Genetic and diet effects on Ppar-α and Ppar-γ signaling pathways in the Berlin Fat Mouse Inbred line with genetic predisposition for obesity
Lipids in Health and Disease
Genetic and diet effects on Ppar-a and Ppar-g signaling pathways in the Berlin Fat Mouse Inbred line with genetic predisposition for obesity
Asja Wagener 0 3
Helge F Goessling 0 3
Armin O Schmitt 0 3
Susanne Mauel 2
Achim D Gruber 2
Richard Reinhardt 1
Gudrun A Brockmann 0 3
0 Humboldt-Universitat zu Berlin, Department for Crop and Animal Sciences , Invalidenstrae 42, 10115 Berlin , Germany
1 Max-Planck-Institut fur molekulare Genetik , Ihnestrae 73, 14195 Berlin , Germany
2 Freie Universitat Berlin, FB Veterinarmedizin, Institut fur Tierpathologie , Robert-von-Ostertag-Strae 15, 14163 Berlin , Germany
3 Humboldt-Universitat zu Berlin, Department for Crop and Animal Sciences , Invalidenstrae 42, 10115 Berlin , Germany
Background: The Berlin Fat Mouse Inbred (BFMI) line is a new mouse model for obesity, which was long-term selected for high fatness. Peroxisome proliferator-activated receptors (PPARs) are involved in the control of energy homeostasis, nutrient metabolism and cell proliferation. Here, we studied the expression patterns of the different Ppar genes and the genes in the PPAR pathway in the BFMI line in comparison to physiological changes. Results: At the age of 10 weeks, the BFMI mice exhibited marked obesity with enlarged adipocytes and high serum triglycerides concentrations in comparison to the often used mouse line C57BL/6 (B6). Between these two lines, gene expression analyses revealed differentially expressed genes belonging to the PPAR pathway, in particular genes of the lipogenesis and the fatty acid transport. Conclusion: Surprisingly, the Ppar-a gene expression was up-regulated in liver and Ppar-g gene expression was down-regulated in the white adipose tissue, indicating the activation of a mechanism that counteracts the rise of obesity.
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Background
The peroxisome proliferator-activated receptors (PPARs)
constitute a family of three genes, which are involved in
the control of energy homeostasis and cell proliferation.
The PPAR family members have distinct patterns of
tissue distribution and tissue specific functions. PPAR-a is
predominantly present in liver where it has a critical
role in the regulation of nutrient metabolism as it
stimulates the uptake and oxidation of fatty acids. PPAR-g
is mainly expressed in adipose tissue. It is induced
during adipocyte differentiation and is a regulator in the
formation of fat cells and lipid accumulation. PPAR- is
abundantly expressed throughout the body and it has
been proposed to be involved in adipogenesis and
energy metabolism [for review, see [1-3]]. Activation of
PPAR-a by agonists leads to reduced adiposity and
lowered triglyceride levels by reduced food intake [4-6],
whereas activation of PPAR-g by agonist stimulates lipid
storage and is associated with body weight gain [7,8].
Recently, we have generated the high-fatness selected
Berlin Fat Mouse inbred line BFMI as a model for
juvenile obesity [9]. BFMI mice harbour natural mutations
leading to a five fold increased fat percentage due to
hyperphagia at young age and an altered lipid
metabolism in comparison to C57BL/6 mice [10,11]. A specific
regulation of PPAR genes in the development of obesity
in the BFMI mice is very likely.
Therefore, the intention of this study was to
investigate whether the Ppars and their responsive genes are
involved in the fat accumulation of the BFMI line. Our
aims were (i) to identify differences in gene regulation
of Ppars and their responsive genes between the obese
BFMI mouse model and B6 mice as a control and (ii) to
analyze responses of PPAR pathway genes to high-fat
diet feeding in BFMI mice. Therefore, we analysed
transcript amounts of genes belonging to the PPAR pathway
in white adipose tissue and liver. Furthermore, we
analysed body composition, adipocyte size and serum
parameters.
Results
Phenotypic differences between lines BFMI and B6
To compare the body composition of the two lines,
male mice of BFMI and B6 were fed a standard
maintenance diet (SMD) until week 10. On SMD, animals of
the BFMI line were significantly heavier and had more
body fat and lean mass than B6 mice over the entire
period (Figure 1). At 10 weeks, mice of the BFMI line
were 1.8 times as heavy as B6 mice (41.4 2.9 g and
23.5 1.5 g, respectively). The body weight gain was
due to increased fat mass. BFMI mice had almost 10
times as much body fat mass but only 1.5 times as
much lean mass as B6 animals. In BFMI mice, fat was
accumulated in all three investigated adipose tissues
mainly due to enlarged adipocytes (Table 1, Figure 2
and 3). The weight of the liver was slightly higher in10
weeks old BFMI mice compared to B6 mice which
could be due to increased fat accumulation in liver of
BFMI mice (Table 1, Figure 3). Serum triglyceride
concentrations, but not total cholesterol concentrations,
were elevated in BFMI mice compared to B6.
Feeding of HFD in mice of the BFMI line caused an
additional body weight and body fat mass gain (9.0 g
and 6 (...truncated)