Behavioral responses to orexin, orexin receptor gene expression, and spontaneous physical activity contribute to individual sensitivity to obesity

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.

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

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00536.2005 ◽

2006 ◽

Vol 291 (4) ◽

pp. R889-R899 ◽

Cited By ~ 76

Author(s):

J. A. Teske ◽

A. S. Levine ◽

M. Kuskowski ◽

J. A. Levine ◽

C. M. Kotz

Keyword(s):

Gene Expression ◽

Physical Activity ◽

Caloric Intake ◽

Sprague Dawley ◽

Rt Pcr ◽

Orexin A ◽

Daily Caloric Intake ◽

Behavioral Studies ◽

Sprague Dawley Rats ◽

Spontaneous Physical Activity

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 μl). 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.

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Role of the locus coeruleus in enhanced orexin A-induced spontaneous physical activity in obesity-resistant rats

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00229.2013 ◽

2013 ◽

Vol 305 (11) ◽

pp. R1337-R1345 ◽

Cited By ~ 20

Author(s):

Jennifer A. Teske ◽

Claudio E. Perez-Leighton ◽

Charles J. Billington ◽

Catherine M. Kotz

Keyword(s):

Physical Activity ◽

Locus Coeruleus ◽

Expression Pattern ◽

Principal Component ◽

Brain Regions ◽

Sprague Dawley ◽

Orexin A ◽

Orexin Receptors ◽

Sprague Dawley Rats ◽

Spontaneous Physical Activity

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 with 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) nonresting 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 the OXR mRNA in the LC is important in defining the OR phenotype. Compared with Sprague-Dawley rats, OR rats had greater SPA and NREE and lower resting EE and adiposity. SPA responsivity to OXA in the LC was greater in OR rats compared with 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 nonresting EE.

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Effect of acute and chronic caloric restriction and metabolic glucoprivation on spontaneous physical activity in obesity-prone and obesity-resistant rats

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.90866.2008 ◽

2009 ◽

Vol 297 (1) ◽

pp. R176-R184 ◽

Cited By ~ 11

Author(s):

J. A. Teske ◽

C. M. Kotz

Keyword(s):

Physical Activity ◽

Caloric Restriction ◽

Phenotypic Traits ◽

Time Interval ◽

Sprague Dawley ◽

Orexin A ◽

Time Period ◽

Sprague Dawley Rats ◽

Spontaneous Physical Activity

Caloric restriction (CR) and metabolic glucoprivation affect spontaneous physical activity (SPA), but it's unknown whether these treatments similarly affect SPA in selectively bred obesity-prone (OP) and -resistant (OR) rats. OR rats have greater basal SPA and are more responsive to treatments that modulate SPA, such as orexin A administration. We hypothesized that OR rats would be more sensitive to other treatments modulating SPA. To test this, continuous 24-h SPA was measured before and during acute (24 h) and chronic (8 wk) CR in OR, OP, and Sprague-Dawley rats. Pharmacological glucoprivation was produced by injection of 2-deoxyglucose (2-DG), and SPA was measured 5 h postinjection. Acute CR increased SPA in all groups; however, the effect was dependent on the index of SPA and time interval during the 24-h time period. In contrast to OR rats, chronic CR increased distance traveled, ambulatory episodes, and time spent in ambulation and stereotypy during the time interval preceding anticipation of food in OP and Sprague-Dawley rats. Although the effects of 2-DG treatment on SPA were minimal, OR rats had significantly greater SPA than OP and Sprague-Dawley rats independent of treatment. That chronic CR failed to result in significant changes in SPA in OR rats suggests that these rats may be especially unresponsive to treatments modulating feeding. This insensitivity coupled with elevated basal SPA levels may in part mediate phenotypic traits of lean rats.

