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. 2020 Dec;34(12):16073-16085.
doi: 10.1096/fj.202000985RR. Epub 2020 Oct 13.

Maternal food restriction-induced intrauterine growth restriction in a rat model leads to sex-specific adipogenic programming

Sreevidya Sreekantha  1   2 , Ying Wang  1   2 , Reiko Sakurai  1   2 , Jie Liu  1   2 , Virender K Rehan  1   2
Affiliations

Maternal food restriction-induced intrauterine growth restriction in a rat model leads to sex-specific adipogenic programming

Sreevidya Sreekantha et al. FASEB J. 2020 Dec.

Abstract

Intrauterine growth restriction (IUGR) leads to offspring obesity. In a maternal food restriction (MFR) during pregnancy-related IUGR rat model, bone marrow stem cells showed enhanced adipogenic programming; however, the effect of IUGR on white adipose tissue (WAT) progenitors is unknown. Here, by mRNA and functional profiling, we determined sex-specific adipogenic programming of WAT progenitors isolated from pups on the postnatal day (PND) 1 and 21. On PND1, PPARγ and Pref-1 expression was significantly downregulated in preadipocytes of both MFR males and females; however, at PND21, preadipocytes of MFR males showed upregulation in these genes. Even following adipogenic induction, both male and female MFR adipocytes exhibited lower PPARγ, ADRP, and adiponectin levels at PND1; however, at PND21 MFR male adipocytes showed an upward trend in the expression of these genes. An adipogenesis-specific RT-PCR array showed that male MFR adipocytes were programmed to exhibit stronger adipogenic propensity than females. Last, serum sex hormone and adipocyte estrogen/testosterone receptor expression profiles provide preliminary insights into the possible mechanism underlying sex-specific adipogenic programming in the IUGR offspring. In summary, IUGR programs WAT preadipocytes to greater adipogenic potential in males. Although the altered adipogenic programming following MFR was detectable at PND1, the changes were more pronounced at PND21, suggesting a potential role of postnatal nutrition in facilitating the sex-specific adipogenic programming in the IUGR offspring.

Keywords: adipocytes; adipogenesis; obesity; preadipocytes; white adipose tissue.

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Conflict of interest statement

CONFLICT OF INTEREST: The authors declare that they have no conflict of interest.

Figures

FIGURE 1.
FIGURE 1.. Effect of maternal food restriction on offspring body weight from postnatal day 1 to postnatal day 21.
Both male and female MFR pups had significantly lower body weights vs. controls at postnatal days 1 and 21 (#p<0.001 vs controls).
FIGURE 2.
FIGURE 2.. Cell characterization by flow cytometry.
The isolated adipocyte progenitors, as characterized by flow cytometry, were negatively selected for CD34 and CD45, and positively selected for CD73 and CD90. Pref-1, a specific preadipocyte marker, was positive in only 40% of the cells. However, Western analysis showed abundant Pref-1 positivity indicating technical reasons for flow cytometry to not adequately identify these cells as Pref-1 positive (N=3).
FIGURE 3.
FIGURE 3.. Effect of maternal food restriction on mRNA profiling of preadipocytes.
On PND1, the combined data showed decreased expression of PPARγ (A), Pref-1 (B) and Zfp423 (C) in the MFR group. When stratified by sex, both MFR male (MFR M) and MFR female (MFR F) cells showed downregulation of these 3 genes as well. At PND21, compared with the control group, MFR group showed increased PPARγ, but similar Pref-1 and still reduced Zfp423 expression. When stratified by sex, MFR M group showed upregulation of PPARγ and Pref-1, but continued decreased expression of Zfp423. In contrast, MFR F group continued to show decreased expression of all 3 genes (PPARγ, Pref-1, and Zfp423) (N=4–12, *p<0.05, ** p<0.01 vs controls).
FIGURE 4.
FIGURE 4.. Effect of maternal food restriction on mRNA profiling of adipocytes.
On PND1, the combined data showed decreased expression of PPARγ (A), Adiponectin (B), ADRP (C) and C/EBPα (D) in maternal food restricted group (MFR). When stratified by sex, MFR male (MFR M) and MFR female (MFR F) showed downregulation of these adipogenic markers as well. On PND21, the combined data showed no significant change in PPARγ, Adiponectin and ADRP expression, but still a significant decrease in C/EBPα expression in the MFR vs. the control group. When stratified by sex, the MFR M group showed a significant upregulation in PPARγ and Adiponectin expression with no change in ADRP and a decreased expression in C/EBPα. In contrast, the MFR F group continued to show significant downregulation in the expression of PPARγ, ADRP, and C/EBPα (N=4-12, *p<0.05, ** p<0.01 vs controls).
FIGURE 5.
FIGURE 5.. Adipogenesis Real-time RT-PCR array.
The expression of PPARγ downstream target genes promoting adipogenesis was increased in MFR male adipocytes. Pro-adipogenesis markers c/ebpβ and fos had increased expression in MFR male adipocytes. Anti-adipogenesis markers, in particular, jun, ccnd1, and gata2, were significantly elevated in MFR female adipocytes. Pro-BAT markers particularly Dio2 and Wnt 5a were more than 15-fold increased in MFR female adipocytes (N=4, p<0.01 for all).
FIGURE 6.
FIGURE 6.. Oil Red O Staining.
Oil Red O staining of postnatal day (PND) 1 and 21 male and female MFR and control preadipocytes and adipocytes is shown in the upper panels, with the objective measurement of the ORO content, as determined by measurement of absorbance at 490 nm of the eluted ORO, in the lower panel. In preadipocytes, MFR male group at PND 1 and PND 21 showed increased absorbance compared to controls (**p<0.01 vs controls). In adipocytes at PND 1, MFR male and female cells showed decreased absorbance; however, at PND21, only MFR females showed decreased absorbance (data from 3 separate experiments).
FIGURE 7.
FIGURE 7.. Effect of maternal food restriction on serum sex hormones and adipocyte estrogen receptor 1 and androgen receptor mRNA expression.
There was no differences on serum estradiol levels in both males and females at PND1 compared to controls; there was decreased significantly in males but increased in females at PND 21 (A). The serum testosterone level was higher in males at PND1, but no effect in females at PND 1 and in both at PND 21 (B). Estrogen receptor 1 mRNA expression was decreased in adipocyte in both males and females at PND 1 and 21 (C). Androgen receptor mRNA expression was decreased significantly in male adipocytes at PND 1 and 21, but no effect on female adipocytes at PND 1 and 21 (D). (N=4-7, *p<0.05; **p<0.01; ****p<0.001 vs. controls)
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