Dodge Center, MN, United States
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Teske J.A.,Minneapolis VA Health Care System | Teske J.A.,Minnesota Obesity Center | Teske J.A.,University of Minnesota | Billington C.J.,Minneapolis VA Health Care System | And 8 more authors.
International Journal of Obesity | Year: 2012

Objective: It is unclear whether elevated spontaneous physical activity (SPA, very low-intensity physical activity) positively influences body composition long term. We determined whether SPA and caloric intake were differentially related to the growth curve trajectories of body weight, fat mass (FM) and fat-free mass (FFM) between obesity resistant and Sprague-Dawley rats at specific age intervals. Design and Subjects: Body composition, SPA and caloric intake were measured in selectively-bred obesity-resistant and out-bred Sprague-Dawley rats from 1 to 18 months. Data from development throughout maturation were analyzed by longitudinal growth curve modeling to determine the rate and acceleration of body weight, FM- and FFM-gain. Results: Obesity-resistant rats had a lower rate of FM gain overall, a lower acceleration in body weight early in life, significantly greater SPA and lower cumulative caloric intake. Greater SPA in obesity-resistant rats was significantly associated with a lower rate of FM gain overall and lower acceleration in body weight early in life. Obesity resistant rats lost less FFM compared with Sprague-Dawley rats despite that obesity-resistant rats had a lower acceleration in FFM gain early in life. Obesity-resistant rats gained less FM and more FFM per gram body weight and were less energy efficient than Sprague-Dawley rats. Caloric intake was significantly and positively related to body weight, FM and FFM gain in both groups. Circadian patterns of caloric intake were group and age-dependent. Our data demonstrate that elevated and sustained SPA during development and over the lifespan are related to the reduced the rate of FM gain and may preserve FFM. Conclusion: These data support the idea that SPA level is a reproducible marker that reliably predicts propensity for obesity in rats, and that elevated levels of SPA maintained during the lifespan promote a lean phenotype. © 2012 Macmillan Publishers Limited All rights reserved.


Noble E.E.,Minnesota Obesity Center | Noble E.E.,University of Minnesota | Mavanji V.,Veterans Affairs Medical Center | Mavanji V.,Minnesota Obesity Center | And 11 more authors.
Neurobiology of Learning and Memory | Year: 2014

Background: Previous studies have shown that a western diet impairs, whereas physical exercise enhances hippocampus-dependent learning and memory. Both diet and exercise influence expression of hippocampal brain-derived neurotrophic factor (BDNF), which is associated with improved cognition. We hypothesized that exercise reverses diet-induced cognitive decline while increasing hippocampal BDNF. Methods: To test the effects of exercise on hippocampal-dependent memory, we compared cognitive scores of Sprague-Dawley rats exercised by voluntary running wheel (RW) access or forced treadmill (TM) to sedentary (Sed) animals. Memory was tested by two-way active avoidance test (TWAA), in which animals are exposed to a brief shock in a specific chamber area. When an animal avoids, escapes or has reduced latency to do either, this is considered a measure of memory. In a second experiment, rats were fed either a high-fat diet or control diet for 16. weeks, then randomly assigned to running wheel access or sedentary condition, and TWAA memory was tested once a week for 7. weeks of exercise intervention. Results: Both groups of exercised animals had improved memory as indicated by reduced latency to avoid and escape shock, and increased avoid and escape episodes ( p<. 0.05). Exposure to a high-fat diet resulted in poor performance during both the acquisition and retrieval phases of the memory test as compared to controls. Exercise reversed high-fat diet-induced memory impairment, and increased brain-derived neurotrophic factor (BDNF) in neurons of the hippocampal CA3 region. Conclusions: These data suggest that exercise improves memory retrieval, particularly with respect to avoiding aversive stimuli, and may be beneficial in protecting against diet induced cognitive decline, likely via elevated BDNF in neurons of the CA3 region. © 2014 .


