Biomedical subjects

C M Kotz

Publications and source records attributed to C M Kotz.

At least 19 recordsLinked to original sources

PubMed2006

Orexin A in the rostrolateral hypothalamic area induces feeding by modulating GABAergic transmission.

The neuromodulatory peptides orexin A and B are important central nervous system regulators of appetite. We previously identified the rostral lateral portion of the hypothalamus as an area important to orexin A feeding regulation. As gamma-aminobutyric-acid (GABA) within the lateral hypothalamus also mediates feeding, we sought to determine the relationship between orexin and GABA signaling within this site. Adult male Sprague-Dawley rats were implanted with cannulae directed to the rostral lateral hypothalamus and saclofen (GABA-B receptor antagonist), biccuculine (GABA-A receptor antagonist) or muscimol (GABA-A receptor agonist) were injected prior to orexin A. Both GABA antagonists failed to significantly affect orexin A-induced feeding, but muscimol significantly and dose dependently inhibited orexin A-induced feeding. Using in vivo microdialysis GABA release within this region significantly dropped during the first hour following orexin A administration, coinciding with orexin A-induced feeding. Together, these data indicate that orexin A may influence food intake by decreasing GABAergic tone within the rostral lateral hypothalamus.

Analysis of Variance↗

PubMed2006

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.

Analysis of Variance↗

PubMed2006

Elevated hypothalamic orexin signaling, sensitivity to orexin A, and spontaneous physical activity in obesity-resistant rats.

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.

Age Factors↗

PubMed2005

Centrally administered orexin A increases motivation for sweet pellets in rats.

RATIONALE: Centrally administered orexin A induces both feeding and locomotion in rats. Thus, the feeding response following orexin A administration may be secondary to general increases in activity rather than a specific motivation to eat. OBJECTIVE: The aim of the study is to determine whether orexin A increases the motivation to eat. METHODS: The effect of orexin A (0, 31.25, 62.5, 125, 250, and 500 pmol) on breakpoint was determined in male Sprague-Dawley rats with rostro-lateral hypothalamic cannulae under a progressive ratio of five schedule (PR5). The effect of orexin A (0, 31.25, 125, and 500 pmol) on pressing rate under a fixed ratio (20) schedule was obtained to analyze the time course of orexin-A-induced pressing. The effect of 24-h food deprivation on breakpoint under PR5 and the effect of orexin A (125 pmol) on free feeding (sweet pellets) and on open-field locomotor activity (0, 100, 500, and 1,000 pmol) were also tested. RESULTS: Orexin A significantly augmented free feeding of sweet pellets, open-field locomotor activity, rate of pressing (FR20 schedule), and breakpoint (PR5 schedule), although compared to 24-h deprivation, the effect of orexin A on breakpoint was mild. However, there was a differential dose response relationship and time course of stimulation between orexin A's effects on locomotion and lever pressing. CONCLUSION: These data indicate that infusion of orexin A enhances free feeding by enhancing and possibly prolonging motivation to eat.

Animals↗

PubMed2005

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.

Animals↗

PubMed2005

Orexin A-induced feeding is augmented by caloric challenge.

Orexin neurons are stimulated by conditions that are glucoprivic, suggesting that orexin signaling may be increased during nutritional duress. We have previously shown that injection of orexin A (OxA) into the rostral lateral hypothalamic area (rLHa) robustly and dose-dependently increases feeding behavior. Thus we hypothesized that exogenous administration of orexin A would induce a greater feeding response after acute food deprivation or perceived caloric duress achieved through 2-deoxyglucose (2DG) administration. To test our hypothesis, male Sprague-Dawley rats implanted with internal guide cannulas directed to the rLHa were exposed to varying degrees of food deprivation (0, 3, 12, 24 h) and 2DG (200 mg/kg) before intra-rLHa OxA (500 pmol) infusion. We also performed a dose-response study using graded doses of OxA (0, 31.25, 125, and 500 pmol) in fed and 24-h fasted rats. OxA administration in conjunction with the highest level of prior food deprivation (24 h) resulted in the greatest feeding response (above baseline means; 0 h deprivation: 1.9 +/- 0.6; 24 h deprivation: 4.4 +/- 0.8; P = 0.0034) and showed a dose-dependent enhancement of feeding. Additionally, 2DG administration before OxA administration resulted in a significantly higher feeding response (above baseline means: 2DG = 1.8 +/- 0.5; OxA = 1.8 +/- 0.4; 2DG + OxA = 5.1 +/- 0.6; P < 0.0001). These data support the hypothesis that orexin signaling may be important in modulating the feeding network under times of nutritional duress.