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Orexin signaling in rostral lateral hypothalamus and nucleus accumbens shell in the control of spontaneous physical activity in high- and low-activity rats

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00339.2016 ◽

2017 ◽

Vol 312 (3) ◽

pp. R338-R346 ◽

Cited By ~ 13

Author(s):

Claudio Perez-Leighton ◽

Morgan R. Little ◽

Martha Grace ◽

Charles Billington ◽

Catherine M. Kotz

Keyword(s):

Physical Activity ◽

Nucleus Accumbens ◽

Lateral Hypothalamus ◽

Receptor Expression ◽

Nucleus Accumbens Shell ◽

Orexin A ◽

Orexin Neuron ◽

Spontaneous Physical Activity ◽

Low Activity ◽

Higher Sensitivity

Spontaneous physical activity (SPA) describes activity outside of formal exercise and shows large interindividual variability. The hypothalamic orexin/hypocretin peptides are key regulators of SPA. Orexins drive SPA within multiple brain sites, including rostral lateral hypothalamus (LH) and nucleus accumbens shell (NAcSh). Rats with high basal SPA (high activity, HA) show higher orexin mRNA expression and SPA after injection of orexin-A in rostral LH compared with low-activity (LA) rats. Here, we explored the contribution of orexin signaling in rostral LH and NAcSh to the HA/LA phenotype. We found that HA rats have higher sensitivity to SPA after injection of orexin-A in rostral LH, but not in NAcSh. HA and LA rats showed similar levels of orexin receptor expression in rostral LH, and activation of orexin-producing neurons after orexin-A injection in rostral LH. Also, in HA and LA rats, the coinjection of orexin-A in rostral LH and NAcSh failed to further increase SPA beyond the effects of orexin-A in rostral LH. Pretreatment with muscimol, a GABAA receptor agonist, in NAcSh potentiated SPA produced by orexin-A injection in rostral LH in HA but not in LA rats. Our results suggest that a feedback loop from orexin-responsive neurons in rostral LH to orexin neurons and a the NAcSh–orexin neuron–rostral LH circuit regulate SPA. Overall, our data suggest that differences in orexin sensitivity in rostral LH and its modulation by GABA afferents from NAcSh contribute to individual SPA differences.

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The effect of orexin A on food intake and spontaneous physical activity in the paraventricular nucleus and ventral tegmental area

Appetite ◽

10.1016/j.appet.2010.04.052 ◽

2010 ◽

Vol 54 (3) ◽

pp. 641

Author(s):

P. David ◽

J.A. Teske ◽

M.K. Grace ◽

C.J. Billington ◽

C.M. Kotz

Keyword(s):

Physical Activity ◽

Food Intake ◽

Ventral Tegmental Area ◽

Paraventricular Nucleus ◽

Orexin A ◽

Spontaneous Physical Activity ◽

Ventral Tegmental

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Orexin A (hypocretin 1) injected into hypothalamic paraventricular nucleus and spontaneous physical activity in rats

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00126.2003 ◽

2004 ◽

Vol 286 (4) ◽

pp. E551-E559 ◽

Cited By ~ 100

Author(s):

Kohji Kiwaki ◽

Catherine M. Kotz ◽

Chuanfeng Wang ◽

Lorraine Lanningham-Foster ◽

James A. Levine

Keyword(s):

Physical Activity ◽

Energy Balance ◽

Paraventricular Nucleus ◽

Night Vision ◽

Hypothalamic Paraventricular Nucleus ◽

Positive Energy ◽

Orexin A ◽

Positive Energy Balance ◽

Activity Sensors ◽

Spontaneous Physical Activity

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). O2 consumption and CO2 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 × 103 beam break count, n = 24; vehicle: 1.85 ± 1.13 × 103, n = 38). This increase in SPA was accompanied by compatible increase in O2 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.

