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. 2010 Nov 16;5(11):e14005.
doi: 10.1371/journal.pone.0014005.

The fat mass and obesity associated gene FTO functions in the brain to regulate postnatal growth in mice

Xue Gao  1 , Yong-Hyun Shin, Min Li, Fei Wang, Qiang Tong, Pumin Zhang
Affiliations

The fat mass and obesity associated gene FTO functions in the brain to regulate postnatal growth in mice

"V体育2025版" Xue Gao et al. PLoS One. .

Abstract

FTO (fat mass and obesity associated) was identified as an obesity-susceptibility gene by several independent large-scale genome association studies. A cluster of SNPs (single nucleotide polymorphism) located in the first intron of FTO was found to be significantly associated with obesity-related traits, such as body mass index, hip circumference, and body weight. FTO encodes a protein with a novel C-terminal α-helical domain and an N-terminal double-strand β-helix domain which is conserved in Fe(II) and 2-oxoglutarate-dependent oxygenase family. In vitro, FTO protein can demethylate single-stranded DNA or RNA with a preference for 3-methylthymine or 3-methyluracil VSports手机版. Its physiological substrates and function, however, remain to be defined. Here we report the generation and analysis of mice carrying a conditional deletion allele of Fto. Our results demonstrate that Fto plays an essential role in postnatal growth. The mice lacking Fto completely display immediate postnatal growth retardation with shorter body length, lower body weight, and lower bone mineral density than control mice, but their body compositions are relatively normal. Consistent with the growth retardation, the Fto mutant mice have reduced serum levels of IGF-1. Moreover, despite the ubiquitous expression of Fto, its specific deletion in the nervous system results in similar phenotypes as the whole body deletion, indicating that Fto functions in the central nerve system to regulate postnatal growth. .