Animals↗

PubMed2005

NEAT--non-exercise activity thermogenesis--egocentric & geocentric environmental factors vs. biological regulation.

Non-exercise activity thermogenesis (NEAT) is the energy expenditure of all physical activities other than volitional sporting-like exercise. NEAT includes all those activities that render us vibrant, unique and independent beings such as going to work, playing guitar, toe-tapping and dancing. The factors that account for the 2000 kcal day(-1) variability of NEAT can be categorized as environmental or biological. The environmental determinants of NEAT can be view using one of two models. In the egocentric model we consider a single person as the focus, e.g. 'my job'. In the geocentric model we consider the 'environment' as the focus, e.g. well-lit and safe walk ways. These models provide us with a theoretical framework to understand NEAT and how best to intervene to promote NEAT. As well as environmental effectors of NEAT, there are also biological regulatory mechanisms that enable us to account for three-quarters of the biological variance in susceptibility and resistance to fat gain with human over-feeding. NEAT is likely to be regulated through a central mechanism that integrates NEAT with energy intake and energy stores so that NEAT is activated with over-feeding and suppressed with under-feeding. In conclusion, NEAT is likely to serve as a crucial thermoregulatory switch between energy storage and dissipation that is biologically regulated and influenced, and perhaps over-ridden, by environment. Deciphering the role of NEAT may lead to a better understanding of the pathogenesis, prevention and treatment of obesity.

Eating↗

PubMed2001

Feeding inhibition by urocortin in the rat hypothalamic paraventricular nucleus.

Ventricular administration of urocortin (UCN) inhibits feeding, but specific site(s) of UCN action are unknown. In the current studies we examined the effect of UCN in the hypothalamic paraventricular nucleus (PVN) on feeding. We tested UCN administered into the PVN in several paradigms: deprivation-induced, nocturnal, and neuropeptide Y (NPY)-induced feeding. We compared the effect of equimolar doses of UCN and corticotrophin releasing hormone (CRH) on NPY-induced and nocturnal feeding, determined whether UCN in the PVN produced a conditioned taste aversion (CTA) and induced changes in c-Fos immunoreactivity (c-Fos-ir) after UCN and NPY administration in the PVN. UCN in the PVN significantly decreased NPY and nocturnal and deprivation-induced feeding at doses of 1, 10, and 100 pmol, respectively. UCN anorectic effects lasted longer than those attributed to CRH. Ten and thirty picomoles UCN did not induce a CTA, whereas 100 pmol UCN produced a CTA. UCN (100 pmol) in the PVN neither increased c-Fos-ir in any brain region assayed nor altered c-Fos-ir patterns resulting from PVN NPY administration. These data suggest the hypothalamic PVN as a site of UCN action.

Animals↗

PubMed2000

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.

Adipose Tissue, Brown↗

PubMed2000

Hypocretin I in the lateral hypothalamus activates key feeding-regulatory brain sites.

Hypocretin I (also referred to as orexin A) administered into the lateral hypothalamus (LH) stimulates feeding in rats. We undertook the present study to determine the brain regions activated by LH administration of hypocretin I. Hypocretin I administered into the LH significantly elevated cFos-immunoreactivity in the lateral septal area, the central nucleus of the amygdala, the shell of the nucleus accumbens, the bed nucleus of the stria terminalis, the LH, the posterior and dorsomedial hypothalamus, the perifornical, arcuate and paraventricular nuclei and the nucleus of the solitary tract. These data indicate that LH hypocretin I communicates with other key energy regulatory sites within the hypothalamus, the limbic region and the hindbrain, and suggest that these areas are important in the feeding-stimulatory actions of hypocretin I.

