Adipose Tissue Dysfunction in Polycystic Ovary Syndrome

Abstract

Purpose: Polycystic ovary syndrome (PCOS) is a complex genetic trait and the most common endocrine disorder of women, clinically evident in 5% to 15% of reproductive-aged women globally, with associated cardiometabolic dysfunction. Adipose tissue (AT) dysfunction appears to play an important role in the pathophysiology of PCOS even in patients who do not have excess adiposity.

Methods: We undertook a systematic review concerning AT dysfunction in PCOS, and prioritized studies that assessed AT function directly. We also explored therapies that targeted AT dysfunction for the treatment of PCOS.

Results: Various mechanisms of AT dysfunction in PCOS were identified including dysregulation in storage capacity, hypoxia, and hyperplasia; impaired adipogenesis; impaired insulin signaling and glucose transport; dysregulated lipolysis and nonesterified free fatty acids (NEFAs) kinetics; adipokine and cytokine dysregulation and subacute inflammation; epigenetic dysregulation; and mitochondrial dysfunction and endoplasmic reticulum and oxidative stress. Decreased glucose transporter-4 expression and content in adipocytes, leading to decreased insulin-mediated glucose transport in AT, was a consistent abnormality despite no alterations in insulin binding or in IRS/PI3K/Akt signaling. Adiponectin secretion in response to cytokines/chemokines is affected in PCOS compared to controls. Interestingly, epigenetic modulation via DNA methylation and microRNA regulation appears to be important mechanisms underlying AT dysfunction in PCOS.

Conclusion: AT dysfunction, more than AT distribution and excess adiposity, contributes to the metabolic and inflammation abnormalities of PCOS. Nonetheless, many studies provided contradictory, unclear, or limited data, highlighting the urgent need for additional research in this important field.

Keywords: DNA methylation; GLP-1R agonists; GLUT-4; PCOS; adipokines; adiponectin; adipose tissue; cytokines; diet; exercise; fat; hyperandrogenism; inflammation; insulin signaling; metabolic dysfunction; metabolic syndrome; metformin; miRNAs; thiazolidinediones; weight loss.

Figure 1.

Schematic of polycystic ovary syndrome metabolic pathophysiology.

Figure 2.

PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analysis) flow diagram of systematic review. PubMed and Embase were systematically searched to retrieve human studies assessing adipose tissue dysfunction in patients with polycystic ovary syndrome (PCOS) published until November 2022 without language limitations. The search strategy for each database can be found in Supplementary Table S1 (23). The references of all included studies were also reviewed for any additional publications missed with the original search. Observational and interventional studies were eligible for inclusion if they assessed adipose tissue function in PCOS patients diagnosed by the 1990 National Institutes of Health, the 2003 Rotterdam, and/or the 2006 Androgen Excess & PCOS Society (AE-PCOS) criteria and compared results against body mass index (BMI)-matched controls without PCOS. Studies with other designs such as reviews, meta-analyses, or letters, animal studies, studies including hyperandrogenic or amenorrheic women without defined PCOS, and those without matched-BMI controls were excluded from the study. Search strategy and study identification were performed by 2 reviewers (M.A. and S.H.) using a standardized protocol. Any disagreement in the study selection was resolved by other reviewers (F.B. and R.A.). All investigators extracted data from relevant articles. Out of 3431 records retrieved from searching databases, 103 original articles were selected for the review.

Figure 3.

Potential mechanisms leading to adipose tissue dysfunction in polycystic ovary syndrome.

Figure 4.

PI3K/Akt insulin signaling cascade. No obvious defect in insulin binding, or insulin receptor (InsR) or PI3K/AKT insulin-signaling pathway activity was observed in the adipose tissue (AT) of polycystic ovary syndrome (PCOS) women (based on data from Chen et al (55)).

Figure 5.

Effect of interleukin-6 (IL-6), monocyte chemoattractant protein 1 (MCP-1), and tumor necrosis factor-α (TNF-α) on adiponectin secretion in adipose tissue of polycystic ovary syndrome (PCOS) and control women. The graphs depict the log scale means of the absolute adiponectin levels in picograms per milliliter (panels A to C) and the net changes in log adiponectin concentration (panels D to F) secreted by PCOS and control adipocytes in response to incubation with 10 ng/mL IL-6 (A and D), MCP-1 (B and E), and TNF-α (C and F). All values were log-transformed before analysis. Sample numbers (n) per group are indicated for each experiment. Reproduced from Chazenbalk G, et al Regulation of adiponectin secretion by adipocytes in the polycystic ovary syndrome: role of tumor necrosis factor-{alpha}. J Clin Endocrinol Metab. 2010 Feb; 95(2):935-42 with permission from Oxford University Press (70).