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How Targeting Fat Cells’ Estrogen Receptors Could Fight Obesity
Tracy Hampton, PhD
In adipocytes, fat cells, a particular estrogen-receptor appears critical for energy supplying mitochondria to function properly. The discovery points to a potential drug target for boosting fat tissue metabolism, which could help combat obesity and other metabolic conditions.
The research addresses a vexing problem that many middle-aged adults face as they get older—added fat tissue and weight gain due to a slowing metabolism. The problem is especially prominent for women, as estrogen deprivation after menopause leads to an increase in total body fat.
Previous studies have offered a potential explanation in a link between fat accumulation, mitochondria-related dysfunction, and lower expression of the gene ESR1, which encodes a form of the estrogen receptor called ERα. Indeed, healthy identical twins who differ by body mass index have different mitochondria-related RNA signatures in their fat cells, indicating a link between mitochondrial dysfunction and adiposity. In addition, ESR1 expression is reduced in fat tissue from women with obesity, and adipocyte ERα deletion disrupts the metabolic balance in rodents.
With this knowledge in mind, investigators first examined the clinical relationships between ESR1 expression and markers of metabolic health. “We hypothesized that low ESR1 expression in adipose tissue— both variability in genetic inheritance as well as reduced expression as a consequence of environmental factors and aging—underlies susceptibility for obesity and metabolic dysfunction,” Andrea Hevener, PhD, a professor in the division of endocrinology, diabetes, and hypertension at the University of California, Los Angeles (UCLA) David Geffen School of Medicine, said in an interview.
In a study published in Science Translational Medicine, Hevener and her colleagues discovered that ESR1 fat tissue expression among more than 700 women and nearly 800 men were inversely associated with abdominal fat mass and positively correlated with insulin sensitivity. Therefore, people with lower levels of ESR1 expression tended to have higher fat stores and insulin resistance, clinical features of metabolic dysfunction. The findings in males were unexpected and suggest that men’s estrogen levels could affect their body weight more than is currently appreciated. “Although it is known that estrogen action is important for metabolic health because tissue ESR1 expression and estradiol levels are much lower in men than women, many have assumed that estrogen action is less important for men compared with women,” Hevener said. “Our findings do not support this notion.”
The team next examined the mechanistic links between ERα absence, mitochondrial function, and obesity. In mice, selectively deleting the Esr1 gene from energy-storing white adipocytes and energy-burning brown adipocytes impaired mitochondria. The deletion reduced the expression of Polg1, a subunit of the polymerase enzyme that replicates and transcribes mitochondrial DNA. This led to increased fat in white adipocytes and reduced energy burning in brown adipocytes.
The investigators have now pivoted to studying mice that overexpress Esr1 in their white and brown adipose tissue. “We want to know if these mice will be protected against high-fat diet-induced weight gain and insulin resistance,” Hevener explained. Her team is also studying the relationship between aerobic exercise training and adipose tissue ESR1 expression. Their goal is to learn if people need ERα and healthy mitochondrial function in adipocytes to lose weight from exercising.
The researchers seek to translate their findings into clinical interventions to help counter obesity and metabolic dysfunction. Targeting ERα and its effects—along the lines of selective estrogen receptor modulators currently used to treat breast cancer and osteoporosis—may be especially promising among women during the menopausal transition. Although premenopausal women are less prone to metabolic disease than men, menopause reverses this protection.
The study’s potential implications for men are also intriguing, said Franck Mauvais-Jarvis, MD, PhD, director of the Diabetes Discovery Research and SexBased Medicine Laboratory at Tulane University School of Medicine. “We know that testosterone needs to be converted to estrogens to prevent abdominal fat accumulation in men and that men with mutations in ERα accumulate abdominal fat,” he said in an email. More research is needed to explore the full range of metabolic effects of estrogens and their receptors in both women and men, he added.
Tracy Hampton, PhD
In adipocytes, fat cells, a particular estrogen-receptor appears critical for energy supplying mitochondria to function properly. The discovery points to a potential drug target for boosting fat tissue metabolism, which could help combat obesity and other metabolic conditions.
The research addresses a vexing problem that many middle-aged adults face as they get older—added fat tissue and weight gain due to a slowing metabolism. The problem is especially prominent for women, as estrogen deprivation after menopause leads to an increase in total body fat.
Previous studies have offered a potential explanation in a link between fat accumulation, mitochondria-related dysfunction, and lower expression of the gene ESR1, which encodes a form of the estrogen receptor called ERα. Indeed, healthy identical twins who differ by body mass index have different mitochondria-related RNA signatures in their fat cells, indicating a link between mitochondrial dysfunction and adiposity. In addition, ESR1 expression is reduced in fat tissue from women with obesity, and adipocyte ERα deletion disrupts the metabolic balance in rodents.
With this knowledge in mind, investigators first examined the clinical relationships between ESR1 expression and markers of metabolic health. “We hypothesized that low ESR1 expression in adipose tissue— both variability in genetic inheritance as well as reduced expression as a consequence of environmental factors and aging—underlies susceptibility for obesity and metabolic dysfunction,” Andrea Hevener, PhD, a professor in the division of endocrinology, diabetes, and hypertension at the University of California, Los Angeles (UCLA) David Geffen School of Medicine, said in an interview.
In a study published in Science Translational Medicine, Hevener and her colleagues discovered that ESR1 fat tissue expression among more than 700 women and nearly 800 men were inversely associated with abdominal fat mass and positively correlated with insulin sensitivity. Therefore, people with lower levels of ESR1 expression tended to have higher fat stores and insulin resistance, clinical features of metabolic dysfunction. The findings in males were unexpected and suggest that men’s estrogen levels could affect their body weight more than is currently appreciated. “Although it is known that estrogen action is important for metabolic health because tissue ESR1 expression and estradiol levels are much lower in men than women, many have assumed that estrogen action is less important for men compared with women,” Hevener said. “Our findings do not support this notion.”
The team next examined the mechanistic links between ERα absence, mitochondrial function, and obesity. In mice, selectively deleting the Esr1 gene from energy-storing white adipocytes and energy-burning brown adipocytes impaired mitochondria. The deletion reduced the expression of Polg1, a subunit of the polymerase enzyme that replicates and transcribes mitochondrial DNA. This led to increased fat in white adipocytes and reduced energy burning in brown adipocytes.
The investigators have now pivoted to studying mice that overexpress Esr1 in their white and brown adipose tissue. “We want to know if these mice will be protected against high-fat diet-induced weight gain and insulin resistance,” Hevener explained. Her team is also studying the relationship between aerobic exercise training and adipose tissue ESR1 expression. Their goal is to learn if people need ERα and healthy mitochondrial function in adipocytes to lose weight from exercising.
The researchers seek to translate their findings into clinical interventions to help counter obesity and metabolic dysfunction. Targeting ERα and its effects—along the lines of selective estrogen receptor modulators currently used to treat breast cancer and osteoporosis—may be especially promising among women during the menopausal transition. Although premenopausal women are less prone to metabolic disease than men, menopause reverses this protection.
The study’s potential implications for men are also intriguing, said Franck Mauvais-Jarvis, MD, PhD, director of the Diabetes Discovery Research and SexBased Medicine Laboratory at Tulane University School of Medicine. “We know that testosterone needs to be converted to estrogens to prevent abdominal fat accumulation in men and that men with mutations in ERα accumulate abdominal fat,” he said in an email. More research is needed to explore the full range of metabolic effects of estrogens and their receptors in both women and men, he added.
