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

Abstract

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 μg estradiol benzoate, im) and repeated (25 μg estradiol-17β, iv) injections as well as chronic (3 × 3 cm estradiol-17β 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-17β injections. On the other hand, continuous treatment reduced food intake but had no effect on thermogenesis. To determine possible mechanisms that underpin estradiol-17β-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-17β on the expression of UCP1, -2, or -3 mRNA in visceral fat or skeletal muscle. Acute injection of estradiol-17β increased the phosphorylation of AMP-activated protein kinase and Akt in muscle only. Estradiol-17β treatment did not alter femoral artery blood flow. Thus, the stimulatory effect of estradiol-17β on thermogenesis in female sheep is dependent upon a pulsatile pattern of treatment and not constant continuous exposure.

Innate Obesity, Revealed by Selection Markers, Confers Significant Imprint of Hypothalamic Genes Controlling Energy Expenditure

“…In adult sheep, UCP1 expression is higher in the retroperitoneal adipose tissue than in subcutaneous adipose tissue, indicative of more brown adipocytes in the former [60] . Consistent with this, the thermogenic response to feeding, leptin, and oestrogen treatment is greater in retroperitoneal fat than subcutaneous gluteal fat [61,62] . Longitudinal temperature profiling reveals elevated postprandial thermogenesis in retroperitoneal adipose tissue of lean sheep, and this coincides with greater post-prandial expression of UCP1 in the lean genotype than that in the obese genotype [58] .…”

High cortisol responses identify propensity for obesity that is linked to thermogenesis in skeletal muscle

“…We focused on the retroperitoneal fat bed, because our work in adults has shown greater expression of UCP‐1 in this fat bed than in subcutaneous fat (30). Furthermore, the thermogenic effect of both leptin and estrogen is greater in retroperitoneal fat than in subcutaneous adipose tissue (15, 42). Thus, our previous work suggests that, at least in adult sheep, the retroperitoneal fat depot contributes to total body adaptive thermogenesis.…”

Non‐shivering thermogenesis as a mechanism to facilitate sustainable weight loss

“…In attempts to determine the factors that diverge between men and women and drive these differences, men have been supplemented with 17β estradiol for 8 days, and following this, there is a reduction in the respiratory exchange ratio during exercise accompanied by increased β‐oxidation capacity as measured in skeletal muscle biopsy specimens . Additionally, supporting a direct role of estrogens, administration of 17β‐estradiol to ovariectomized ewes increases heat production in skeletal muscle without an associated change in blood flow suggesting the thermogenic response is a cellular event . To begin to unravel the mechanisms by which estrogens may do this, researchers have removed endogenous estrogens in ovariectomized animals and found that exogenous return of estrogen activates skeletal muscle AMPK which in turn inhibits acetyl‐CoA carboxylase causing a decrease in malonyl‐CoA levels and facilitating mitochondrial fatty acid use via increases in CPT activity .…”