Animals↗

PubMed2000

Effect of NPY in the hypothalamic paraventricular nucleus on uncoupling proteins 1, 2, and 3 in the rat.

Neuropeptide Y (NPY) injected into the hypothalamic paraventricular nucleus (PVN) stimulates feeding and decreases uncoupling protein (UCP)-1 mRNA in brown adipose tissue (BAT). The present studies were undertaken to determine whether UCP-2 in white adipose tissue (WAT) and UCP-3 in muscle are regulated by NPY in the PVN. PVN-cannulated male Sprague-Dawley rats were injected with either saline or NPY (PVN, 117 pmol, 0.5 microl) every 6 h for 24 h. NPY in the PVN stimulated feeding and decreased UCP-1 mRNA in BAT independent of NPY-induced feeding. UCP-2 mRNA in WAT was unchanged by NPY. In acromiotrapezius muscle, NPY decreased UCP-3 mRNA, but this was reversed by restricting food intake to control levels. In biceps femoris muscle, NPY alone had no effect on UCP-3 mRNA, but UCP-3 mRNA was significantly increased in the NPY-treated rats that were restricted to control levels of intake. These results suggest that UCP-2 in WAT and UCP-3 in muscle are not subject to specific regulation by NPY in the PVN.

Adipose Tissue↗

PubMed2000

Regional effect of naltrexone in the nucleus of the solitary tract in blockade of NPY-induced feeding.

Naltrexone (NLTX) in the nucleus of the solitary tract (NTS) decreases feeding induced by neuropeptide Y (NPY) in the paraventricular nucleus (PVN). We sought to determine the NTS region most sensitive to NLTX blockade of PVN NPY-induced feeding. Male Sprague-Dawley rats were fitted with two cannulas; one in the PVN and one in a hindbrain region: caudal, medial, or rostral NTS or 1 mm outside the NTS. Animals received NLTX (0, 1, 3, 10, and 30 microg in 0.3 microl) into the hindbrain region just prior to PVN NPY (0.5 microg, 0.3 microl) or artificial cerebrospinal fluid (0.3 microl). Food intake was measured at 2 h following injection. PVN NPY stimulated feeding, and NLTX in the medial NTS significantly decreased NPY-induced feeding at 2 h, whereas administration of NLTX in the other hindbrain regions did not significantly influence PVN NPY induced feeding. These data suggest that opioid receptors in the medial NTS are most responsive to feeding signals originating in the PVN after NPY stimulation.

Animals↗

PubMed2000

Sucrose consumption increases naloxone-induced c-Fos immunoreactivity in limbic forebrain.

Opioids have long been known to have an important role in feeding behavior, particularly related to the rewarding aspects of food. Considerable behavioral evidence suggests that sucrose consumption induces endogenous opioid release, affecting feeding behavior as well as other opioid-mediated behaviors, such as analgesia, dependence, and withdrawal. In the present study, rats were given access to a 10% sucrose solution or water for 3 wk, then they were injected with 10 mg/kg naloxone or saline. Brains were subsequently analyzed for c-Fos immunoreactivity (c-Fos-IR) in limbic and autonomic regions in the forebrain and hindbrain. Main effects of sucrose consumption or naloxone injection were seen in several areas, but a significant interaction was seen only in the central nucleus of the amygdala and in the lateral division of the periaqueductal gray. In the central nucleus of the amygdala, naloxone administration to those rats drinking water significantly increased c-Fos-IR, an effect that was significantly enhanced by sucrose consumption, suggesting an upregulation of endogenous opioid tone in this area. The data from this study indicate that the central nucleus of the amygdala has a key role in the integration of gustatory, hedonic, and autonomic signals as they relate to sucrose consumption, if not to food intake regulation in general. Furthermore, the data from this study lend further support to the hypothesis that sucrose consumption induces the release of endogenous opioids.

Animals↗

PubMed1999

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.

Animals↗

PubMed1999

Obesity and aging.

This review focuses on studies that pertain to obesity and aging. The prevalence of obesity in the elderly is discussed, with an emphasis on body-fat distribution as it relates to morbidity and mortality rates. Treatment options, such as physical activity, growth hormones, and drug therapy, are briefly mentioned. A section that covers some of the most recent issues pertaining to the neuroregulation of feeding and energy expenditure is included. Finally, we briefly discuss anorexia in the aged.