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Neuroregulation of nonexercise activity thermogenesis and obesity resistance

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00095.2007 ◽

2008 ◽

Vol 294 (3) ◽

pp. R699-R710 ◽

Cited By ~ 56

Author(s):

Catherine M. Kotz ◽

Jennifer A. Teske ◽

Charles J. Billington

Keyword(s):

Physical Activity ◽

Body Weight ◽

Weight Gain ◽

Body Weight Gain ◽

Strain Differences ◽

Mechanistic Explanation ◽

The Body ◽

Current Status ◽

Energetic Cost ◽

Spontaneous Physical Activity

High levels of spontaneous physical activity in lean people and the nonexercise activity thermogenesis (NEAT) derived from that activity appear to protect lean people from obesity during caloric challenge, while obesity in humans is characterized by dramatically reduced spontaneous physical activity. We have similarly demonstrated that obesity-resistant rats have significantly greater spontaneous physical activity than obesity-prone rats, and that spontaneous physical activity predicts body weight gain. Although the energetic cost of activity varies between types of activity and may be regulated, individual level of spontaneous physical activity is important in determining propensity for obesity. We review the current status of knowledge about the brain mechanisms involved in controlling the level of spontaneous physical activity and the NEAT so generated. Focus is on potential neural mediators of spontaneous physical activity and NEAT, including orexin A (also known as hypocretin 1), agouti-related protein, ghrelin, and neuromedin U, in addition to brief mention of neuropeptide Y, corticotrophin releasing hormone, cholecystokinin, estrogen, leptin, and dopamine effects on spontaneous physical activity. We further review evidence that strain differences in orexin stimulation pathways for spontaneous physical activity and NEAT appear to track with the body weight phenotype, thus providing a potential mechanistic explanation for reduced activity and weight gain.

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Unabated anorexic and enhanced thermogenic responses to melanotan II in diet-induced obese rats despite reduced melanocortin 3 and 4 receptor expression

Journal of Endocrinology ◽

10.1677/joe.0.1820123 ◽

2004 ◽

Vol 182 (1) ◽

pp. 123-132 ◽

Cited By ~ 40

Author(s):

G Li ◽

Y Zhang ◽

JT Wilsey ◽

PJ Scarpace

Keyword(s):

Cholesterol Metabolism ◽

Uncoupling Protein ◽

Serum Insulin ◽

Caloric Intake ◽

Receptor Expression ◽

Delayed Response ◽

Sprague Dawley ◽

Reduced Body ◽

Brown Adipose ◽

Melanotan Ii

The effects of the chronic activation of the central melanocortin (MC) system by melanotan II (MTII) were assessed in chow-fed (CH) and high-fat (HF) diet-induced obese (DIO) Sprague-Dawley rats. Six-day central infusion of MTII (1 nmol/day) reduced body weight and visceral adiposity compared with ad libitum-fed control and pair-fed groups and markedly suppressed caloric intake in both CH and DIO rats. The anorexic response to MTII was similar in DIO relative to CH rats. MTII induced a sustained increase in oxygen consumption in DIO but a delayed response in CH rats. In both diet groups, MTII reduced serum insulin and cholesterol levels compared with controls. HF feeding increased brown adipose tissue (BAT) uncoupling protein 1 (UCP1) by over twofold, and UCP1 levels were further elevated in MTII-treated CH and DIO rats. MTII lowered acetyl-CoA carboxylase expression and prevented the reduction in muscle-type carnitine palmitoyltransferase I mRNA by pair-feeding in the muscle of DIO rats. Compared with CH controls, hypothalamic MC3 and MC4 receptor expression levels were reduced in DIO controls. This study has demonstrated that, despite reduced hypothalamic MC3/MC4 receptor expression, anorexic and thermogenic responses to MTII are unabated with an initial augmentation of energy expenditure in DIO versus CH rats. The HF-induced up-regulation of UCP1 in BAT may contribute to the immediate increase in MTII-stimulated thermogenesis in DIO rats. MTII also increased fat catabolism in the muscle of DIO rats and improved glucose and cholesterol metabolism in both groups.

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