Obesity is a growing health concern. As obesity has increased, the amount of physical activity in the population has decreased. In our sedentary society, low levels of physical activity have a significant impact on weight gain. Whereas the neural, hormonal, molecular, and genetic mechanisms of energy intake are well studied, very little is known about the mechanisms through which energy is expended through physical activity. Non-exercise activity thermogenesis (NEAT) in humans is comprised of the energy expenditure of all physical activity outside of volitional exercise; NEAT contributes significantly to the ability to resist weight gain in the face of overfeeding. We have previously demonstrated that central administration of the neuropeptide orexin A increases NEAT in rats. Moreover, obesity-prone rats are less sensitive to the NEAT-activating effects of orexin in the paraventricular hypothalamic nucleus (PVN) after access to a high-fat diet compared to obesity-resistant rats. Here, we propose to systematically examine the mechanisms through which PVN orexin differentially affects NEAT in obese and lean animals. We hypothesize that the energy expenditure from orexin-induced NEAT induces weight loss. Therefore, we will determine if twice-daily central orexin treatment decreases body weight and increases NEAT in rats. Next, we hypothesize that decreases in orexin-induced NEAT contribute to weight gain in obesity-prone rats. Therefore, in the second study, we will determine how the high-fat diet contributes to the ability of orexin to stimulate NEAT in the obesity-prone, obesity-resistant, and control rats. Third, we will determine how a high-carbohydrate diet alters daily NEAT in obesity-prone, obesity-resistant, and control rats, as well as how the diet affects orexin-induced NEAT. Lastly, we will examine the neural mechanisms of the differential effects of orexin on NEAT in obesity-prone, obesity- resistant, and control rats by comparing orexin synthesis and orexin content in targeted brain regions in these animals. With these studies, we hope to delineate the neural mechanisms of how orexin affects changes in NEAT, as well as to assess how orexin interacts with diet to affect NEAT and obesity. Understanding the mechanisms through which the energy expenditure of physical activity affects NEAT is a critical step in developing effective behavioral and pharmacological strategies to combat obesity. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS055859-01A1
Application #
7251566
Study Section
Neuroendocrinology, Neuroimmunology, and Behavior Study Section (NNB)
Program Officer
Mitler, Merrill
Project Start
2007-06-01
Project End
2011-05-31
Budget Start
2007-06-01
Budget End
2008-05-31
Support Year
1
Fiscal Year
2007
Total Cost
$326,335
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Gavini, Chaitanya K; Britton, Steven L; Koch, Lauren G et al. (2018) Inherently Lean Rats Have Enhanced Activity and Skeletal Muscle Response to Central Melanocortin Receptors. Obesity (Silver Spring) 26:885-894
Almundarij, Tariq I; Smyers, Mark E; Spriggs, Addison et al. (2016) Physical Activity, Energy Expenditure, and Defense of Body Weight in Melanocortin 4 Receptor-Deficient Male Rats. Sci Rep 6:37435
Gavini, Chaitanya K; Jones 2nd, William C; Novak, Colleen M (2016) Ventromedial hypothalamic melanocortin receptor activation: regulation of activity energy expenditure and skeletal muscle thermogenesis. J Physiol 594:5285-301
Shukla, C; Koch, L G; Britton, S L et al. (2015) Contribution of regional brain melanocortin receptor subtypes to elevated activity energy expenditure in lean, active rats. Neuroscience 310:252-67
Smyers, Mark E; Bachir, Kailey Z; Britton, Steven L et al. (2015) Physically active rats lose more weight during calorie restriction. Physiol Behav 139:303-13
Gavini, Chaitanya K; Mukherjee, Sromona; Shukla, Charu et al. (2014) Leanness and heightened nonresting energy expenditure: role of skeletal muscle activity thermogenesis. Am J Physiol Endocrinol Metab 306:E635-47
Novak, Colleen M; Burghardt, Paul R; Levine, James A (2012) The use of a running wheel to measure activity in rodents: relationship to energy balance, general activity, and reward. Neurosci Biobehav Rev 36:1001-1014
Nixon, Joshua P; Kotz, Catherine M; Novak, Colleen M et al. (2012) Neuropeptides controlling energy balance: orexins and neuromedins. Handb Exp Pharmacol :77-109
Shukla, Charu; Britton, Steven L; Koch, Lauren G et al. (2012) Region-specific differences in brain melanocortin receptors in rats of the lean phenotype. Neuroreport 23:596-600
Park, Young Joo; Kim, Seong Chul; Kim, Jeehee et al. (2011) Dissociation of diabetes and obesity in mice lacking orphan nuclear receptor small heterodimer partner. J Lipid Res 52:2234-44

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