Adiponectin to the rescue: how the embryo maintains glucose uptake in a diabetic mother.

Obesity is one of the most serious health challenges facing the United States and other western countries. The rates of childhood and adult obesity have more than doubled over the past 40 years with approximately two-thirds of Americans now qualifying as overweight or obese. Although obesity is linked directly to increases in a number of diseases, particularly type II diabetes and metabolic syndrome, there is mounting evidence that obesity can also lead to significant reproductive problems in women. The effects of obesity and type II diabetes on reproductive function in women manifest themselves at several levels. Numerous studies have confirmed that insulin resistance associated with these conditions is an important causal factor in the development of polycystic ovarian syndrome in a subset of these women (1, 2). This is due primarily to alterations in the hypothalamic-pituitary-ovarian axis as well as effects on ovarian follicle function. Obesity and diabetes have also been shown to have significant detrimental effects on oocyte quality (3–5) and on endometrial receptivity (5). Women with type 1 diabetes also show several reproductive disturbances including delayed menarche, oligomenorrhea, and gestational problems (6, 7). Endometrial receptivity defects and impaired implantation have also been reported in nonobese diabetic mice (8, 9). Adipose cells secrete a number of adipokines that have been shown to regulate metabolism and other biologic functions in various tissues of the body including the liver, kidney, and muscle. Adiponectin (Adipoq) is a 244-amino acid, collagen-like adipokine produced by adipose cells. It is known to increase insulin sensitivity and action and also to have antiinflammatory effects. Adipoq may decrease the risk of type 2 diabetes through several mechanisms including suppression of hepatic gluconeogenesis, stimulation of fatty acid oxidation in the liver, stimulation of fatty acid oxidation and glucose uptake in skeletal muscle, and stimulation of insulin secretion (10). The production of Adipoq by fat cells decreases as the amount of adipose tissue increases (11). Serum Adipoq levels are known to decrease in individuals with type 2 diabetes and also in obese individuals with insulin resistance (11, 12). Levels are also decreased in rhesus monkeys with type 2 diabetes (12). A study of a Japanese population also showed that a decline in serum Adipoq levels was associated with progression to type 2 diabetes and was, in fact, a risk factor for development of diabetes (13). In contrast, Adipoq levels are higher in type 1 persons with diabetes (14–16). Recently Adipoq and adiponectin receptors (AdipoR1 and AdipoR2) have been shown to be expressed in the female reproductive tract. Takemura et al. (17) reported that AdipoR1 and AdipoR2 are highly expressed in the midsecretory phase of the human endometrium, during the window of implantation. Kim et al. (18) reported that Adipoq, AdipoR1 and AdipoR2 are expressed in mouse preimplantation embryos as well as in the decidual cells of the mouse uterus at the implantation site or in response to artificial decidualization. Adipoq and AdipoR1 and -R2 are also expressed in rabbit blastocysts and in the uterine glands of rabbits during the preimplantation stage (19). A recent study by Fischer et al. (20) demonstrated that Adipoq and both AdipoR1 and -R2 are expressed in day 6 rabbit blastocysts and that treatment with exogenous Adipoq stimulated glucose uptake by these blastocysts. Insulin does not increase glucose uptake in rabbit blastocysts but does stimulate glucose uptake in mouse embryos (18). These findings support a paracrine or autocrine role for Adipoq during embryo development and implantation. Adipoq may, in fact, play an important role in regulating glucose metabolism in preimplantation embryos as well as in decidualizing uterine stromal cells. The mechanisms by which the tight regulation of glucose metabolism in embryos of type 1 or type 2 diabetic mothers is maintained and the role of Adipoq in this process are not yet fully understood. It is not known, for example, whether alterations in expression of Adipoq or its receptors in the preimplantation embryo or maternal endometrium play a role in the embryo's ability to adapt to a hypoinsulinemic environment of the type 1 diabetic mother. Dr. Santos (21) and her colleagues present an elegant study in which they investigated the transcription factor pathway involved in the Adipoq-mediated regulation of glucose uptake by rabbit blastocysts of type 1 diabetic mothers and how this pathway acts in a cell lineage-specific manner to maintain normal glucose uptake in the blastocyst. The authors focused on the cAMP-responsive element-binding protein and activating transcription factors that are downstream of the insulin/IGF-signaling pathway and the interaction of these transcription factors in regulating Adipoq in the embryoblast (inner cell mass) vs trophoblast cells (trophectoderm) of the blastocyst. The authors first confirmed that expression of Adipoq was increased in the serum and endometrium of diabetic rabbits. They then determined that Adipoq protein showed a cell lineage-specific pattern of expression with greatly decreased Adipoq in the embryoblast cells but markedly increased levels in the trophoblast cells. In vitro studies showed that expression of Adipoq and the AdipoRs was decreased in blastocysts treated with either insulin or IGF-1. This decrease in Adipoq occurred in response to an increase in phosphorylation of cAMP-responsive element-binding protein and a concomitant increase in activating transcription factor 4 expression specifically in the embryoblast of the blastocysts. No change was observed in the trophoblast cells. The different effects of insulin or IGF-1 on Adipoq expression in the embryoblast vs the trophoblast cells are due to key differences in receptor expression between these two cell types in the rabbit blastocyst. The embryoblast cells express insulin receptor isoform A as well as the IGF-1 receptor and are therefore able to respond to IGF-1 or IGF-2. In contrast, the trophoblast cells express primarily insulin receptor isoform B. Thus the trophoblast cells are not able to respond to the elevated levels of IGF-1 and IGF-2 that occur in response to the lack of insulin with a decrease in Adipoq synthesis. Instead, the Adipoq levels are maintained in trophoblast cells, and Adipoq may help maintain glucose uptake in these cells. The results presented in the study by Santos et al (21) support an important role for Adipoq from autocrine (produced by the embryo itself), paracrine (secreted by the endometrium or oviduct), and/or endocrine sources (adipose tissue) in preimplantation embryo development and implantation. Expression of Adipoq is decreased in obese women and women with type 2 diabetes (22). This decline in Adipoq levels may lead to perturbations in glucose uptake and energy metabolism by the embryo and may also lead to suboptimal endometrial receptivity, thus contributing to infertility in these women. Further studies focusing on identifying additional signaling pathways and gene networks regulated by Adipoq in the preimplantation embryo and uterine endometrium during the implantation window are warranted.