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. 2020 Nov 20;21(22):8772.
doi: 10.3390/ijms21228772.

Obese Mice with Dyslipidemia Exhibit Meibomian Gland Hypertrophy and Alterations in Meibum Composition and Aqueous Tear Production

Eugene A Osae  1 , Tiffany Bullock  2 , Madhavi Chintapalati  2 , Susanne Brodesser  3 , Samuel Hanlon  1 , Rachel Redfern  1 , Philipp Steven  4 , C Wayne Smith  2 , Rolando E Rumbaut  2   5 , Alan R Burns  1
Affiliations

Obese Mice with Dyslipidemia Exhibit Meibomian Gland Hypertrophy and Alterations in Meibum Composition and Aqueous Tear Production

Eugene A Osae et al. Int J Mol Sci. .

Abstract

Background: Dyslipidemia may be linked to meibomian gland dysfunction (MGD) and altered meibum lipid composition. The purpose was to determine if plasma and meibum cholesteryl esters (CE), triglycerides (TG), ceramides (Cer) and sphingomyelins (SM) change in a mouse model of diet-induced obesity where mice develop dyslipidemia.

Methods: Male C57/BL6 mice (8/group, age = 6 wks) were fed a normal (ND; 15% kcal fat) or an obesogenic high-fat diet (HFD; 42% kcal fat) for 10 wks. Tear production was measured and meibography was performed. Body and epididymal adipose tissue (eAT) weights were determined. Nano-ESI-MS/MS and LC-ESI-MS/MS were used to detect CE, TG, Cer and SM species. Data were analyzed by principal component analysis, Pearson's correlation and unpaired t-tests adjusted for multiple comparisons; significance set at p ≤ 0.05.

Results: Compared to ND mice, HFD mice gained more weight and showed heavier eAT and dyslipidemia with higher levels of plasma CE, TG, Cer and SM. HFD mice had hypertrophic meibomian glands, increased levels of lipid species acylated by saturated fatty acids in plasma and meibum and excessive tear production.

Conclusions: The majority of meibum lipid species with saturated fatty acids increased with HFD feeding with evidence of meibomian gland hypertrophy and excessive tearing. The dyslipidemia is associated with altered meibum composition, a key feature of MGD.

Keywords: dry eye; dyslipidemia; lipids; mass spectrometry; meibomian gland dysfunction; meibum; obesity.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure A1
Figure A1
Raw meibograph acquired with the STEMI microscope (a) and loaded into image J; then, excess eyelid area was cropped after the CLAHE filter was applied (b).
Figure A2
Figure A2
Classifiers are applied and segmentation ran (a) and the first probability map with a threshold for further quantitative analysis (b).
Figure A3
Figure A3
Total levels of plasma (a) TG-16:0, (b) TG-18:0, (c) TG-18:1, (d) TG-18:2, (e) TG-18:3, (f) TG-20:4 and (g) TG-22:6. Data are expressed as means ± SEM, **** p < 0.0001, n.s = not significant. Asterisks indicate significant difference compared to the matched ND value.
Figure A4
Figure A4
Correlation between mouse body weight and total plasma (a) TG-16:0, (b) TG-18:0, (c) TG-18:1, (d) TG-18:2 (e) TG-18:3 (f) TG- 120:4 and (g) TG-22:6. The grey-shaded regions represent the 95% confidence interval. Asterisks indicate a significance difference compared to the matched ND value.
Figure 1
Figure 1
High-fat diet (HFD)-fed mice (A) weighed significantly more and showed (B) heavier epididymal adipose tissue (eAT) than normal diet (ND)-fed mice. HFD mice also showed elevated total fasting plasma (C) cholesteryl ester (CE), (D) ceramide (Cer) and (E) sphingomyelin (SM) levels. Mouse weight and eAT are expressed as means ± SD and all total lipid data are expressed as means ± SEM. ** p < 0.01, *** p < 0.001, **** p < 0.0001. Asterisks indicate a significant difference compared to the matched ND value.
Figure 2
Figure 2
Correlation between mouse body weight and (A) epididymal adipose tissue (eAT) and total plasma (B) cholesteryl esters (CE), (C) ceramides (Cer), and (D) sphingomyelins (SM). The grey-shaded regions represent the 95% confidence interval. Asterisks indicate a significant difference compared to the matched ND value.
Figure 3
Figure 3
HFD mice showed (A) larger meibomian gland area and (B) similar meibomian gland length. (C) Representative meibographs showing a typical set of glands from an ND mouse and an HFD mouse. (D) HFD mice also showed greater tear volume than ND mice. All data are expressed as means ±SD. * p < 0.05, ** p < 0.01, **** p < 0.0001, n.s. = not significant. Asterisks indicate a significant difference compared to the matched ND value.
Figure 4
Figure 4
(A) Plasma cholesteryl ester species detected; inset shows species with low relative abundance. Data are expressed as means ± SEM, * p < 0.05. Asterisks indicate a significant difference compared to the matched ND value. (B) Meibum cholesteryl ester species detected; inset shows species with low relative abundance. Data are expressed as means ± SEM, * p < 0.05. Asterisks indicate a significant difference compared to the matched ND value.
Figure 5
Figure 5
(A) Plasma triglyceride species detected; inset shows species with low relative abundance. Data are expressed as means ± SEM, * p < 0.05. Asterisks indicate a significant difference compared to the matched ND value. (B) Meibum triglyceride species detected; inset shows species with low relative abundance. Data are expressed as means ± SEM, * p < 0.05. Asterisks indicate a significant difference compared to the matched ND value.
Figure 6
Figure 6
(A) Plasma sphingomyelin (SM) species detected; inset shows species with low relative abundance. Data are expressed as means ± SEM, * p < 0.05. Asterisks indicate a significant difference compared to the matched ND value. (B) Meibum sphingomyelin species detected; inset shows species with low relative abundance. Data are expressed as means ± SEM, * p < 0.05. Asterisks indicate a significant difference compared to the matched ND value.
Figure 7
Figure 7
(A) Plasma ceramide species detected; inset shows species with low relative abundance. Data are expressed as means ± SEM, * p < 0.05. Asterisks indicate a significant difference compared to the matched ND value. (B) Meibum ceramide (Cer) species detected; inset shows species with low relative abundance. Data are expressed as means ± SEM and no significant difference was recorded.
Figure 8
Figure 8
Variable correlation plots of (A) plasma CE and (B) meibum CE species.
Figure 9
Figure 9
Variable correlation plots of (A) plasma TG and (B) meibum TG species.
Figure 10
Figure 10
Variable correlation plots of (A) plasma SM and (B) meibum SM species. Variable correlation plots of plasma (C) Cer and (D) meibum Cer species.
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