Cross Talk between Adipose Tissue and Placenta in Obese and Gestational Diabetes Mellitus Pregnancies via Exosomes

Abstract

Obesity is an important public health issue worldwide, where it is commonly associated with the development of metabolic disorders, especially insulin resistance (IR). Maternal obesity is associated with an increased risk of pregnancy complications, especially gestational diabetes mellitus (GDM). Metabolism is a vital process for energy production and the maintenance of essential cellular functions. Excess energy storage is predominantly regulated by the adipose tissue. Primarily made up of adipocytes, adipose tissue acts as the body's major energy reservoir. The role of adipose tissue, however, is not restricted to a "bag of fat." The adipose tissue is an endocrine organ, secreting various adipokines, enzymes, growth factors, and hormones that take part in glucose and lipid metabolism. In obesity, the greater portion of the adipose tissue comprises fat, and there is increased pro-inflammatory cytokine secretion, macrophage infiltration, and reduced insulin sensitivity. Obesity contributes to systemic IR and its associated metabolic complications. Similar to adipose tissue, the placenta is also an endocrine organ. During pregnancy, the placenta secretes various molecules to maintain pregnancy physiology. In addition, the placenta plays an important role in metabolism and exchange of nutrients between mother and fetus. Inflammation at the placenta may contribute to the severity of maternal IR and her likelihood of developing GDM and may also mediate the adverse consequences of obesity and GDM on the fetus. Interestingly, studies on maternal insulin sensitivity and secretion of placental hormones have not shown a positive correlation between these phenomena. Recently, a great interest in the field of extracellular vesicles (EVs) has been observed in the literature. EVs are produced by a wide range of cells and are present in all biological fluids. EVs are involved in cell-to-cell communication. Recent evidence points to an association between adipose tissue-derived EVs and metabolic syndrome in obesity. In this review, we will discuss the changes in human placenta and adipose tissue in GDM and obesity and summarize the findings regarding the role of adipose tissue and placenta-derived EVs, with an emphasis on exosomes in obesity, and the contribution of obesity to the development of GDM.

Keywords: adipose tissue; adipose tissue-derived exosomes; extracellular vesicles; gestational diabetes; obesity.

Figure 1

Schematic diagram of intercellular communication between adipose tissue and placenta mediated by adipose tissue-derived exosomes. Obesity refers to an accumulation of excessive fat in adipose tissue due to an imbalance between energy intake and expenditure. This causes hypertrophic expansion of adipocytes and abnormalities in physiological regulation. This is associated with increased free fatty acid release, activation of macrophages, and secretion of elevated amount of pro-inflammatory cytokines, causing systemic inflammation. This is known as metabolically induced inflammation. The marked increase in systemic inflammation is associated with the development of obesity-induced insulin resistance. Gestational diabetes mellitus (GDM) is glucose intolerance diagnosed for the first time during pregnancy. Placental morphological changes as well as altered placental metabolic status are observed in GDM. The placental dysfunction seen in GDM represents an adaptation of the placenta to increased maternal inflammation and results in increased secretion of inflammatory cytokines, further exacerbating inflammation. This potentially causes impairment in insulin sensitivity and development of GDM. However, the evolving concept of maternal obesity and inflammation may not be the full story in the development of GDM. This is due to insufficient data supporting a role for inflammatory cytokines as an initiator of insulin resistance in pregnancy. Interestingly, the various functions of adipose tissue are also orchestrated by the exosomes. Exosomes are mediators of intercellular communication and are capable of regulating cellular mechanisms. Exosomes from adipose tissue are known to regulate the metabolic activity of various cells via paracrine mechanisms. In obesity, adipose tissue-derived exosomes cargo profiles are dysregulated and mediate obesity-associated diseases, including insulin resistance. Thus, it is fair to speculate that the adipose tissue-derived exosomes potentially mediate the communication between adipose tissue and placenta, playing an important role in the development of GDM.