BMP4 Cross-talks With Estrogen/ERα Signaling to Regulate Adiposity and Glucose Metabolism in Females

Similar to estrogens, bone morphogenetic protein 4 (BMP4) promotes the accumulation of more metabolically active subcutaneous fat and reduction of visceral fat. However, whether there is a cross-talk between BMP4 and estrogen signaling remained unknown. Herein, we found that BMP4 deficiency in white adipose tissue (WAT) increased the estrogen receptor α (ERα) level and its signaling, which prevented adult female mice from developing high fat diet (HFD)-induced obesity and insulin resistance; estrogens depletion up regulated BMP4 expression to overcome overt adiposity and impaired insulin sensitivity with aging, and failure of BMP4 regulation due to genetic knockout led to more fat gain in aged female mice. This mutual regulation between BMP4 and estrogen/ERα signaling may also happen in adipose tissue of women, since the BMP4 level significantly increased after menopause, and was inversely correlated with body mass index (BMI). These findings suggest a counterbalance between BMP4 and estrogen/ERα signaling in the regulation of adiposity and relative metabolism in females. •BMP4 knockout improves ERα stability and its signaling in WAT of female mice.•BMP4 knockout female mice get higher energy expenditure.•Depletion of estrogens up regulates BMP4 level in adipose tissue.•Failure of BMP4 regulation leads to obesity and insulin resistance in aged females. Estrogens play a beneficial role in regulating adiposity and glucose metabolism, however not all women with low estrogen levels become obese and develop insulin resistance. Such variation may be related to other factors involved. In the present study, we revealed a reciprocal interaction between bone morphogenetic protein 4 (BMP4) and estrogen/ERα signaling in regulating fat accumulation and insulin sensitivity. Our findings may explain why cycling females are less prone to gain weight and less susceptible to glucose dysmetabolism than menopausal females and males. The regulation of BMP4 may offer a new opportunity of intervention in the control of excessive obesity.