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Intrinsic abnormalities of adipose tissue and adipose tissue dysfunction in PCOS
Funding sources
This work was supported by the Brazilian National Institute of Hormones and Women's Health/Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq INCT grant number 465482/2014-7) and Fundação de Amparo à Pesquisa do Rio Grande do Sul (FAPERGS INCT grant number 17/2551-0000519-8). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Declarations of interest
All authors declare no conflict of interest.
Introduction
Polycystic ovary syndrome (PCOS) is a multifactorial condition with different phenotypes, characterized by clinical or biochemical hyperandrogenism, ovarian dysfunction, and/or polycystic ovaries. Insulin resistance and central adiposity are often present , and women with PCOS are at higher risk for prediabetes and type 2 diabetes ; these clinical features are highly associated with adipose tissue dysfunction . Obesity is also a common finding in patients with PCOS, with a reported prevalence ranging from 30% to 60% and a pooled estimated prevalence of 49%, as shown by a metaanalysis . Obesity, through insulin resistance, may exacerbate the metabolic comorbidities associated with the syndrome . In this sense, insulin resistance is a common finding even in lean women with PCOS, reaching about 45% in a previous study conducted by our group ( Fig. 1 ). In turn, the prevalence of metabolic syndrome is much higher in obese women compared to those with body mass index (BMI) lower than 25.
Hyperinsulinemia resulting from insulin resistance also stimulates androgen production by ovarian theca cells and suppresses the hepatic production of sex hormone-binding globulin (SHBG), increasing the availability of free androgens . In addition, the adipose tissue provides storage and is a site of androgen metabolism, which contributes further to hyperandrogenism . Besides, the development of insulin resistance in these patients leads to defects in lipolysis and to a state of chronic low-grade inflammation, free fatty acid metabolism dysregulation, adipocytokine dysfunction and epigenetic abnormalities . Finally, insulin resistance induces preadipocytes in the abdominal region to differentiate into adipocytes, leading to central obesity in women with PCOS .
Adipose tissue is as an endocrine organ involved in the regulation of multiple processes, including glucose and fatty metabolism, immunity, inflammatory response, and reproduction. Current evidence indicates that dysfunctional adipose tissue is implicated in pathophysiological mechanisms of metabolic and reproductive disturbances in PCOS.
Intrinsic abnormalities of adipose tissue and adipose tissue dysfunction in PCOS
Adipose tissue is a major site for storage and metabolism of energy sources and sex steroids and contributes to regulation of endocrine processes. It is composed mainly of adipocytes and preadipocytes, with the rest represented by fibroblasts, endothelial cells, macrophages, stromal cells and immune cells.
There are two main types of functional adipose tissue: brown and white. Despite being primarily involved in thermogenesis in newborns, brown adipose tissue responds to cold and sympathetic nervous system activation in adult humans as well . White adipose tissue plays a pivotal role in the regulation of physiological and pathological processes, synthetizing and secreting specific adipokines and other pro and antiinflammatory factors . Depending on their anatomical location, white adipose depots are broadly classified into the subcutaneous (located under the skin) and the visceral/omental (located intra-abdominally, over the internal organs in the omentum, mesentery and retroperitoneal space) . Subcutaneous adipose depots provide energy storage and protection against mechanical damage and heat loss, while visceral fat is highly metabolically active, constantly releasing free fatty acids into the portal circulation . In fact, the accumulation of visceral fat has been linked to the onset of metabolic syndrome as the protagonist of an unfavorable metabolic profile in obesity . Obesity is associated with anatomic and functional derangements in adipose tissue: enlarged volume and increased number of adipocytes (hypertrophy and hyperplasia of adipocytes), immune cell infiltration, impaired adipogenesis, and abnormal inflammatory responses—characterizing the low-grade inflammation of obesity . Farkhondeh et al. suggested that an altered adipokine secretion profile is probably the cause of chronic low-grade inflammation of obesity.
Adipokines consist of hormones, cytokines, growth factors, vasodilators, and several other substances with a variety of functions, including important signaling molecules . Adipokines have been linked to the development of insulin resistance and other obesity-associated abnormalities, influencing blood pressure, lipid profile and degree of inflammation. Moreover, they are involved in several disease states, including cardiovascular disease, type 2 diabetes, cancer, immune diseases, and metabolic syndrome . Secretion of these adipose tissue-derived molecules appears to be compartment-specific, varying according to the adipose tissue depot and leading to variable effects of adipokines within particular depots .
Adipokines and PCOS
Patients with PCOS are at increased risk of developing insulin resistance and visceral obesity. In fact, elevated visceral adiposity has been found in obese and nonobese patients with PCOS in comparison with age- and BMI-matched healthy controls ; this has been associated with worse metabolic profile . The regulatory mechanism of adipokines may differ according to BMI status between healthy populations and women with PCOS. Adipokines may be a connecting factor between obesity and PCOS, with a role in the pathogenesis of the syndrome. In recent years, studies involving new adipokines and PCOS have advanced knowledge in the field ( Table 1 ).
Table 1
Main adipokines implicated in PCOS.
