Estrogen replacement therapy reduces the incidence of
type 2 diabetes in postmenopausal women; however, the mechanism is unknown. Therefore, the aim of this study was to evaluate the metabolic effects of
estrogen replacement therapy in an experimental model of menopause. At 8 weeks of age, female mice were ovariectomized (OVX) or
sham (
SHAM) operated, and OVX mice were treated with vehicle (OVX) or
estradiol (E2) (OVX+E2). After 4 weeks of high-fat diet feeding, OVX mice had increased
body weight and fat mass compared with
SHAM and OVX+E2 mice. OVX mice displayed reduced whole-body energy expenditure, as well as
impaired glucose tolerance and whole-body
insulin resistance. Differences in whole-body
insulin sensitivity in OVX compared with
SHAM mice were accounted for by impaired muscle
insulin sensitivity, whereas both hepatic and muscle
insulin sensitivity were impaired in OVX compared with OVX+E2 mice. Muscle
diacylglycerol (DAG), content in OVX mice was increased relative to
SHAM and OVX+E2 mice. In contrast, E2 treatment prevented the increase in hepatic DAG content observed in both
SHAM and OVX mice. Increases in tissue DAG content were associated with increased
protein kinase Cε activation in liver of
SHAM and OVX mice compared with OVX+E2 and
protein kinase Cθ activation in skeletal muscle of OVX mice compared with
SHAM and OVX+E2. Taken together, these data demonstrate that E2 plays a pivotal role in the regulation of whole-body energy homeostasis, increasing O(2) consumption and energy expenditure in OVX mice, and in turn preventing diet-induced ectopic
lipid (DAG) deposition and hepatic and muscle
insulin resistance.