Mavanji V.,University of Minnesota | Teske J.A.,University of Minnesota | Teske J.A.,Veterans Affairs Medical Center | Billington C.J.,Veterans Affairs Medical Center | And 5 more authors.
International Journal of Obesity | Year: 2010

Objective: To determine if resistance to weight gain is associated with alterations in sleep-wake states and orexin receptor gene expression.Design: 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.Subjects: Adult male obesity-susceptible SD and selectively bred OR rats.Measurements: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. Results: 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. Conclusion: These results show that prolonged wakefulness, better sleep quality, lower sleep drive and greater orexin signaling may confer protection against obesity. © 2010 Macmillan Publishers Limited All rights reserved.


Teske J.A.,Veterans Affairs Medical Center | Teske J.A.,University of Minnesota | Billington C.J.,Veterans Affairs Medical Center | Billington C.J.,Minnesota Obesity Center | And 4 more authors.
Acta Physiologica | Year: 2010

The hypocretins or orexins are endogenous neuropeptides synthesized in discrete lateral, perifornical and dorsal hypothalamic neurones. These multi-functional neuropeptides modulate energy homeostasis, arousal, stress, reward, reproduction and cardiovascular function. This review summarizes the role of hypocretins in modulating non-sleep-related energy expenditure with specific focus on the augmentation of whole body energy expenditure as well as hypocretin-induced physical activity and sympathetic outflow. We compare the efficacy of hypocretin-1 and 2 on energy expenditure and evaluate whether the literature implicates hypocretin signalling though the hypocretin-1 and -2 receptor as having shared and or functionally specific physiological effects. Thus far data suggest that hypocretin-1 has a more robust stimulatory effect relative to hypocretin-2. Furthermore, hypocretin-1 receptor predominantly mediates behaviours known to influence energy expenditure. Further studies on the hypocretin-2 receptor are needed. © 2010 Scandinavian Physiological Society.


Wang C.F.,Veterans Affairs Medical Center | Wang C.F.,Minnesota Obesity Center | Wang C.F.,University of Minnesota | Godar R.J.,Veterans Affairs Medical Center | And 5 more authors.
American Journal of Physiology - Regulatory Integrative and Comparative Physiology | Year: 2010

An acute injection of brain-derived neurotrophic factor (BDNF) in the hypothalamic paraventricular nucleus (PVN) reduces body weight by decreasing feeding and increasing energy expenditure (EE), in animals on standard laboratory chow. Animals have divergent responses to a high-fat diet (HFD) exposure, with some developing obesity and others remaining lean. In the current study, we tested two hypotheses: 1) BDNF in the PVN reverses HFD-induced obesity, and 2) animals with higher body fat have a greater physiological response to BDNF than those with less body fat. Eighty-four 10-wk old rats were allowed HFD ad libitum for 9 wk and then prepared with bilateral PVN cannulas. Animals were then divided into tertiles based on their body fat rank: high, intermediate, and low (H, I, and L). Each group was further divided into 2 subgroups and then PVN injected with BDNF or control (artificial cerebrospinal fluid, aCSF) every other day for 3 wk. Energy intake (EI), body weight, and body composition were measured. At study's end, rats were killed to allow measurement of other metabolic indices. In parallel, another 12 rats were fed control diet (CD), PVN-cannulated and injected with aCSF. HFD exposure induced obesity, particularly in the H body fat group, with a significant increase in EI, body weight, fat mass, liver size, and serum glucose, triglycerides, insulin, and leptin. BDNF significantly reduced EI, body weight, body fat, lean mass, and serum metabolic indices. These BDNF effects were greatest in the H body fat group. These data indicate that BDNF reduced HFD-induced obesity and metabolic syndrome-like measures, and the animals with the most body fat had the most significant response to BDNF.


