The goal of this project is to investigate the impairment of thermogenesis in brown adipose tissue (BAT) in the senescent rat. Nonshivering thermogenesis in BAT is an important source of heat to warm an animal after exposure to the cold, especially in the cold-adapted rat. There are four specific aims to this proposal. (1) To determine if the cold-induced gene expression of BAT uncoupling protein (UCP) is mediated by other than beta-3-adrenergic receptors (beta-3ARs) in senescent rats. The population of beta-ARs in BAT consists mostly of the atypical beta-3AR subtype and this receptor mediates the induction of BAT UCP in young rats.However, cold-induced thermogenesis is preserved in senescent rats to a greater extent than is beta-3AR stimulated thermogenesis, suggesting another pathway may be mediating thermogenesis in older rats. The first goal will be to examine and compare the time-course of cold-stimulated and beta-3-agonist-stimulated gene expression of UCP by assessment of UCP mRNA and the level of UCP by immunoreactivity in rats of 6-, 12- and 24-months. (2) To determine if thermogenesis is mediated by beta-1ARs or alpha-1-adrenergic receptors (alpha-1 ARs) rather than beta-3ARs in senescent rats. The applicants' data indicate that alpha-1 ARs are more important for the thermogenic response in old compared to young rats. The second goal will be to examine and compare thermogenesis (O2 consumption and mitochondrial GDP binding), the gene expression of UCP and the level of UCP following stimulation with the endogenous agonist, norepinephrine (NE); the beta-3-agonist, CGP-1277A; the alpha-1-agonist, phenylephrine; the beta-1 selective agonist, tazolol; as well as post receptor agents such as forskolin and the cAMP analog, Sp-cAMPS in rats of three ages. (3) To determine if beta-3ARs are desensitized by beta-agonists. It has been suggested that beta- 3ARs may not be desensitized by catecholamines in the same manner as beta-1 or beta-2ARs. The applicants propose to assess desensitization of beta-3 and beta-1 signal transduction by assessing receptor number, adenylate cyclase activity, and the gene expression of beta-3 and beta-1ARs by assessing beta-3 and beta-1 mRNA in BAT following NE, CGP-12177A and tazolol administration in rats of three ages. (4) To determine if cold adaptation or chronic drug treatment can restore the BAT thermogenic response to beta-3-agonists in aged rats. The synthesis of UCP (and therefore the capacity for thermogenesis) can be increased by drugs (beta-agonists) or physiologically (cold exposure). In addition, some data suggest that beta-agonist treatment can up regulate beta- 3ARs. The fourth goal of this proposal is to restore the reduced beta- 3AR-mediated thermogenic response with age by cold adaptation or chronic administration of CGP-12177A and/or phenylephrine. Thermogenesis (body temperature and oxygen consumption) will be examined and correlated with UCP gene expression, GDP binding, and beta-AR signal transduction in control and chronically drug-treated and cold-adapted rats of two ages.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG011465-02
Application #
2052646
Study Section
Respiratory and Applied Physiology Study Section (RAP)
Project Start
1993-12-01
Project End
1998-11-30
Budget Start
1994-12-01
Budget End
1995-11-30
Support Year
2
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Florida
Department
Pharmacology
Type
Schools of Medicine
DUNS #
073130411
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Kim, Yong-Woon; Scarpace, Philip J (2003) Repeated fasting/refeeding elevates plasma leptin without increasing fat mass in rats. Physiol Behav 78:459-64
Scarpace, P J; Matheny, M; Tumer, N (2001) Hypothalamic leptin resistance is associated with impaired leptin signal transduction in aged obese rats. Neuroscience 104:1111-7
Scarpace, P J; Tumer, N (2001) Peripheral and hypothalamic leptin resistance with age-related obesity. Physiol Behav 74:721-7
Scarpace, P J; Matheny, M; Moore, R L et al. (2000) Impaired leptin responsiveness in aged rats. Diabetes 49:431-5
Scarpace, P J; Matheny, M; Shek, E W (2000) Impaired leptin signal transduction with age-related obesity. Neuropharmacology 39:1872-9
Scarpace, P J; Matheny, M; Moore, R L et al. (2000) Modulation of uncoupling protein 2 and uncoupling protein 3: regulation by denervation, leptin and retinoic acid treatment. J Endocrinol 164:331-7
Kumar, M V; Moore, R L; Scarpace, P J (1999) Beta3-adrenergic regulation of leptin, food intake, and adiposity is impaired with age. Pflugers Arch 438:681-8
Kumar, M V; Sunvold, G D; Scarpace, P J (1999) Dietary vitamin A supplementation in rats: suppression of leptin and induction of UCP1 mRNA. J Lipid Res 40:824-9
Scarpace, P J; Matheny, M; Tumer, N (1999) Differential down-regulation of beta3-adrenergic receptor mRNA and signal transduction by cold exposure in brown adipose tissue of young and senescent rats. Pflugers Arch 437:479-83
Kumar, M V; Scarpace, P J (1998) Differential effects of retinoic acid on uncoupling protein-1 and leptin gene expression. J Endocrinol 157:237-43

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