Differential Effects of Acute and Chronic Estrogen Treatment on Thermogenic and Metabolic Pathways in Ovariectomized Sheep

Estrogen is protective against weight gain, but the underlying mechanisms are not fully elucidated. We sought to characterize the effects of estrogen on energy expenditure in skeletal muscle and adipose tissue in ovariectomized sheep. Temperature probes were implanted into sc (gluteal) and visceral (retroperitoneal) fat depots and skeletal muscle of the hind limb (vastus lateralis). Food was available from 1100-1600 h to entrain postprandial thermogenesis. We characterized the effects of single (50 mu g estradiol benzoate, im) and repeated (25 mu g estradiol-17 beta, iv) injections as well as chronic (3 x 3 cm estradiol-17 beta implants for 7 d) treatment on heat production. A single injection of estrogen increased heat production in visceral fat and skeletal muscle, without an effect on food intake. Increased heat production in skeletal muscle was sustained by repeated estradiol-17 beta injections. On the other hand, continuous treatment reduced food intake but had no effect on thermogenesis. To determine possible mechanisms that underpin estradiol-17 beta-induced heat production, we measured femoral artery blood flow, the expression of uncoupling protein (UCP) mRNA and the phosphorylation of AMP-activated protein kinase and Akt in fat and muscle. There was little effect of either single or repeated injections of estradiol-17 beta on the expression of UCP1, -2, or -3 mRNA in visceral fat or skeletal muscle. Acute injection of estradiol-17 beta increased the phosphorylation of AMP-activated protein kinase and Akt in muscle only. Estradiol-17 beta treatment did not alter femoral artery blood flow. Thus, the stimulatory effect of estradiol-17 beta on thermogenesis in female sheep is dependent upon a pulsatile pattern of treatment and not constant continuous exposure. (Endocrinology 154: 184-192, 2013)