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. 2018 Oct 25;8(1):15757.
doi: 10.1038/s41598-018-34113-3.

Adipose tissue dysfunction is associated with low levels of the novel Palmitic Acid Hydroxystearic Acids

Ann Hammarstedt  1 , Ismail Syed  2 , Archana Vijayakumar  2 , Björn Eliasson  3 , Silvia Gogg  3 , Barbara B Kahn  2 , Ulf Smith  3
Affiliations

Adipose tissue dysfunction is associated with low levels of the novel Palmitic Acid Hydroxystearic Acids

Ann Hammarstedt et al. Sci Rep. .

Abstract

Adipose tissue dysfunction is considered an important contributor to systemic insulin resistance and Type 2 diabetes (T2D). Recently, a novel family of endogenous lipids, palmitic acid hydroxy stearic acids (PAHSAs), was discovered. These have anti-diabetic and anti-inflammatory effects in mice and are reduced in serum and adipose tissue of insulin resistant humans. In the present study, we investigate if adipose tissue dysfunction is associated with reduced PAHSA levels in human subjects and if PAHSAs influence adipocyte differentiation. Our results show that low expression of adipocyte GLUT4 and adipocyte hypertrophy, markers of adipose tissue dysfunction, are associated with reduced expression of key enzymes for de novo lipogenesis and adipose tissue levels of PAHSAs in human subjects. We also show that GLUT4 is not only a marker of adipose tissue dysfunction, but may be causally related to the observed impairments. PAHSAs may also act locally in the adipose tissue to improve adipogenesis through a mechanism bypassing direct activation of peroxisome proliferator-activated receptor (PPARγ). The discovery of PAHSAs and our current results provide novel insights into positive effects of lipid species in adipose tissue and mechanisms by which dysfunctional adipose tissue is associated with insulin resistance and risk of developing T2D.

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Conflict of interest statement

IS and BK are inventors on patents related to FAHFAs. Other authors have no competing interest.

Figures

Figure 1
Figure 1
Adipose tissue dysfunction is associated with reduced insulin sensitivity – (A) Relative protein expression of GLUT4 determined by WB in isolated adipocytes from insulin sensitive (IS) and insulin resistant (IR) subjects. Data is presented as mean ± SEM (B) Relative protein expression of GLUT4 in relation to whole body insulin sensitivity measured by hyper-insulinemic euglycemic clamp. (C) Adipocyte cell size in relation to insulin sensitivity measured by hyper-insulinemic euglycemic clamp. (D) Relative expression of GLUT4 in relation to adipocyte differentiations markers PPARγ, C/EBPα and adiponectin. **p-value < 0.01.
Figure 2
Figure 2
Adipose tissue dysfunction is associated with reduced lipogenesis and low adipose tissue PAHSA levels. (A) Relative quantification of GLUT4 mRNA measured in adipose tissue in relation to the lipogenic transcription factor ChREBP and its target genes ACACA and FASN. (B) Correlations of relative protein expression of GLUT4 determined by WB in isolated adipocytes in relation to different adipose tissue PAHSA isomers. Filled circles: subjects assigned to the IS group; filled squares: subjects assigned to the IR group. (C) Relative mRNA expression of the lipogenic enzymes ACACA and FASN in adipose tissue in relation to serum levels 9-PAHSA. (D) Relative mRNA expression of the lipogenic enzymes ACACA and FASN in adipose tissue in relation to serum levels of total-PAHSA (E) Correlations of adipocyte cell size and different adipose tissue PAHSA isomers. Filled circles: subjects assigned to the IS group; filled squares: subjects assigned to the IR group. (F) Correlation of GLUT4 protein expression and adipocyte cell size.
Figure 3
Figure 3
Silencing GLUT4 results in impaired adipocyte differentiation. (A) Relative gene expression of GLUT4 in 3T3-L1 pre-adipocytes in the presence of anti-GLUT4 siRNA or scrambled at day 4 and 8 of differentiation. (B) Relative gene expression of adipocyte differentiation markers PPARγ and adiponection in the presence of anti-GLUT4 siRNA or scrambled at day 4 and 8 of differentiation. (C) Relative gene and protein expression of ChREBP, aP2 and perilipin in the presence of anti-GLUT4 siRNA or scrambled at day 4 and 8 of adipocyte differentiation. (D) Lipid accumulation visualized by Oil Red O staining in the presence of anti-GLUT4 siRNA or scrambled at day 8 of adipocyte differentiation. (E) Relative gene expression of PPARγ, ChREBP and adiponectin and Oil Red O staining of in vitro differentiated adipocytes from wt and GLUT4ko mice. (F) Relative gene expression of TEMEM26 in the presence of anti-GLUT4 siRNA or scrambled at day 4 and 8 of differentiation. Data is presented as mean ± SEM related to control siRNA, n = 4–6. *p-value < 0.05, **p-value < 0.01, ***p-value < 0.001.
Figure 4
Figure 4
Addition of 5- and 9-PAHSA to pre-adipocytes promote adipocyte differentiation. (A) Relative gene expression of gpr120, GLUT4, adiponectin and aP2 in the presence or absence of 5- and 9-PAHSA during adipocyte differentiation. (B) Relative gene expression of adiponectin and aP2 and Oil Red O staining in the presence or absence of 5-PAHSA during differentiation of primary human pre-adipocytes. (C) Relative gene expression of PPARγ in the presence or absence of 5- and 9-PAHSA during the first 24hrs of adipocyte differentiation and AUC for time points 0, 2, 4 and 8 days. (D) Relative gene expression of C/EBPα in the presence or absence of 5- and 9-PAHSA at 24hrs and 2, 4 and 8 days. (E) Transcriptional activity of PPARγ in the presence of 1, 10 and 20uM 5- or 9-PAHSA. (F) Transcriptional activity of C/EBPs in the presence of 5 and 20uM 5- or 9-PAHSA. (G) Relative gene expression of IL6 at day 2 of adipocyte differentiation in the presence or absence of 5- and 9-PAHSA (H) Relative gene expression of GLUT4, Adiponectin and ChREBP in the presence of scrambled or anti-GLUT4 siRNA ± 5-and 9-PAHSA (20uM). Data is presented as mean ± SEM related to control, n = 3–6. *p-value < 0.05, **p-value < 0.01.
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References

    1. Arner E, et al. Adipocyte turnover: relevance to human adipose tissue morphology. Diabetes. 2010;59:105–109. doi: 10.2337/db09-0942. - DOI - PMC - PubMed
    1. Arner P, Arner E, Hammarstedt A, Smith U. Genetic predisposition for Type 2 diabetes, but not for overweight/obesity, is associated with a restricted adipogenesis. PloS one. 2011;6:e18284. doi: 10.1371/journal.pone.0018284. - DOI - PMC - PubMed
    1. Weyer C, Foley JE, Bogardus C, Tataranni PA, Pratley RE. Enlarged subcutaneous abdominal adipocyte size, but not obesity itself, predicts type II diabetes independent of insulin resistance. Diabetologia. 2000;43:1498–1506. doi: 10.1007/s001250051560. - DOI - PubMed
    1. Lonn M, Mehlig K, Bengtsson C, Lissner L. Adipocyte size predicts incidence of type 2 diabetes in women. FASEB journal: official publication of the Federation of American Societies for Experimental Biology. 2010;24:326–331. doi: 10.1096/fj.09-133058. - DOI - PubMed
    1. Kloting N, et al. Insulin-sensitive obesity. American journal of physiology. Endocrinology and metabolism. 2010;299:E506–515. doi: 10.1152/ajpendo.00586.2009. - DOI - PubMed

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