Mavanji V.,University of Minnesota | Teske J.A.,University of Arizona | Teske J.A.,Southern Arizona Veterans Affairs Health Care System | Billington C.J.,University of Minnesota | And 5 more authors.
Obesity | Year: 2013

Objective Sleep restriction in humans increases risk for obesity, but previous rodent studies show weight loss following sleep deprivation, possibly due to stressful methods used to prevent sleep. Obesity-resistant (OR) rats exhibit consolidated-sleep and resistance to weight gain. It was hypothesized that sleep disruption by a less-stressful method would increase body weight, and the effect of partial sleep deprivation (PSD) on body weight in OR and Sprague-Dawley (SD) rats was examined. Design and Methods OR and SD rats (n = 12/group) were implanted with transmitters to record sleep/wake. After baseline recording, six SD and six OR rats underwent 8 h PSD during light phase for 9 days. Sleep was reduced using recordings of random noise. Sleep/wake states were scored as wakefulness (W), slow-wave-sleep (SWS), and rapid-eye-movement-sleep (REMS). Total number of transitions between stages, SWS-delta-power, food intake, and body weight were documented. Results Exposure to noise decreased SWS and REMS time, while increasing W time. Sleep-deprivation increased the number of transitions between stages and SWS-delta-power. Further, PSD during the rest phase increased recovery sleep during the active phase. The PSD SD and OR rats had greater food intake and body weight compared to controls Conclusions PSD by less-stressful means increases body weight in rats. Also, PSD during the rest phase increases active period sleep. Copyright © 2012 The Obesity Society.


Olszewski P.K.,University of Waikato | Olszewski P.K.,Minnesota Obesity Center | Waas J.R.,University of Waikato | Brooks L.L.,University of Waikato | And 3 more authors.
Peptides | Year: 2013

When gastrointestinal sickness induced by toxin injection is associated with exposure to novel food, the animal acquires a conditioned taste aversion (CTA). Malaise is accompanied by a surge in oxytocin release and in oxytocin neuronal activity; however, it is unclear whether oxytocin is a key facilitator of aversion or merely its marker. Herein we investigated whether blockade of the oxytocin receptor with the blood-brain barrier penetrant oxytocin receptor antagonist L-368,899 is detrimental for the acquisition and/or retrieval of lithium chloride (LiCl)-dependent CTA to a saccharin solution in mice. We also examined whether L-368,899 given prior to LiCl affects neuronal activity defined through c-Fos immunohistochemistry in select brain sites facilitating CTA acquisition. L-368,899 given prior to LiCl caused a 30% increase in saccharin solution intake in a two-bottle test, but when the antagonist was administered before the two-bottle test, it failed to diminish the retrieval of an existing CTA. LiCl administration increased c-Fos expression in the hypothalamic paraventricular and supraoptic nuclei, area postrema, nucleus of the solitary tract and basolateral and central (CNA) nuclei of the amygdala. L-368,899 injected before LiCl reduced the number of c-Fos positive CNA neurons and brought it down to levels similar to those observed in mice treated only with L-368,899. We conclude that oxytocin is one of the key components in acquisition of LiCl-induced CTA and the aversive response can be alleviated by the oxytocin receptor blockade. Oxytocin receptor antagonism blunts responsiveness of CNA to peripherally injected LiCl. © 2013 Elsevier Inc. All rights reserved.


Rask-Andersen M.,Uppsala University | Olszewski P.K.,Uppsala University | Olszewski P.K.,Minnesota Obesity Center | Levine A.S.,Minnesota Obesity Center | Schioth H.B.,Uppsala University
Brain Research Reviews | Year: 2010

Anorexia nervosa (AN) is a complex multi-factorial disease with high heritability. The psychological AN symptoms are poorly connected with specific molecular mechanisms. Here we review the molecular basis of AN with the focus on human genetic association studies; we put these in the experimental biological context with emphasis on molecular systems controlling food intake and body weight in a direct or indirect manner. We systematically searched for human genetic studies related to AN and grouped data into main categories/systems reflecting their major known roles: (1) Systems related to mental disorders (serotonin, brain-derived neurotrophic factor (BDNF), norepinephrine (NE), glutamate (NMDA) receptor and SK3 channel, KCCN3). (2) Hunger regulatory systems (leptin, AGRP, MSH, melanocortin 4 receptor (MC4R), NPY, ghrelin, cholecystokinin (CCK). (3) Feeding motivation- and reward-related systems (opioids, OPRD1, cannabinoids (anandamide (AEA), THC, CBR1), dopamine, DRD2, DRD3, DRD4, catecholamine-O-methyl transferase (COMT). (4) Systems regulating energy metabolism (uncoupling proteins 2 and 3 (UCP2 and UCP3). (5) Neuroendocrine systems with emphasis on sex hormones (estrogen receptor-β (ESR2). (6) The immune system and inflammatory response (tumor necrosis factor-alpha (TNF-α). Overall, we found that in total 175 association studies have been performed on AN cohorts on 128 different polymorphisms related to 43 genes. We review the strongest associations, identify some genes that have an important role in regulating BMI whose possible relationship to AN has not been investigated and discuss the potential targets for pharmacological interventions. © 2009 Elsevier B.V.


