Saturated fat ingestion stimulates proatherogenic inflammation in polycystic ovary syndrome

Abstract

Inflammation and dyslipidemia are often present in polycystic ovary syndrome (PCOS). We determined the effect of saturated fat ingestion on circulating heat shock protein-70 (HSP-70) and mononuclear cell (MNC) toll-like receptor-2 (TLR2) gene expression, activator protein-1 (AP-1) activation, and matrix matalloproteinase-2 (MMP-2) protein in women with PCOS. Twenty reproductive-age women with PCOS (10 lean, 10 with obesity) and 20 ovulatory controls (10 lean, 10 with obesity) participated in the study. HSP-70 was measured in serum and TLR2 mRNA and protein, AP-1 activation, and MMP-2 protein were quantified in MNC from blood drawn while fasting and 2, 3, and 5 h after saturated fat ingestion. Insulin sensitivity was derived from an oral glucose tolerance test (IS_OGTT). Androgen secretion was assessed from blood drawn while fasting and 24, 48, and 72 h after human chorionic gonadotropin (HCG) administration. In response to saturated fat ingestion, serum HSP-70, TLR2 gene expression, activated AP-1, and MMP-2 protein were greater in lean women with PCOS compared with lean controls and in women with PCOS and obesity compared with controls with obesity. Both PCOS groups exhibited lower IS_OGTT and greater HCG-stimulated androgen secretion compared with control subjects of their respective weight classes. Lipid-stimulated proatherogenic inflammation marker responses were negatively correlated with IS_OGTT and positively correlated with abdominal adiposity and HCG-stimulated androgen secretion. In PCOS, saturated fat ingestion stimulates proatherogenic inflammation independent of obesity. This effect is greater when PCOS is combined with obesity compared with obesity alone. Abdominal adiposity and hyperandrogenism may perpetuate proatherogenic inflammation.NEW & NOTEWORTHY This paper demonstrates that in polycystic ovary syndrome (PCOS), ingestion of saturated fat triggers a molecular pathway of inflammation known to drive atherogenesis. This effect is independent of obesity as it occurs in lean women with PCOS and not in lean ovulatory control subjects. Furthermore, the combined effects of PCOS and obesity are greater compared with obesity alone.

Keywords: abdominal adiposity; atherogenesis; hyperandrogenism; polycystic ovary syndrome; saturated fat.

Graphical abstract

Figure 1.

Comparison of the 4 study groups (n = 10 subjects per group) of the change from baseline (%) in serum heat shock protein-70 (HSP-70; A) and mononuclear cell (MNC)-derived toll-like receptor-2 (TLR-2) mRNA content (B) and protein content (C) from blood samples collected while fasting and 2, 3, and 5 h after saturated fat ingestion. Representative Western blots (C) show the change in quantity of TLR-2 and actin in MNC homogenates in samples collected before and after saturated fat ingestion. The samples used to quantify TLR-2 and actin protein content by densitometry were run on the same gel. Data are presented as means ± SE. Differences across groups (repeated-measures ANOVA). *Response in women with polycystic ovary syndrome (PCOS) and obesity, lean women with PCOS and control subjects with obesity was significantly different compared with lean control subjects; P < 0.003 (A), P < 0.0004 (B), and P < 0.001 (C). †Response in women with PCOS and obesity was significantly different compared with control subjects with obesity; P < 0.04 (A), P < 0.05 (B), and P < 0.02 (C). ‡Residual response in women with PCOS and obesity was significantly different compared with the other 3 groups; P < 0.0005 (A) and P < 0.0001 (B and C).

Figure 2.

Comparison of the four study groups (n = 10 subjects per group) of the change from baseline (%) in mononuclear cell (MNC)-derived activated activator protein-1 (AP-1; A) and matrix metalloproteinase-2 (MMP-2; B) from blood samples collected while fasting and 2, 3, and 5 h after saturated fat ingestion. Representative Western blots (B) show the change in quantity of MMP-2 and actin in MNC homogenates in samples collected before and after saturated fat ingestion. The samples used to quantify MMP-2 protein content by densitometry were run on the same gel. Data are presented as means ± SE. Differences across groups (repeated measures ANOVA). *Response in women with polycystic ovary syndrome (PCOS) and obesity, lean women with PCOS and control subjects with obesity was significantly different compared with lean control subjects; P < 0.0001 (A and B). †Response in women with PCOS and obesity was significantly different compared with control subjects with obesity; P < 0.04 (A) and P < 0.02 (B). ‡Residual response in women with PCOS and obesity was significantly different compared with the other 3 groups; P < 0.009 (A) and P < 0.0001 (B).

Figure 3.

Comparison of the 4 study groups (n = 10 subjects per group) of the incremental area under the curve (iAUC) in response to saturated fat ingestion for serum heat shock protein-70 (HSP-70; A) and mononuclear cell (MNC)-derived toll-like receptor-2 (TLR-2) mRNA content (B) and protein content (C) as well as MNC-derived activated activator protein-1 (AP-1; D) and matrix metalloproteinase-2 (MMP-2) protein content (E). Data are presented as means ± SE. Comparison across groups (one-way ANOVA and post hoc Tukey’s Honestly Significant Difference test). *The iAUC in lean control subjects was significantly different compared with the other 3 groups; P < 0.002 (A) and P < 0.0001 (B and C). †The iAUC in control subjects with obesity was significantly different compared with women with polycystic ovary syndrome (PCOS) and obesity; P < 0.03 (A), P < 0.007 (B), P < 0.0008 (C), P < 0.008 (D), and P < 0.004 (E). ‡The iAUC in lean women with PCOS was significantly different compared with women with PCOS and obesity; P <0.03 (C) and P < 0.04 (D).