Silencing of estrogen receptor α in the ventromedial nucleus of hypothalamus leads to metabolic syndrome

Abstract

Estrogen receptor ␣ (ER␣) plays a pivotal role in the regulation of food intake and energy expenditure by estrogens. Although it is well documented that a disruption of ER␣ signaling in ER␣ knockout (ERKO) mice leads to an obese phenotype, the sites of estrogen action and mechanisms underlying this phenomenon are still largely unknown. In the present study, we exploited RNA interference mediated by adeno-associated viral vectors to achieve focused silencing of ER␣ in the ventromedial nucleus of the hypothalamus, a key center of energy homeostasis. After suppression of ER␣ expression in this nucleus, female mice and rats developed a phenotype characteristic for metabolic syndrome and marked by obesity, hyperphagia, impaired tolerance to glucose, and reduced energy expenditure. This phenotype persisted despite normal ER␣ levels elsewhere in the brain. Although an increase in food intake preceded weight gain, our data suggest that a leading factor of obesity in this model is likely a decline in energy expenditure with all three major constituents being affected, including voluntary activity, basal metabolic rate, and diet-induced thermogenesis. Together, these findings indicate that ER␣ in the ventromedial nucleus of the hypothalamus neurons plays an essential role in the control of energy balance and the maintenance of normal body weight.adeno-associated virus ͉ body weight ͉ energy metabolism ͉ obesity ͉ RNA interference E strogen receptor ␣ (ER␣) is the main mediator of estrogen effects on energy homeostasis. ER␣ knockout (ERKO) mice with targeted deletion of this receptor develop several hallmark features often associated with obesity including increased visceral adiposity, elevated insulin levels, and impaired glucose tolerance (1). Although the nature of events leading to this phenotype is unclear, hyperphagia does not seem to be the cause because food consumption was not altered in ERKO mice. Instead, several observations suggest that the weight gain in this model is due to a decrease in energy expenditure, which given the normal food intake would result in a state of positive energy balance (1, 2). In this respect, this condition partially resembles an obesity syndrome following lesions of the ventromedial nucleus of hypothalamus (VMN), which is also marked by a significant weight gain due to an accumulation of visceral fat, impaired glucose homeostasis, and reduced energy expenditure (3, 4). Although VMN-lesioned animals initially become hyperphagic as well, when tube-pair-fed with control animals to ensure equal food consumption, lesioned rats still gained more weight and accumulated more fat, albeit to a lesser extent than rats fed ad libitum (3, 5). There are additional lines of evidence that are consistent with a functional role of VMN ER␣ in the regulation of body weight. VMN has a high density of estrogenbinding sites (6), and the neurons in this nucleus express ER␣ at high levels (7). Although VMN lesioning or ovariectomy both lead to increased food intake and body weight, the effect does not appear...

Withdrawal of dietary phytoestrogens in adult male rats affects hypothalamic regulation of food intake, induces obesity and alters glucose metabolism

“…Heine et al (2000) reported that male and female mice with total body deletion of ERα (ER-knock-out mice) have increased adiposity regardless of gender, suggesting an important role for this estrogen receptor in the regulation of body weight and adiposity. Other authors reported that specific silencing of ERα in the hypothalamus leads to metabolic syndrome (Musatov et al, 2007), demonstrating the importance of estrogens and ERα in the central regulation of energy balance. ERα is more abundant in the arcuate nucleus compared to other relevant nuclei and is predominantly expressed in POMC neurons (de Souza et al, 2011).…”

The pancreatic β-cell as a target of estrogens and xenoestrogens: Implications for blood glucose homeostasis and diabetes

“…The ratio ER/ER seems to be associated with obesity as well as with the serum level and the production of leptin in omental adipose tissue in women (Shin et al, 2007). In the brain, the disruption of the ER in the ventromedial nucleus of the hypothalamus leads to weight gain, increased visceral adiposity, hyperphagia, hyperglycaemia and impaired energy expenditure in female mice (Musatov et al, 2007). …”

Functional requirement of AgRP and NPY neurons in ovarian cycle-dependent regulation of food intake

“…Feeding and body weight increase in ovariectomized females and estrogen replacement reverses such effects (11,12). Furthermore, acute ablation of ER alpha (ER␣) in the brain results in severe obesity and metabolic syndrome (13). Thus, decreased estrogen signaling also activates regulatory mechanisms to increase body adiposity.…”