Sreedharan S.,Uppsala University | Shaik J.H.A.,Uppsala University | Olszewski P.K.,Uppsala University | Olszewski P.K.,Minnesota Obesity Center | And 3 more authors.
BMC Genomics | Year: 2010

Background: The SLC17 family of transporters transports the amino acids: glutamate and aspartate, and, as shown recently, also nucleotides. Vesicular glutamate transporters are found in distinct species, such as C. elegans, but the evolutionary origin of most of the genes in this family has been obscure.Results: Our phylogenetic analysis shows that the SLC17 family consists of four main phylogenetic clades which were all present before the divergence of the insect lineage. One of these clades has not been previously described and it is not found in vertebrates. The clade containing Slc17a9 had the most restricted evolutionary history with only one member in most species. We detected expression of Slc17a1-17a4 only in the peripheral tissues but not in the CNS, while Slc17a5- Slc17a9 are highly expressed in both the CNS and periphery.Conclusions: The in situ hybridization studies on vesicular nucleotide transporter revealed high expression throughout the cerebral cortex, certain areas in the hippocampus and in specific nuclei of the hypothalamus and thalamus. Some of the regions with high expression, such as the medial habenula and the dentate gyrus of the hippocampus, are important sites for purinergic neurotransmission. Noteworthy, other areas relying on purine-mediated signaling, such as the molecular layer of the dentate gyrus and the periaqueductal gray, lack or have a very low expression of Slc17a9, suggesting that there could be another nucleotide transporter in these regions. © 2010 Sreedharan et al; licensee BioMed Central Ltd.


Herisson F.M.,University of Waikato | Brooks L.L.,University of Waikato | Waas J.R.,University of Waikato | Levine A.S.,University of Minnesota | And 3 more authors.
NeuroReport | Year: 2014

Centrally acting oxytocin (OT) inhibits feeding. Recent evidence suggests a link between OT and control of carbohydrate and saccharin intake, but it is unclear whether OT affects appetite for only carbohydrates, especially sweet ones, or sweet tastants irrespective of their carbohydrate content. Therefore, a blood-brain barrier penetrant OT receptor antagonist, L-368,899, was administered in mice and intake of liquid diets containing carbohydrates sucrose, glucose, fructose, polycose, or cornstarch (CS) or the noncarbohydrate, noncaloric sweetener saccharin was studied in episodic intake paradigms: one in which only one tastant was available and the other in which a choice between a carbohydrate (sucrose, glucose, or fructose) and saccharin was provided. We also used real-time PCR to examine hypothalamic Ot mRNA levels in mice provided short-term access to sucrose, CS, or saccharin. In the no-choice paradigm, L-368,899 increased the intake of all carbohydrates, whereas its effect on saccharin consumption showed only a trend. A 10 times lower dose (0.3mg/kg) stimulated intake of sucrose than other carbohydrates. In the choice test, a very low 0.1mg/kg dose of L-368,899 doubled the proportion of sucrose consumption relative to saccharin, but did not affect fructose or glucose preference. Ot gene expression increased after sucrose and CS, but not saccharin exposure compared with the controls; however, a higher level of significance was detected in the sucrose group. We conclude that OT inhibits appetite for carbohydrates. Sucrose consumption considerably enhances Ot gene expression and is particularly sensitive to OT receptor blockade, suggesting a special functional relationship between OT and sugar intake. © 2014 Wolters Kluwer Health Lippincott Williams & Wilkins.

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