Increased adipose tissue in male and female estrogen receptor-α knockout mice

Estrogen regulates the amount of white adipose tissue (WAT) in females, but its role in males and whether WAT effects involve estrogen receptor-alpha (ER alpha) or ER beta were unclear. We analyzed the role of ER alpha in WAT and brown adipose tissue by comparing these tissues in wild-type (WT) and ER alpha -knockout (alpha ERKO) male and female mice. Brown adipose tissue weight was similar in alpha ERKO and WT males at all ages. Progressive increases in WAT were seen in alpha ERKO males with advancing age. Epididymal. perirenal, and inguinal WAT weighed 139-185% more in alpha ERKO than in WT males by 270-360 days of age. Epididymal and perirenal adipocyte size was increased 20 % in alpha ERKO males. Adipocyte number was 82-168% greater in fat pads of alpha ERKO vs. WT males. Compared with WT, 90-day-old alpha ERKO females had increases in fat pad weights (54-103%), adipocyte size, and number. Both alpha ERKO males and females had insulin resistance and impaired glucose tolerance, similar to humans lacking ER alpha or aromatase. Energy intake was equal in WT and alpha ERKO males, indicating that obesity was not induced by hyperphagia. In contrast, energy expenditure was reduced by 11% in alpha ERKO compared with WT males, indicating that altered energy expenditure may be important for the observed obesity. In summary, ER alpha absence causes adipocyte hyperplasia and hypertrophy, insulin resistance, and glucose intolerance in both sexes. These results are evidence that estrogen/ER alpha signaling is critical in female and male WAT; obesity in alpha ERKO males involves a mechanism of reduced energy expenditure rather than increased energy intake.