Adapted from Spritzer PM, Lecke SB, Satler F, Morsch DM. Adipose tissue dysfunction, adipokines, and low-grade chronic inflammation in polycystic ovary syndrome. Reproduction 2015;149(5):R219–R227.
| Adipokine | Source | Effects | Serum levels in PCOS a |
|---|---|---|---|
| Adiponectin | Adipose tissue, placenta | Antiproliferative, antidiabetic, antiinflammatory, and antiatherogenic | ↓ or ↔ |
| Leptin | Adipose tissue, gastric epithelium, hypothalamus, placenta, gonads | Appetite and weight regulation, pro-diabetic, and pro-inflammatory | ↑ with body fat |
| Resistin | Adipose tissue, monocyte, macrophages | Insulin resistance, pro-inflammatory | ↑ or ↔ |
| PEDF | Adipose tissue | Antiangiogenic, antiinflammatory, and antidiabetic | ? |
| RBP4 | Adipose tissue | Insulin resistance | ? |
| Visfatin | Adipose tissue, liver, muscle, bone marrow, lymphocytes, trophoblast, fetal membranes | Insulin-mimetic, pro-inflammatory | ↑ or ↔ |
| Apelin | Adipose tissue, brain, peripheral tissues | Insulin resistance | ↑ |
↔ unchanged; ↓ decreased; ↑ increased; ? inconclusive; BMI, body mass index; PCOS, polycystic ovary syndrome; PEDF, pigment-epithelium derived factor; RBP4, retinol-binding protein 4.
Adiponectin
Adiponectin is a 244 amino acid protein with a molecular weight of 28 kDa. It is the product of the APM1 gene transcript, encoded on chromosome 3q27—close to a known locus for type 2 diabetes and adiposity . This adipokine is mainly produced by adipocytes, and also detected in skeletal muscle, cardiomyocytes, osteoblasts, lymphocytes, adrenal gland, placenta, testis, ovary, pituitary gland, and liver tissue .
Adiponectin is well recognized for its antiproliferative, antidiabetic, antiinflammatory, and antiatherogenic properties . Adiponectin inhibits gluconeogenesis, improving insulin sensitivity through peroxisome proliferator-activated receptor (PPAR)-α activation in the liver. Moreover, it promotes adipogenesis and oxidation of free fatty acids in the skeletal muscles and adipose tissue through AMP-activated protein kinase (AMPK) signaling .
It has been suggested that overweight and obesity are characterized by low adiponectin concentrations . Indeed, this adipocyte product correlates negatively with BMI. An altered leptin/adiponectin ratio is also associated with BMI, impaired insulin signaling, and inflammatory state .
The existing data are not as conclusive regarding the role of adiponectin in PCOS. Previous reports from our group and other authors found similar circulating adiponectin levels in BMI-matched PCOS and control women . In contrast, some studies have reported lower adiponectin levels in women with PCOS than in healthy controls, independently of BMI . Recently, Asian studies showed significantly lower serum levels of adiponectin in lean women with PCOS than that in age- and BMI-matched controls . A metaanalysis conducted by Toulis et al. including 36 articles with more than 3000 subjects (PCOS women and BMI-matched healthy controls), of various ages and different levels of total testosterone and insulin, found that adiponectin was significantly lower in those with PCOS. Li et al. analyzed 38 articles with more than 3500 women (PCOS and BMI-matched healthy controls) and concluded that pooled adiponectin levels in PCOS women were significantly reduced compared with those of healthy controls. As reported by Groth in a systematic review of 15 articles, the majority of studies support the finding of low adiponectin levels in women with PCOS, irrespective of BMI. The disagreement among published data may be related to heterogeneity across studies, including variations in subject ethnicity, study design and sample size, or methodological techniques used to measure adiponectin, since this adipokine can be secreted by adipose tissue as a low-molecular-weight trimer, as a combination of two intermediate-molecular-weight trimers, or as six high-molecular-weight (HMW) trimers, and circulates either as a trimer or as an oligomer . These issues notwithstanding, the current evidence strongly reinforces that PCOS is accompanied by a state of adipose tissue dysfunction.
Leptin
Leptin, the product of the OB gene, located at 7q31.3, is implicated in energy balance through the central control of satiety, and consequently, of body weight, playing a key role in decreasing food intake and increasing energy expenditure . This hormone participates in the regulation of lipid and carbohydrate metabolism. It also acts on the immune system to modulate the inflammatory response .
Leptin serum levels are associated with adiposity; they are significantly increased in overweight and obese subjects, regardless of whether PCOS is present . However, despite elevated leptin concentrations in obesity, the effect of leptin is reduced due to a leptin-resistance state which is linked to insulin resistance and metabolic comorbidities .
We have previously reported higher leptin serum levels in overweight/obese PCOS and BMI-matched controls than in normal-weight PCOS and control women . Other published studies showed similar levels of circulating leptin in women with PCOS and BMI-matched controls , as well as higher leptin levels in overweight/obese women compared with nonoverweight controls . In turn, some studies showed higher levels of leptin in overweight/obese Iranian women and Russian adolescents with PCOS in comparison to a healthy control group, and one study reported elevated concentrations of leptin in normal weight and overweight Croatian PCOS in relation to age- and WHR-matched controls.
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