Obesity Reduces Maternal Blood Triglyceride Concentrations by Reducing Angiopoietin-Like Protein 4 Expression in Mice - PubMed (original) (raw)

. 2020 Jun;69(6):1100-1109.

doi: 10.2337/db19-1181. Epub 2020 Feb 12.

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Obesity Reduces Maternal Blood Triglyceride Concentrations by Reducing Angiopoietin-Like Protein 4 Expression in Mice

Liping Qiao et al. Diabetes. 2020 Jun.

Abstract

To ensure fetal lipid supply, maternal blood triglyceride (TG) concentrations are robustly elevated during pregnancy. Interestingly, a lower increase in maternal blood TG concentrations has been observed in some obese mothers. We have shown that high-fat (HF) feeding during pregnancy significantly reduces maternal blood TG levels. Therefore, we performed this study to investigate if and how obesity alters maternal blood TG levels. Maternal obesity was established by prepregnant HF (ppHF) feeding, which avoided the dietary effect during pregnancy. We found not only that maternal blood TG concentrations in ppHF dams were remarkably lower than in control dams but also that the TG peak occurred earlier during gestation. Hepatic TG production and intestinal TG absorption were unchanged in ppHF dams, but systemic lipoprotein lipase (LPL) activity was increased, suggesting that increased blood TG clearance contributes to the decreased blood TG concentrations in ppHF dams. Although significantly higher levels of UCP1 protein were observed in interscapular brown adipose tissue (iBAT) of ppHF dams, Ucp1 gene deletion did not restore blood TG concentrations in ppHF dams. Expression of the angiopoietin-like protein 4 (ANGPTL4), a potent endogenous LPL inhibitor, was significantly increased during pregnancy. However, the pregnancy-induced elevation of blood TG was almost abolished in Angptl4 -/- dams. Compared with control dams, Angptl4 mRNA levels were significantly lower in iBAT, gonadal white adipose tissue, and livers of ppHF dams. Importantly, ectopic overexpression of ANGPTL4 restored maternal blood TG concentrations in ppHF dams. Together, these results indicate that ANGPTL4 plays a vital role in increasing maternal blood TG concentrations during pregnancy. Obesity impairs the rise of maternal blood TG concentrations by reducing ANGPTL4 expression in mice.

© 2020 by the American Diabetes Association.

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Figures

Figure 1

Figure 1

ppHF induced maternal obesity and reduced maternal blood TG concentration. C57BL/6 female mice were fed with HF diet for 12 weeks and then returned to regular chow 2 weeks before mating and during pregnancy. Body weight (A) and fat tissue mass (B) were monitored using EchoMRI. Increased blood glucose (C) and insulin (D) concentrations were observed in ppHF-fed mice before pregnancy in the fed state. E: Blood TG concentrations were monitored during pregnancy. F: The area under the blood TG curve (AUC) (E) was calculated. Data are presented as mean ± SEM; n = 8–12 or shown in the bar graph. *P < 0.05 vs. samples from Con dams; #P < 0.05 vs. samples from the same group at E0.0.

Figure 2

Figure 2

ppHF increased maternal blood LPL activity but showed no effect on hepatic and intestinal TG release rates. A: Blood TG concentrations were measured after an oil gavage. B: Hepatic TG release rates were determined by measuring blood TG concentrations after injection of LPL inhibitor Poloxamer 407 in fasted mice. C: The liver tissue weight was measured by a scale. D: Liver TG content was determined by extracting TG from homogenized tissue. E: Levels of target mRNAs were measured by real-time PCR. F: Blood TG concentrations were measured after oil load and LPL inhibition (E14.5). G: Postheparin blood (PHB) LPL activity was measured using maternal samples at E14.5. Data are presented as mean ± SEM; n = 6–8 or shown in bar graph. *P < 0.05, **P < 0.001 vs. Con dams.

Figure 3

Figure 3

ppHF increased UCP1 expression, but Ucp1 −/− mice exhibited no significant change in blood TG concentrations during pregnancy. Ucp1 −/− and WT female mice were fed with HF diet for 12 weeks and then returned to regular chow 2 weeks before mating and during pregnancy. A: UCP1 protein levels were measured by Western blotting using iBAT from Con and ppHF WT dams (E18.5; n = 14). B: Blood TG concentrations of both chow- or ppHF-fed WT and Ucp1 −/− dams were monitored during pregnancy. C: The area under the curve (AUC) of blood TG concentrations was compared between Con and ppHF dams. Data are presented as mean ± SEM. *P < 0.05 vs. Con dams (WT or Ucp1 −/−); #P < 0.05 vs. samples from the same group at E0.0. AU, arbitrary units.

Figure 4

Figure 4

Angptl4 gene deletion impaired the rise in maternal blood TG levels, and overexpression of ANGPTL4 restored maternal blood TG concentrations in ppHF dams. A and B: Lpl mRNA levels were measured by real-time PCR using gWAT and iBAT samples from nonpregnant C57BL/6 mice (Non-Preg), Con, and ppHF dams (E18.5). C and D: gWAT and iBAT tissue samples were collected from C57BL/6 dams at indicated embryonic ages. mRNA levels of Angptl4 and Angptl8 were determined by real-time PCR. E and F: WT and Angptl4 −/− mice were crossed to produce Angptl4 −/+ fetuses, which ensured the same genotype of fetuses. E: Maternal blood TG concentrations were measured during pregnancy. F: The area under the curve (AUC) of maternal blood TG was compared. G and H: mRNA levels of indicated genes were measured by real-time PCR using gWAT and iBAT samples from Con and ppHF dams. I: Three days after Ad-GFP or Ad-hANGPTL4 injection, maternal blood TG concentrations were measured in Con and ppHF dams. Data are presented as mean ± SEM; n = 11–16 or shown in bar graph. *P < 0.05 vs. E0.0, WT, or Con dams. AU, arbitrary units.

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