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 incr
eases 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 i
ncreased 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 ERK
O females had increases in fat pad weights (54-103%), adipocyte size, and n
umber. Both alpha ERKO males and females had insulin resistance and impaire
d glucose tolerance, similar to humans lacking ER alpha or aromatase. Energ
y 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 ex
penditure may be important for the observed obesity. In summary, ER alpha a
bsence causes adipocyte hyperplasia and hypertrophy, insulin resistance, an
d glucose intolerance in both sexes. These results are evidence that estrog
en/ER alpha signaling is critical in female and male WAT; obesity in alpha
ERKO males involves a mechanism of reduced energy expenditure rather than i
ncreased energy intake.