decreased paraventricular nucleus neuropeptide Y-induced feeding and did not affect neuropeptide Y-induced reductions in brown fat activity. Peripheral naloxone blocked intracerebroventricular neuropeptide Y-induced feeding and brown fat alterations. Fourth ventricular naloxone decreased paraventricular nucleus neuropeptide Y-induced feeding, and naltrexone given into the nucleus of the solitary tract blocked paraventricular nucleus neuropeptide Y-induced alterations in feeding and brown fat. These data indicate that neuropeptide Y in the paraventricular nucleus may act on feeding and brown fat thermogenesis through opioidergic pathways in the nucleus of the solitary tract.