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

F22 Genetic Analysis of the Regulatory System Controlling the Induction of Brown Adipocytes in White Fat Tissues

Ann Allen Coulter, Robert A. Koza, Wolfgang Hofmann and Leslie P. Kozak. Pennington Biomedical Research Center, 6400 Perkins Rd. Baton Rouge, LA 70808

Thermogenesis in brown adipocytes, a function of uncoupling protein 1 (UCP1) in mitochondria, is an important metabolic component of the regulation of body weight in mice. An enhanced capacity of certain strains of mice to generate brown adipocytes in white adipose tissues correlates with a reduction in obesity following adrenergic-agonist stimulation of thermogenesis. We have initiated a project to identify and clone the genes controlling the induction of brown adipocytes by a comprehensive QTL analysis of mRNAs critical for brown adipocyte formation and mitochondria DNA synthesis, since induction of brown fat must be accompanied by mitochondrial biogenesis.

The chromosomal location of four genes controlling Ucp1 induction in the retroperitoneal fat pad have been identified by a QTL analysis of Ucp1 mRNA levels (see abstract by Koza et al). Since increased expression of Pcg1 has been linked to induction of differentiation of brown adipocytes, increased Ucp1 mRNA levels and mitochondrial DNA (mtDNA) levels, we are determining whether Pcg1 is involved in the induction of Ucp1. Mapping of Pcg1 by SSCP to chromosome 5 indicated that the Pcg1 structural gene was not associated with the QTLs controlling Ucp1 mRNA levels, however, Pcg1 mRNA levels are different between A/J and C57BL/6J mice. After 7 days at 5oC, the Pcg1 mRNA level in RP fat total RNA was 545 in A/J mice and 355 in C57BL/6J mice mice, as determined by quantitative RT-PCR (PE 7700). The differences in Pcg1 mRNA levels among 220 (C57BL/6J X A/J)F1 X A/J backcross progeny ranged from 7 to 179. We have detected a significant association between one of the chromosomal regions that controls Ucp1 mRNA levels with the control of Pcg1 expression.

Cold exposure of A/J and C57BL/6J mice also induces increases in mitochondrial number in retroperitoneal fat. Mitochondrial DNA was assayed using quantitative PCR (PE 7700) of the total DNA fraction isolated from fat tissue using cytochrome-c oxidase subunit II as the mitochondrial DNA target sequence. After cold exposure, mitochondrial DNA levels were significantly higher in A/J mice (30518; p<0.05) than in C57BL/6J mice, 24119 . As in the Pcg1 study, backcross mice were also analyzed. The level of mtDNA ranged from 105 to a high of 1215 in the 220 backcross mice analyzed. As with Ucp1 and Pcg1, a genome wide scan to identify chromosomal regions controlling the level of mitochondrial DNA also suggests common genes are associated with Ucp1 expression and mitochondrial biogenesis.

 


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