Administration of 17β-estradiol to ovariectomized obese female mice reverses obesity-hypertension through an ACE2-dependent mechanism

Abstract

nikouris F, English VL, Cassis LA. Administration of 17␤-estradiol to ovariectomized obese female mice reverses obesityhypertension through an ACE2-dependent mechanism. Am J Physiol Endocrinol Metab 308: E1066 -E1075, 2015. First published April 14, 2015 doi:10.1152/ajpendo.00030.2015-We recently demonstrated that female mice are resistant to the development of obesity-induced hypertension through a sex hormone-dependent mechanism that involved adipose angiotensin-converting enzyme 2 (ACE2). In this study, we hypothesized that provision of 17␤-estradiol (E2) to ovariectomized (OVX) high-fat (HF)-fed female hypertensive mice would reverse obesity-hypertension through an ACE2-dependent mechanism. Pilot studies defined dose-dependent effects of E2 in OVX female mice on serum E2 concentrations and uterine weights. An E2 dose of 36 g/ml restored normal serum E2 concentrations and uterine weights. Therefore, HF-fed OVX female Ace2and Ace2 Ϫ/Ϫ mice were administered vehicle or E2 (36 g/ml) for 16 wk. E2 administration significantly decreased body weights of HF-fed OVX female Ace2 ϩ/ϩ and Ace2 Ϫ/Ϫ mice of either genotype. At 15 wk, E2 administration decreased systolic blood pressure (SBP) of OVX HF-fed Ace2 ϩ/ϩ but not Ace2 Ϫ/Ϫ females during the light but not the dark cycle. E2-mediated reductions in SBP in Ace2 ϩ/ϩ females were associated with significant elevations in adipose ACE2 mRNA abundance and activity and reduced plasma ANG II concentrations. In contrast to females, E2 administration had no effect on any parameter quantified in HF-fed male hypertensive mice. In 3T3-L1 adipocytes, E2 promoted ACE2 mRNA abundance through effects at estrogen receptor-␣ (ER␣) and resulted in ER␣-mediated binding at the ACE2 promoter. These results demonstrate that E2 administration to OVX females reduces obesity-induced elevations in SBP (light cycle) through an ACE2-dependent mechanism. Beneficial effects of E2 to decrease blood pressure in OVX obese females may result from stimulation of adipose ACE2.17␤-estradiol; blood pressure; ovariectomy; renin-angiotensin system THE PREVALENCE OF HYPERTENSION has consistently risen in the United States largely due to the increasing prevalence of obesity. Data from the most recent National Health and Nutrition Examination Survey (NHANES) demonstrate that the prevalence of hypertension is rising at a faster rate in females than in males (6). It is generally well accepted, based on data from cross-sectional studies, that adult males are at a higher risk to develop hypertension than females until after menopause, when female prevalence of both obesity and hypertension increases markedly (27,28). Mechanisms for the role of menopause in the increasing prevalence of hypertension in females, or for the faster rise in hypertension prevalence in females compared with males are unclear.An activated renin-angiotensin system (RAS) has been suggested to contribute to the development of experimental and human obesity-induced hypertension (2,9,12,14). Indeed, recent studies from our laboratory demonstrate...

Pharmacologic activation of estrogen receptor α increases mitochondrial function, energy expenditure, and brown adipose tissue

“…The difference in body composition between pre‐ and postmenopausal women clearly indicates the beneficial effect of estrogens in adipose biology. Studies have shown that administration of estradiol to ovariectomized rats or mice reduces obesity (21), supporting the hypothesis that estrogens are responsible for tightly regulating body weight in women. In addition to favorable effects on adipose tissue, estrogens also attenuate hyperphagia through ER‐a (22,23) and through actions in the central nervous system (24, 25), all culminating in weight loss.…”

A model of neglect during postnatal life heightens obesity-induced hypertension and is linked to a greater metabolic compromise in female mice

“…Blood pressure was measured by radiotelemetry during week 16 as previously described 41 . Briefly, anesthetized (isoflurane) male and female mice fed a HF were implanted with carotid artery catheters and telemetry devices (Data Sciences, Inc., St. Paul, MN) during week 15 of HF feeding, allowed 10 days to recover.…”

Effects of Korean red ginseng (Panax ginseng) on obesity and adipose inflammation in ovariectomized mice

“…Ovariectomized (OVX) mice have an increased susceptibility to obesity and its complications including adipose inflammation, insulin resistance, and hepatic steatosis (You et al, 2004;Kaaja, 2008;Hong et al, 2009;Ludgero-Correia et al, 2012). Conversely, estrogen replacement decreases body weight and blood pressure and protects against fatty liver and insulin resistance (Zhu et al, 2013;Wang et al, 2015). Our previous study demonstrated that ginseng prevented obesity through angiogenesis inhibition (Lee et al, 2013(Lee et al, , 2014; however, these results were obtained using male mice and db/db mice.…”