Abstract

The beta3 adrenergic receptor (AR) has been proposed to be a therapeutic target for the treatment of obesity and adult-onset diabetes, and recent work has identified a polymorphism in the human beta3-AR gene that is associated with excess weight gain and insulin resistance. Beta3-AR are expressed almost exclusively in adipocytes where they are co-expressed with beta1-AR. The tissue-specific pattern of beta3-AR gene expression and its co-existence in adipose tissue with beta1-AR has raised several fundamental questions. First, the coexpression of beta1-and beta3-AR in fat cells implies that the beta3-AR subtypes serve different signaling functions in adipocytes, and recent evidence indicates that beta1- and beta3-AR have unique signaling properties and that these receptors activate distinct pathways in adipocytes. The organization of beta1- and beta3-AR signaling in adipocytes will be further characterized and specific hypotheses regarding the biochemical and cellular basis of that organization will be tested. Second, beta1- and beta3-AR exhibit several unique pharmacological and biochemical properties that are amenable to molecular analysis. A panel of epitope- tagged, mutated and chimeric receptors have been created that will allow validation of observations made in adipocyte and further dissection of the molecular bases of beta3-AR subtype-specific signaling properties. These analyses will include examination of the molecular pharmacology of aryloxypropranolamine and phenethanolamine agonists, compounds being developed as selective beta3-AR agonists. An understanding of how these compounds differentially interact with the beta 3-AR subtypes, and the impact of that interaction on receptor signaling is key to understanding their biological actions.
Specific aims are:
Aim 1. To investigate the biochemical organization of beta3-AR signaling in adipocytes.
Aim 2. To further characterize the differential signaling properties of beta1- beta3-AR and to examine the cellular and molecular basis.
Specific Aim 3. To examine the molecular pharmacology of beta3-AR-selective agonists.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK046339-05A1
Application #
2689285
Study Section
Endocrinology Study Section (END)
Program Officer
Haft, Carol R
Project Start
1993-12-01
Project End
1999-06-30
Budget Start
1998-09-30
Budget End
1999-06-30
Support Year
5
Fiscal Year
1998
Total Cost
Indirect Cost

  Institution

Name
Wayne State University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
City
Detroit
State
MI
Country
United States
Zip Code
48202

  Publications

Granneman, J G (2001) The putative beta4-adrenergic receptor is a novel state of the beta1-adrenergic receptor. Am J Physiol Endocrinol Metab 280:E199-202
Sacchetti, P; Mitchell, T R; Granneman, J G et al. (2001) Nurr1 enhances transcription of the human dopamine transporter gene through a novel mechanism. J Neurochem 76:1565-72
Konkar, A A; Zhai, Y; Granneman, J G (2000) beta1-adrenergic receptors mediate beta3-adrenergic-independent effects of CGP 12177 in brown adipose tissue. Mol Pharmacol 57:252-8
Konkar, A A; Zhu, Z; Granneman, J G (2000) Aryloxypropanolamine and catecholamine ligand interactions with the beta(1)-adrenergic receptor: evidence for interaction with distinct conformations of beta(1)-adrenergic receptors. J Pharmacol Exp Ther 294:923-32
Burchett, S A; Bannon, M J; Granneman, J G (1999) RGS mRNA expression in rat striatum: modulation by dopamine receptors and effects of repeated amphetamine administration. J Neurochem 72:1529-33
Sacchetti, P; Brownschidle, L A; Granneman, J G et al. (1999) Characterization of the 5'-flanking region of the human dopamine transporter gene. Brain Res Mol Brain Res 74:167-74
Granneman, J G; Zhai, Y; Zhu, Z et al. (1998) Molecular characterization of human and rat RGS 9L, a novel splice variant enriched in dopamine target regions, and chromosomal localization of the RGS 9 gene. Mol Pharmacol 54:687-94
Granneman, J G; Lahners, K N; Zhai, Y (1998) Agonist interactions with chimeric and mutant beta1- and beta3-adrenergic receptors: involvement of the seventh transmembrane region in conferring subtype specificity. Mol Pharmacol 53:856-61
Chaudhry, A; Granneman, J G (1997) Effect of hypothyroidism on adenylyl cyclase activity and subtype gene expression in brown adipose tissue. Am J Physiol 273:R762-7
Chaudhry, A; Muffler, L A; Yao, R et al. (1996) Perinatal expression of adenylyl cyclase subtypes in rat brown adipose tissue. Am J Physiol 270:R755-60

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