Journal article
Mice expressing human but not murine β3-adrenergic receptors under the control of human gene regulatory elements
Diabetes (New York, N.Y.), Vol.47(9), pp.1464-1471
1998
DOI: 10.2337/diabetes.47.9.1464
PMID: 9726236
Abstract
Beta-adrenergic receptors (ARs) are expressed predominantly in adipose tissue, and beta3-selective agonists are effective anti-obesity drugs in rodents. Rodent and human beta3-ARs differ with respect to expression in white versus brown adipocytes as well as their ability to be stimulated by beta3-AR-selective agonists. Humans express beta3-AR mRNA abundantly in brown but not white adipocytes, while rodents express beta3-AR mRNA abundantly in both sites. To determine the basis for this difference, we have transgenically introduced 74 kilobases (kb) of human beta3-AR genomic sequence into gene knockout mice lacking beta3-ARs. Importantly, human beta3-AR mRNA was expressed only in brown adipose tissue (BAT) of transgenic mice, with little or no expression being detected in white adipose tissue (WAT), liver, stomach, small intestine, skeletal muscle, and heart. This pattern of expression differed from that observed in mice bearing a murine beta3-AR genomic transgene in which beta3-AR mRNA was expressed in both WAT and BAT, but not in other sites. Furthermore, we have transgenically introduced smaller human constructs containing -14.5 and -0.6 kb of upstream sequence into beta3-AR gene knockout mice. Both -14.5 and -0.6 kb constructs were expressed in BAT but not WAT. Thus, human but not murine cis-regulatory elements direct beta3-AR gene expression preferentially to brown adipocytes. Identification of responsible cis-regulatory element(s) and relevant trans-acting factor(s) should provide insight into mechanisms controlling human beta3-AR gene expression. In addition, the beta3-AR agonist, CGP-12177, stimulated oxygen consumption in mice expressing human but not murine beta3-ARs by 91% compared with only 49% in control beta3-AR gene knockout mice, demonstrating that the human beta3-AR can functionally couple with energy expenditure. These "humanized" mice should assist us in the development of drugs that may become effective anti-obesity agents in humans.
Details
- Title: Subtitle
- Mice expressing human but not murine β3-adrenergic receptors under the control of human gene regulatory elements
- Creators
- Moriko Ito - Division of Endocrinology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, United StatesDanica Grujic - Division of Endocrinology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, United StatesE Dale Abel - Division of Endocrinology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, United StatesAntonio Vidal-Puig - Division of Endocrinology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, United StatesVedrana S Susulic - Division of Endocrinology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, United StatesJoel Lawitts - Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, United StatesMary-Ellen Harper - Department of Biochemistry, University of Ottawa, Ottawa, Ontario, CanadaJean Himms-Hagen - Department of Biochemistry, University of Ottawa, Ottawa, Ontario, CanadaA Donny Strosberg - National Center of Scientific Research and Cochin Institute of Molecular Genetics, Paris VII University, Paris, FranceBradford B Lowell - Division of Endocrinology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, United States
- Resource Type
- Journal article
- Publication Details
- Diabetes (New York, N.Y.), Vol.47(9), pp.1464-1471
- Publisher
- American Diabetes Association; Alexandria, VA
- DOI
- 10.2337/diabetes.47.9.1464
- PMID
- 9726236
- ISSN
- 0012-1797
- eISSN
- 1939-327X
- Language
- English
- Date published
- 1998
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984025294802771
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