Estrogen Regulation of Adiposity and Fuel Partitioning

Abstract

Menopause is associated with increased adiposity and greater risk of metabolic disease. In the ovariectomized (OVX) rodent model of menopause, increased adiposity is prevented by estrogen (E2) replacement, reflecting both anorexigenic and potentially metabolic actions of E2. To elucidate metabolic and molecular mechanisms by which E2 regulates fat storage and fat mobilization independently of reduced energy intake, C57 BL/6 mice were ovariectomized, randomized to estrogen (OVX-E2) or control pellet implants (OVX-C), and pairfed for 40 days. E2 treatment was associated with reduced adipose mass and adipocyte size and downregulation of lipogenic genes in adipocytes under the control of sterol-regulatory element-binding protein 1c. Adipocytes of OVX-E2 mice contained >3-fold more perilipin protein than adipocytes of pairfed control (OVX) mice, and this difference was associated with enhanced ex vivo lipolytic response to catecholamines and with greater levels of serum-free fatty acids following fasting. As in adipose tissue, E2 decreased the expression of lipogenic genes in liver and skeletal muscle. In the latter, E2 appears to promote the partitioning of free fatty acids toward oxidation and away from triglyceride storage by up-regulating the expression of peroxisome proliferation activator receptor-␦ and its downstream targets and also by directly and rapidly activating AMP-activated protein kinase. Thus, novel genomic and non-genomic actions of E2 promote leanness in OVX mice independently of reduced energy intake. Estrogen (E2)3 is a steroid hormone whose actions are mediated by genomic and non-genomic mechanisms (1). The classical genomic mechanism of E2 action involves activation of its nuclear receptor (estrogen receptor (ER) ␣ or ␤), receptor dimerization, and subsequent binding to ER response elements (EREs) located in the promoters of target genes. More recently, E2 has been shown to have rapid, nongenomic biological effects, believed to be mediated through membranebound subpopulations of ER-␣ and ER-␤ and/or the newly described G protein-coupled receptor 30 (GPRC30) (2-7). Here, we provide evidence that E2 has significant effects on energy metabolism through both genomic and non-genomic mechanisms and that these effects collectively promote leanness in pairfed ovariectomized (OVX) mice.Systemic loss of estrogen at menopause is associated with increased adiposity, which is implicated in the elevated risk of age-related metabolic disease in women (8 -12). Estrogen replacement alone, or in combination with progesterone can prevent menopause-induced gains in adipose tissue mass (13)(14)(15)(16)(17)(18)(19). For example, women randomized to hormone replacement therapy in the Women's Health Initiative were leaner, more insulin sensitive, and less likely to develop Type 2 diabetes than women randomized to placebo (20). These observations suggest an important, beneficial role for estrogen in energy regulation. Moreover, the beneficial metabolic role of estrogen may not be limited to women (21,22).The molecular ...

Estrogen and n-3 polyunsaturated fatty acid supplementation have a synergistic hypotriglyceridemic effect in ovariectomized rats

“…Consistent with this result, previous studies showed that E 2 injection increased the expression of PPARa, AMPK, and CPT1 in liver and/or skeletal muscle (D'Eon et al 2005;Paquette et al 2008;Kim et al 2010).…”

“…Previous studies have reported that E 2 directly downregulates SREBP1 (D'Eon et al 2005;Paquette et al 2008) and its downstream targets ACC1 and FAS (D'Eon et al 2005) in the liver of OVX rats, suggesting that E 2 also reduces hepatic synthesis of fatty acids. Although Zhu et al (2013) reported that hepatic DGAT2 expression did not change in OVX rats with or without E 2 injection, they reported that E 2 injection inhibited hepatic accumulation of diacylglycerol.…”

“…Previous studies showed that an ovariectomy procedure in rats caused hypertriglyceridemia (Hassan et al 2013) and, in a human study, circulating TG concentrations were higher in postmenopausal than pre-menopausal women (Furusyo et al 2013). Additionally, an estrogen injection prevented TG accumulation in liver and muscle of ovariectomized (OVX) mice by reducing fatty acid synthesis, increasing b-oxidation by down-regulating ACC1 and FAS, and up-regulating AMPK (D'Eon et al 2005;Gorres et al 2011). However, the effects of E 2 are unknown in regard to hepatic TG synthesis.…”

Estradiol does not directly regulate adipose lipolysis

“…7 Our understanding of the mechanisms by which E2 regulates lipolysis in vivo are largely derived from the ovariectomized (OVX) rodent model. Whole-body circulating FFA concentrations are decreased in OVX mice, but increased after treatment with E2 for 60 d. 8 Further evidence points to visceral adipose tissue as a site of impaired lipolyis in the absence of E2. Reduced adenylate cyclase activity and cAMP production have been observed in visceral adipose tissue from OVX animals.…”

Targeting metabolism in breast cancer: How far we can go?

“…Estrogens, progesterone-toestrogen ratio and androgen levels affect the energy material transporter and metabolic enzyme expressions in cells [2] . Estrogens may increase the expression of peroxisome proliferator activated receptor, Akt and activate AMP-activated protein kinase (AMPK), which consequently influence the metabolic process, including glucose utility, lipid uptake, storage, lipogenesis and lipid oxidation [3,4] . Endocrine therapy plays a pivotal role in estrogen receptor (ER) positive breast cancer treatment.…”