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It has been known for many years that 17β-estradiol (E2) is a major regulator of white adipose tissue deposition in humans and other species. Recent results have indicated that E2 may have broader roles in adipose tissue than previously realized. E2 has important effects on adipose tissue in adult males and also may be a critical regulator of adipocyte development and adult adipocyte number in both sexes.

We have determined that both male and female estrogen receptor alpha (ERα) knockout (αERKO) mice show over a 100% increase in adipose tissue compared to wild-type mice, indicating that E2 normally has anti-lipogenic roles in males as well as females (Heine et al.,2000). Data in human males lacking either aromatase or ERα indicate that these men have a tendency towards obesity, and estrogen treatment of men lacking aromatase has beneficial effects on their adiposity as well as some of the concomitant metabolic abnormalities, such as insulin resistance (Maffei et al.,2004).

Male and female αERKO mice also have an ∼170% increase in adipocyte number, indicating that E2 normally is an inhibitor of adult adipocyte number (Heine et al.,2000). These findings in αERKO mice have been supported by contemporaneous data in aromatase knockout (ArKO) mice, which have also shown that E2 both regulates adipose tissue in adult males and inhibits the number of adult adipocytes (Jones et al.,2000).

There is intense interest in environmental estrogens and the possible health effects of these compounds. Genistein and daidzein, phytoestrogens present in soy, have attracted extensive attention in this regard due to their ubiquity in our diet, the high levels of these compounds that can be obtained in humans under certain nutritional conditions, and epidemiological and laboratory data suggesting that these compounds could have human health effects. Our recent results indicate that genistein, fed to mice at levels that produce serum genistein concentrations that can readily be achieved in humans, has an anti-lipogenic effect in ovariectomized mice (Naaz et al.,2003). The adipose effects of genistein in this system appear to result at least in part from inhibition of the enzyme lipoprotein lipase. The inhibitory effects of genistein on adipose tissue are not seen in αERKO mice, indicating that the genistein effects are mediated through ERα. The anti-lipogenic effects of genistein in laboratory mice are consistent with clinical studies involving dietary administration of phytoestrogens to women, although the decreases in adipose mass and percentage of body fat seen in these studies have been modest.

The mechanism by which E2 may inhibit the increase in adipocyte number is unknown, but recent work from our laboratory has shown that 2 cell cycle regulatory proteins are major regulators of adult adipocyte number and could be an important E2 target during adipogenesis. Progression of the cell cycle from the G1 to S phase requires cyclins to complex with cyclin-dependent kinases (CDKs). Cyclin-dependent kinase inhibitors (CDKIs) bind to these complexes to prevent cell cycle progression and facilitate differentiation and thus play a role in the transition of cells from a proliferating to a nonproliferating state. Previous work with 3T3-L1 cells, a preadipocyte cell line, has shown that the CDKIs p27Kip1 (p27) and p21Cip1 (p21) show marked changes during the mitotic clonal expansion period that occurs in confluent cultures after they are exposed to differentiation media and may be critical both in initiating and terminating mitotic clonal expansion in the preadipocytes. The apparent role of p27 and p21 in inducing a cessation of 3T3-L1 cell proliferation during mitotic clonal expansion led us to hypothesize that loss of these CDKIs could cause adipocyte hyperplasia and, potentially, obesity. Adipose development, body weight, and glucose tolerance were compared in wild-type (WT), p27 knockout (p27KO), p21 knockout (p21KO) and p27/p21 double knockout (DBKO) mice. DBKO mice had 6-fold increases in adipose mass and adipocyte number compared to WT mice by 120 days of age (Naaz et al.,2004). DBKO mice were severely glucose intolerant, had impaired insulin sensitivity, and were hypercholesterolemic. The p27KOs and p21KOs showed increases of 15–20% in body weight compared to controls, far less than the 100% body weight increase in DBKO mice. However, the p27KOs and p21KOs still had 100% increases in adipose mass and adipocyte number compared to controls. Other parameters, such as insulin resistance and serum cholesterol levels, also showed less severe changes compared to the DBKO, although these parameters were altered compared to WT mice by the loss of only 1 CDKI. Our results indicate that both p27 and p21 are important regulators of adipose development and their functions are not redundant, as shown by greater increases in adipocyte number, adipose mass, and metabolic abnormalities in DBKO versus p27KO or p21KO mice (Naaz et al.,2004). The DBKO mouse provides a unique model for producing severe adipocyte hyperplasia, and understanding regulation of p27 and p21 during adipogenesis will provide insights into how adipocyte number is established. The similar adipocyte hyperplasia seen in mice lacking (E2/ERα signaling and the DBKO mice suggests that p27 and p21 could be involved in E2 effects on adipogenesis, and this hypothesis is being tested.

A crucial question that remains unresolved is whether exposure of developing humans or animals to phytoestrogens such as genistein could alter adipocyte development and/or adult adipocyte number. Extensive work with 3T3-L1 and other cell lines has indicated that genistein can inhibit adipogenic differentiation in vitro. These results are consistent with the potential effect of genistein that would be predicted given its estrogenic activity and suggest that genistein exposure in vivo may be capable of inhibiting adipocyte number. However, 1 recent report has suggested that genistein, at high concentrations in vitro, may be able to stimulate adipogenic differentiation and cell number by acting as a peroxisome proliferator-activated receptor gamma (PPARγ) agonist and driving adipogenesis (Dang et al.,2003). It is not clear whether genistein exposure in vivo has the potential to alter adipogenesis and adipocyte number in humans, but since 750,000 human infants per year in the United States alone are fed soy formula and have high circulating levels of genistein and other phytoestrogens such as daidzein during a period of active adipogenesis, this is a question that has serious public health implications and needs to be investigated further.

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