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Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. FTO protein is ubiquitously expressed in mouse tissues and not affected by nutritional status in mice.
(A) Tissues from adult male C57BL/6 mice (except the ovary) were homogenized and immunoblotted. 20 µg total protein was loaded in each lane. (B) Expression of FTO in different regions of the brain. (C) Western blot analysis of FTO in metabolism-related tissues from adult male C57BL/6 mice fed ad libitum or fasted for 24 hrs. (D) Western blot analysis of FTO in tissues from C57BL/6 male mice fed on normal chow or on high fat diet (60 kcal % fat) from 6-week-old for 17 weeks.
Figure 2
Figure 2. Generation of Fto knockout mice.
(A) Strategy to generate various Fto alleles. Hind III indicates the enzyme cutting sites for Southern blot analysis in (C). (B) Schematic representation of predicted Fto wildtype and knockout coding sequences (CDS). (C) Southern blot analysis of wildtype and cko alleles. The genomic DNA was digested by Hind III, separated on agarose gel, blotted, and hybridized with the indicated probes as shown in (A). (D) Western blot analysis of different tissues isolated from wildtype (+/+), heterozygous (+/Δ) and homozygous (Δ/Δ) mice.
Figure 3
Figure 3. Complete knockout of Fto results in postnatal growth retardation.
(A) Representative pictures of wildtype and Fto knockout mice at different ages. (B) Growth curves of Fto+/+, Fto+/Δ, and FtoΔ/Δ mice from postnatal day 1 to 7. n = 16/16/14 (Fto+/+/Fto+/Δ/FtoΔ/Δ). P-values from day 1 to 7: 0.29, 0.062, 0.011, 0.0069, 0.0007, <0.0001, and <0.0001. (C) Body weights of Fto+/+, Fto+/Δ and FtoΔ/Δ embryos at E18.5. n = 11/19/12 (Fto+/+/Fto+/Δ/FtoΔ/Δ). P = 0.68. (D) Growth curves of male and female Fto+/+, Fto+/Δ and FtoΔ/Δ mice. For each genotype (Fto+/+/Fto+/Δ/FtoΔ/Δ), n = 26/31/33 (male), n = 27/37/49 (female). **P<0.01 for all the time points, except in females at 12 weeks old, P = 0.024. (E) Body length of adolescent and adult Fto+/+, Fto+/Δ and FtoΔ/Δ mice. For each genotype (Fto+/+/Fto+/Δ/FtoΔ/Δ), n = 12/16/17 (4-week-old male), and 11/13/15 (4-week-old female); n = 14/13/13 (16-week-old male), and 17/25/32 (16-week-old female). (F) Bone mineral density of 16-week-old Fto+/+, Fto+/Δ and FtoΔ/Δ mice. The femur bone mineral densities were measured by DEXA (dual energy X-ray absorptiometry). For each genotype (Fto+/+/Fto+/Δ/FtoΔ/Δ), n = 14/13/13 (male); n = 17/25/32 (female). (G) Relative serum IGF-1 levels of 4-week-old mice. The serum IGF-1 levels were measured with ELISA. For each genotype (Fto+/+/FtoΔ/Δ), n = 7/8 (male), n = 5/6 (female). P<0.0001 (male), P = 0.0356 (female). Statistical analyses were performed by one-way ANOVA, except that unpaired t-test was used in (G). *P<0.05, **P<0.01. All values are mean ± s.e.m.
Figure 4
Figure 4. Fto knockout mice do not display a lean phenotype.
(A, B, C) Lean mass (A), fat mass (B) and total tissue mass (C) of 16-week-old mice of each genotype. (D) Body composition (fat mass/total tissue mass %) of 16-week-old mice of each genotype. P = 0.35(male), and P<0.0001(female). In (A)–(D), all mice were fed on normal chow after weaning at 3-week-old and were 16-week-old at the time of DEXA (dual energy X-ray absorptiometry) measurement. For each genotype (Fto+/+/Fto+/Δ/FtoΔ/Δ), n = 14/13/13 (male), 17/25/32 (female). Statistical analyses were performed by one-way ANOVA. **P<0.01. All values are mean ± s.e.m.
Figure 5
Figure 5. FtoΔ/Δ mice are susceptible to high fat diet-induced obesity.
(A, B, C) Lean mass (A), fat mass (B) and total tissue mass (C) of Fto+/+, Fto+/Δ and FtoΔ/Δ mice on high fat diet. (D) Body composition (fat mass/total tissue mass %) of Fto+/+, Fto+/Δ and FtoΔ/Δ mice on high fat diet. P = 0.0055 (male), P = 0.1(female). (E, F) Body length (E) and femur bone mineral density (F) of Fto+/+, Fto+/Δ and FtoΔ/Δ mice on high fat diet. In (A)–(F), all mice were fed on 60 kcal% fat diet for 10 weeks starting from 4-week-old. DEXA measurements were performed at the end of the 10-week period. For each genotype (Fto+/+/Fto+/Δ/FtoΔ/Δ), n = 14/14/12 (male), 11/9/8 (female). Statistical analyses were performed by one-way ANOVA. **P<0.01. All values are mean ± s.e.m.
Figure 6
Figure 6. Metabolic parameters in Fto complete knockout mice.
(A) Average hourly oxygen consumption of 16∼17-week-old male Fto+/Δ and FtoΔ/Δ mice during the light and dark period. P = 0.1044 (light), and P = 0.0098(dark). (B) Average hourly oxygen consumption divided by lean mass. P<0.0001. (C) Average hourly carbon dioxide production of 16∼17-week-old male Fto+/Δ and FtoΔ/Δ mice during the light and dark period. P = 0.0463 (light), and P = 0.011(dark). (D) Average hourly carbon dioxide production divided by lean mass. P<0.0001. (E) Accumulative food intake over a period of 72 hours of 16∼17-week-old male Fto+/Δ and FtoΔ/Δ mice. P = 0.3015. (F) Food intake divided by lean mass. P = 0.0001. The number of mice used was 7 for each genotype. Statistical analyses were performed by unpaired t-test. **P<0.01. All values are mean ± s.e.m.
Figure 7
Figure 7. Neural-specific Fto knockout mice are growth retarded.
(A) The breeding scheme to generate neural-specific Fto knockout mice. (B) Western blot analysis of different tissues of FtoN+ and FtoNΔ mice. (C) Body weights of 7-day-old FtoN+/+, FtoN+/Δ and FtoNΔ/Δ pups. For each genotype (FtoN+/+/FtoN+/Δ/FtoNΔ/Δ), n = 17/7/9 (male), and 14/7/8 (female). (D) Growth curves of male and female FtoN+ and FtoNΔ mice. For each genotype (FtoN+/FtoNΔ), n = 30/25(male), and 24/20(female). (E, F) Body length (E) and femur bone mineral density (F) of 16-week-old FtoN+ and FtoNΔ mice measured by DEXA. For each genotype (FtoN+/FtoNΔ), n = 19/21(male), 19/17(female). (G) Relative serum IGF-1 levels of 4-week-old FtoN+ and FtoNΔ mice. For each genotype (FtoN+/FtoNΔ), n = 6/6(male), and n = 5/4(female). Statistical analyses were performed by one-way ANOVA (C) or unpaired t-test (D–G). **P<0.01. All values are mean ± s.e.m.
Figure 8
Figure 8. The body composition of Fto neural-specific knockout mice.
(A) Fat mass of 16-week-old FtoN+ and FtoNΔ mice. P = 0.4551(male), 0.1681(female). (B) Lean mass of 16-week-old FtoN+ and FtoNΔ mice. (C) Total tissue mass of 16-week-old FtoN+ and FtoNΔ mice. P<0.0001(male), and P = 0.0175(female). (D) Body composition (fat mass/total tissue mass %) of 16-week-old FtoN+ and FtoNΔ mice. P = 0.0118(male), 0.0024(female). In (A)–(D), for each genotype (FtoN+/FtoNΔ), n = 19/21(male), 19/17(female). Statistical analyses were performed by unpaired t-test. *P<0.05, **P<0.01. All values are mean ± s.e.m.
Figure 9
Figure 9. The metabolic parameters of Fto neural-specific knockout mice.
(A) Average hourly oxygen consumption of 16∼17-week-old male FtoN+ and FtoNΔ mice during the light and dark period. P = 0.0105 (light), and P = 0.0044 (dark). (B) Average hourly oxygen consumption divided by lean mass. P = 0.00556 (light), and P = 0.0233(dark). (C) Average hourly carbon dioxide production of 16∼17-week-old male FtoN+ and FtoNΔ mice during the light and dark period. P = 0.004 (light), and P = 0.0196(dark). (D) Average hourly carbon dioxide production divided by lean mass. P = 0.0131(light), and P = 0.0142(dark). (E) Accumulative food intake over a period of 72 hours of 16∼17-week-old male FtoN+ and FtoNΔ mice. P = 0.4601. (F) Food intake divided by lean mass. In (A)–(F), the number of animals used were 7 (FtoN+) and 9 (FtoNΔ). Statistical analyses were performed by unpaired t-test. *P<0.05, **P<0.01. All values are mean ± s.e.m.
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References (V体育官网)

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