Reproductive PhysiologyAdipose tissue and reproductive health
Introduction
Obesity remains a growing global health and economic challenge [1], [2]. According to the World Health Organization, obesity prevalence has doubled since 1980, with approximately 600 million adults meeting criteria worldwide [3]. Adipose tissue, which was once thought of as an inert energy storage organ providing insulation from the cold, is now recognized as a dynamic endocrine system. To understand this role, it is critical to examine adipose tissue both in normal physiology and pathologic states. Furthermore, while many understand the metabolic consequences associated with obesity [4], less frequently mentioned are the effects of increased adipose tissue on reproductive health.
Here we present a broad overview of notable features of the relationship of adipose tissue, adipokines and reproductive health. The interplay between body fat and reproduction has been demonstrated since as early as the 1960s [5], and subsequently underscored by the discovery of adipokines, most notably leptin and adiponectin. We discuss knowledge of the influence of sex on adipose tissue, with emphasis on visceral versus subcutaneous fat distribution, and the role of white adipose in the production of adipokines-particularly leptin and adiponectin. We highlight leptin's dynamic relationship with energy/adipose, and its critical role at hypothalamic level, in states of lipodystrophy and potential uses as treatment. We review adiponectin, perhaps the best indicator of metabolic health, and its role in conditions such as polycystic ovary syndrome (PCOS) and reproductive malignancies. More briefly discussed is the role both in pregnancy, as well as growing knowledge regarding other adipokines.
Section snippets
Adipose Tissue
Adipose tissue is the body's largest energy reservoir, comprising of many cells. The most abundant cell types are called “adipocytes.” Variable in size, adipocytes primarily consist of lipid droplets and are separated into two predominant lineages: brown and white adipose tissue (BAT, WAT). These arise from separate progenitor cell lines, with distinct components, functions and effects on metabolic health (Table 1). Brown adipocytes share their origins with myocytes, with progenitor cells
Sex Steroids and Adipose Tissue
Adipose tissue, specifically WAT is under the influence of sex steroids, the breadth of which was extensively reviewed by Newell-Fugate et al. [12]. Their work highlighted dihydrotestosterone's inhibition of adipocyte differentiation from mesenchymal stem cells and its stimulation of lipolysis [13], [14], [15], along with white adipose tissue's expression of estrogen receptors (alpha/beta). While the exact mechanism for estrogen's influence on white adipose tissue remains unclear, the knockout
Adipokines
White adipocytes produce numerous endocrine, paracrine and neuroendocrine signals via the production of adipokines. The numbers and functions of adipokines continue to evolve, and include leptin, adiponectin, resistin, chemerin, retinol binding protein 4 (RBP4). In the context of reproduction and reproductive health, leptin and adiponectin are the most commonly investigated, with newer adipokines also recognized as potential mediators of reproductive health and pathology.
Hypothalamic Amenorrhea and Anorexia Nervosa
There are many states of leptin deficiency, with the most notable being hypothalamic amenorrhea, and the closely associated diagnosis of anorexia nervosa. “Hypothalamic amenorrhea” (HA) or “functional hypothalamic amenorrhea” results from dysfunctional hypothalamic signals to the pituitary, rather than primary pituitary or ovarian abnormalities [157]. While it can only be diagnosed once alternate causes for amenorrhea have been excluded, hypothalamic amenorrhea accounts for approximately 35% of
Insulin Resistant States
There are described pathologies of adipose tissue distribution and insulin resistance. Lipodystrophy represents a range of adipose tissue disorders, while polycystic ovary syndrome is most commonly defined by variable combinations of menstrual irregularities, hyperandrogenism and metabolic derangements. Both represent another avenue by which to examine the interplay of adipose tissue and reproduction.
Pathologic States in Pregnancy
Given the presence of adipokines and their receptors in maternal and fetal tissues, they have also been examined in pathologic states of pregnancy. Briffa et al. recently proposed models for disruption in leptin levels, highlighting potential downstream effects of uteroplacental insufficiency and maternal obesity on fetal growth and development [98] With regards to maternal health, subjects with preeclampsia had lower adiponectin in the first trimester, and then higher at time of delivery, as
Reproductive Cancers
Also evolving is the study of adipose tissue and reproductive malignancies. Obesity is known to increase risk of certain malignancies, including breast and reproductive malignancies [201]. In women in the United States, uterine cancer and ovarian cancer are the fourth and fifth most common malignancies [202]. Cervical cancer affects approximately 12,000 US women, with vaginal and vulvar cancers accounting for 6–7% of cancers. A population based cohort found that body mass index increases were
Future Directions
It is evident that the links between adipose tissue and reproduction are many and diverse. However, there remains significant opportunity for continued investigation into these relationships. There is need for further understanding of estrogen and androgen influence on adipose tissue determination. Leptin's true role at the hypothalamic level and convergence with insulin mediated pathways, requires additional study, particularly in insulin resistant states of reproductive pathologies. The
Contributors
All authors contributed equally in the background research, construction and revision of this article.
Conflicts of Interest
The authors have no financial disclosures or conflicts of interest.
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