Adult↗

PubMed1998

Association between the amygdala and nucleus of the solitary tract in mu-opioid induced feeding in the rat.

The central nucleus of the amygdala (CNA) and the nucleus of the solitary tract (NTS) are important in the regulation of ingestive behavior. We evaluated whether opioid-opioid signaling between the CNA and rostral NTS (rNTS) affect feeding behavior. To test this, rats were doubly cannulated with one cannula placed in the rNTS and one cannula in the CNA, allowing for co-administration of an opioid agonist into one site and an opioid antagonist into the other. Tyr-D-Ala-Gly-(me) Phe-Gly-ol (DAMGO) (2 nmol) injected into the CNA (CNA DAMGO) increased feeding more than two-fold compared to the vehicle-injected rats. This increase in food intake was blocked when doses of 26.5 and 79 nmol of naltrexone (NTX) were injected into the rNTs. In the reverse situation, rNTS DAMGO increased food intake above control levels, and CNA NTX blocked DAMGO-induced feeding when administrated in doses of 26.5 and 79 nmol. This suggests that a bi-directional opioid-opioid signaling pathway exists between the CNA and the rNTS which influences feeding via mu-opioid receptors.

Amygdala↗

PubMed1998

Divergence of the feeding and thermogenic pathways influenced by NPY in the hypothalamic PVN of the rat.

Neuropeptide Y (NPY) injected into the paraventricular nucleus (PVN) increases feeding and decreases brown adipose tissue (BAT) uncoupling protein (UCP) and lipoprotein lipase (LPL) mRNA. Previously we reported that the feeding and BAT effects induced by NPY in the PVN are blocked by 50 microg naltrexone (NTX) in the rostral nucleus of the solitary tract (rNTS). We sought to determine whether the effect of rNTS NTX on PVN NPY-induced alterations in energy metabolism occurred at lower doses of NTX. Male Sprague-Dawley rats were fitted with cannulas into two sites: PVN and rNTS. Feeding response, BAT UCP, and LPL mRNA were measured after injection of 0, 5, 10, and 25 microg NTX in the rNTS +/- 1 microg NPY in the PVN. One-hour feeding response to PVN NPY was significantly and dose dependently decreased by 10 and 25 microg rNTS NTX (-23 and -31%, respectively). However, rNTS NTX did not block the PVN NPY-induced decrease in BAT UCP or LPL mRNA. BAT beta-actin mRNA (as a measure of overall changes in gene expression) was unchanged among treatment groups. These results indicate a possible divergence in the PVN NPY feeding-stimulatory/BAT-inhibitory pathway, such that PVN NPY feeding effects may be routed through the rNTS whereas BAT effects may be due to alterations at another neural site.

Adipose Tissue, Brown↗

PubMed1998

Neural site of leptin influence on neuropeptide Y signaling pathways altering feeding and uncoupling protein.

Inhibition of a signal that produces positive energy balance involving neuropeptide Y (NPY) projection from arcuate nucleus (Arc; site of NPY synthesis) to paraventricular nucleus (PVN; site of NPY release) is one potential mechanism of leptin action. NPY in the PVN increases feeding and decreases uncoupling protein (UCP) activity in brown fat, whereas leptin decreases NPY biosynthesis in the Arc, which presumably decreases PVN NPY. It is hypothesized that decreased NPY activity is necessary for the satiety and thermogenic effects of leptin. To test this, we first determined the effect of leptin on feeding in two paradigms: satiated rats and food-deprived rats. Leptin was effective in decreasing feeding in the satiated rats but ineffective in the food-deprived rats. Next, we determined that leptin decreases NPY and increases UCP gene expression. Finally, we injected leptin intracerebroventricularly before specific PVN NPY microinjection. We found that repletion of NPY in PVN by specific NPY microinjection reverses the feeding-inhibitory and thermogenic effects of centrally administered leptin, the first functional evidence indicating that leptin acts on the Arc-PVN feeding-regulatory pathway.

Analysis of Variance↗