Adipocyte dysfunction in a mouse model of polycystic ovary syndrome (PCOS): evidence of adipocyte hypertrophy and tissue-specific inflammation - PubMed (original) (raw)

Adipocyte dysfunction in a mouse model of polycystic ovary syndrome (PCOS): evidence of adipocyte hypertrophy and tissue-specific inflammation

Joseph S Marino et al. PLoS One. 2012.

Abstract

Clinical research shows an association between polycystic ovary syndrome (PCOS) and chronic inflammation, a pathological state thought to contribute to insulin resistance. The underlying pathways, however, have not been defined. The purpose of this study was to characterize the inflammatory state of a novel mouse model of PCOS. Female mice lacking leptin and insulin receptors in pro-opiomelanocortin neurons (IR/LepR(POMC) mice) and littermate controls were evaluated for estrous cyclicity, ovarian and adipose tissue morphology, and body composition by QMR and CT scan. Tissue-specific macrophage infiltration and cytokine mRNA expression were measured, as well as circulating cytokine levels. Finally, glucose regulation during pregnancy was evaluated as a measure of risk for diabetes development. Forty-five percent of IR/LepR(POMC) mice showed reduced or absent ovulation. IR/LepR(POMC) mice also had increased fat mass and adipocyte hypertrophy. These traits accompanied elevations in macrophage accumulation and inflammatory cytokine production in perigonadal adipose tissue, liver, and ovary. These mice also exhibited gestational hyperglycemia as predicted. This report is the first to show the presence of inflammation in IR/LepR(POMC) mice, which develop a PCOS-like phenotype. Thus, IR/LepR(POMC) mice may serve as a new mouse model to clarify the involvement of adipose and liver tissue in the pathogenesis and etiology of PCOS, allowing more targeted research on the development of PCOS and potential therapeutic interventions.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. Ovarian Morphology of control and IR/LepRPOMC females.

A-E. Ovarian sections throughout the ovaries of individual control and IR/LepRPOMC females were examined for follicle types shown, n = 13–17. F. Ovarian sections throughout the ovaries of control and IR/LepRPOMC females were examined and the percentage of ovaries lacking either preovulatory follicles or corpora lutea (or both) is shown, n = 13–17. Statistical significance was calculated using Fisher's exact test (p = 0.0481).

Figure 2. IR/LepRPOMC females have reduced ovulation but show normal cycling suppression from fasting.

A. Example of delay in resumption of estrous cycles measured by vaginal cytology taken before, during, and after a 48 hour fast. B. Delay from fast quantified for control (white bars) or IR/LepRPOMC (black bars) mice, n = 9–13 (not significant). Mean ± SEM.

Figure 3. Increased fat mass and intra-abdominal adipocyte hypertrophy in IR/LepRPOMC mice.

A. Body weight of IR/LepRPOMC female mice and controls. B. Fat and lean mass of IR/LepRPOMC females and controls measured by NMR (white bars = control mice, black bars = IR/LepRPOMC mice), n = 5–6. C. Subcutaneous and intra-abdominal fat volume measured by CT scan in IR/LepRPOMC females and controls, n = 5–6 D. Section of perigonadal fat tissue, paraffin embedded and stained with H/E. Each panels are shown at 200x. E. Adipocyte size calculated from H/E stained perigonadal fat pads, 50 cells counted per section/mouse, n = 15–24 mice. * indicates p<0.05. F. Serum leptin levels of control (white bars) or IR/LepRPOMC (black bars) mice 3 hours after chow removal. n = 4, ** indicates p<0.01. Mean ± SEM.

Figure 4. IR/LepRPOMC Females have tissue-specific low-grade inflammation.

A. Immunostaining for macrophage marker F4/80 in adipose tissue. F4/80 staining (FITC) was merged with DAPI to identify activated macrophages. B. Adipose tissue F4/80 gene expression. C. Adipose tissue CD11c gene expression. D. Adipose tissue IL-6 gene expression. E. Adipose tissue IL-1β gene expression. F. Ovary IL-6 gene expression. G. Liver IL-1β gene expression. Mean ± SEM, n = 4–5 * = p<.05 and ** = p<.01 compared with controls.

Figure 5. IR/LepRPOMC females are hyperglycemic and show hyperglycemia during pregnancy.

A. IR/LepRPOMC female glucose levels under basal conditions (n = 6–7) ** p<0.01. B. Fasted glucose levels in a second cohort of females, before pregnancy and on gestational day 12 and 15 (Black circles are control dams, open triangles are IR/LepRPOMC dams; n = 11–12) * p<0.05, compared with controls at same timepoint; + p<0.05, compared with pre-pregnancy values of same group. C. Glucose tolerance testing (2 g/kg) performed on day 15–18 of gestation. (Black circles are control dams, open triangles are IR/LepRPOMC dams; n = 6). Mean ± SEM.

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Adipocyte dysfunction in a mouse model of polycystic ovary syndrome (PCOS): evidence of adipocyte hypertrophy and tissue-specific inflammation - PubMed (original) (raw)