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