The role of ovarian hormones in the regulation of energy and muscle metabolism.

摘要

Menopause, an age-related loss of ovarian hormones, promotes adiposity and insulin resistance, but mechanisms remain unclear. To study metabolic perturbations associated with loss of ovarian function, I monitored food intake and weight gain of ovariectomized mice (OVX, model of menopause) and sham-ovariectomized (SHM) mice for 12 weeks. Although food intake was similar, OVX mice gained 25% more weight than SHM mice. OVX mice accumulated 4.7 and 4.4-fold more perigonadal and inguinal adipose tissue, respectively, with 4.4-fold (perigonadal, P<0.001) and 5.3-fold (inguinal, P<0.01) larger adipocytes. Ovariectomy-induced adiposity was coincident with an 18% decrease in metabolic rate during the dark phase (P=0.001), and an 11% decrease during the light phase (P=0.03). Ambulatory activity levels of OVX mice were decreased during the dark phase (40%, P=0.008). OVX mice displayed evidence of immune infiltration and inflammation in adipose tissue, as perigonadal and inguinal adipose depots from OVX mice had increased expression of TNFalpha, iNOS, CD11c, and other hallmarks of adipose tissue inflammation. In contrast, expression of the T-cell marker CD3 (3.5-fold, P=0.03) and cytokine IFNgamma (2.6-fold, P=0.02) were elevated only in perigonadal fat. Additionally, histology revealed OVX-specific liver hepatic steatosis, coincident with increased PPARgamma and downstream lipogenic gene expression. Finally, OVX mice had decreased skeletal muscle expression of PPARdelta and downstream targets PDK-4 and FoxO1, atrogin-1 and MuRF-1, as were slow isoforms of contractile proteins, suggesting a shift in fiber type towards less type I oxidative fibers.;Next, I assessed whether estrogen directly stimulates glucose uptake in skeletal muscle. Ex vivo muscle stimulation with 17beta-estradiol (10 nM) resulted in rapid increases in the phosphorylation of AMP-activated protein kinase (AMPK), Akt, and TBC1D1/4, signaling proteins that regulate muscle glucose uptake. Treatment with the estrogen receptor antagonist, ICI-182,780, partly inhibited this increase, suggesting both estrogen receptor-dependent and independent mechanisms of action. 17beta-estradiol did not stimulate muscle [3H]-2-deoxyglucose uptake or enhance insulin-induced glucose uptake, demonstrating a disconnect between the estradiol-induced stimulation of AMPK, Akt and TC1D1/4 and muscle glucose uptake. This study is the first to demonstrate that estradiol stimulates AMPK, Akt and TBC1D1/4 in intact skeletal muscle, but surprisingly does not stimulate muscle glucose uptake.