International Mammalian Genome Society

The 13th International Mouse Genome Conference
October 31-November 3, 1999

Table of Contents * Structure * Bioinformatics * Sequence * Mapping * New Tools * Gene Discovery * Developmental * Mutagenesis * Functional Genomics

E21 Multiple Loci Contribute to Cold Stimulation of Ucp1 mRNA and Brown Adipocyte Formation in Mouse Retroperitoneal White Fat

Robert A. Koza, Susanna Hohmann, Lana Ritchie, James Mancuso, and Leslie P. Kozak. The Pennington Biomedical Research Center, 6400 Perkins Road, Baton Rouge LA 70808.

The complicated genetics of body weight regulation and obesity in mice may be studied more easily by analysis of very specific metabolic pathways rather than general phenotypes. One particular pathway, brown fat thermogenesis, has been linked to weight loss in mice. It has been demonstrated that among mouse strains susceptible to dietary obesity, only the animals with an enhanced capacity for B3-adrenergic stimulation of Ucp1 mRNA and brown adipocytes in white fat lose weight after treatment with the B3-adrenergic agonist CL316, 243. Similar elevations of Ucp1 expression and brown adipocyte formation were observed in the white fat of mice after exposure to cold temperatures (5oC) for one week. In this study, we used a (C57BL/6J X A/J)F1 X A/J backcross and selected intercrosses between AXB recombinant inbred (RI) strains derived from the C57BL/6J and A/J parentals to determine the genetics controlling cold-induced stimulation of Ucp1 mRNA and brown adipocyte formation in retroperitoneal (RP) fat. RP fat RNA's were isolated from the males of the parental strains, backcross, and RI intercross's after exposure to the cold for 1 week. Ucp1 mRNA expression was measured using both Northern blot procedures and quantitative RT-PCR (ABI 7700). The average RP fat Ucp1 mRNA expression in A/J mice was 668 140 SEM, more than 40-fold and 5 to 6-fold higher than the C57BL/6J (16 4 SEM) and (C57BL/6J X A/J)F1 (129 31 SEM) mice respectively. RI strains exhibited a wide range of phenotypes ranging from 1719 156 SEM for AXB8 to 13 8 SEM for AXB10. A microsatellite marker based genome wide scan using the 20 highest and lowest RP fat Ucp1 mRNA expressing backcross mice followed by more extensive genotyping (789 backcross progeny) of suggestive genomic regions revealed at least 4 loci with linkage to RP fat Ucp1 mRNA induction. These Iba (Induction of Brown Adipocyte) loci are linked to markers on chromosomes 2 (D2Mit66; LOD=8.06), 3 (D3Mit10; LOD=4.97), 8 (D8Mit128; LOD=12.67) and 19 (D19Mit86; LOD=3.67). Understanding the underlying mechanisms regulating brown fat thermogenesis in white fat may ultimately lead to new therapeutic treatments for human polygenic obesity. Supported by Glaxo-Wellcome Inc.


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