Estradiol, the most important form of estrogen, and its binding partner, estrogen receptor alpha (ER-alpha), are usually associated with women’s health, but research done during the last decade has found that ER-alpha is critical for proper metabolic function in both men and women.
The association between ER-alpha and metabolic conditions, such as type 2 diabetes, was the main focus of a seminar by Andrea Hevener, Ph.D., a professor with the David Geffen School of Medicine at the University of California, Los Angeles. Hevener is a long-time collaborator of Kenneth Korach, Ph.D., chief of the NIEHS Reproductive and Developmental Biology Laboratory (RDBL) and host of her April 15 seminar.
In "Strong Enough for a Man, Made for a Woman — The Impact of ER-alpha on Mitochondrial Health and Metabolic Homeostasis," Hevener explained that the seminar title was taken from a commercial that aired during the 1980s for the antiperspirant Secret. She said it perfectly describes what ER-alpha does for men.
Knockout mice provide vital clues
Hevener and her group studied ER-alpha in skeletal muscle, because skeletal muscle is a primary tissue responsible for fat oxidation, or the process of breaking down fat into smaller particles used for energy. Skeletal muscle also accounts for 75 to 85 percent of the body’s insulin-stimulated glucose disposal, or breakdown of glucose needed for energy production.
She said that research groups like hers, Korach’s lab, and others have shown that whole body ER-alpha knockout mice experience a profound increase in adiposity, or fat, and metabolic dysfunction, including severe insulin resistance. When the pancreas is unable to secrete enough insulin to overcome that resistance in muscle and other peripheral tissues, it promotes failure of pancreatic beta cells that store and release insulin. Type 2 diabetes is a consequence of this failure.
To test the impact of ER-alpha expression on muscle metabolism and insulin sensitivity, the Hevener lab, with Korach’s help, generated a muscle-specific, ER-alpha knockout (MERKO) mouse. A muscle-specific deletion of ER-alpha promoted glucose intolerance, insulin resistance, and obesity similar to that observed for the whole body ER-alpha knockout mouse.
This metabolic dysfunction was accompanied by an accumulation of bioactive lipids in muscle, and was associated with marked skeletal muscle inflammation in the MERKO mouse. "This inflammation was more than what we were used to seeing in a high fat diet, so we knew it was a complex phenotype," Hevener said.
ER-alpha and mitochondria
After seeing the inflammation in MERKO mice, Hevener developed a new hypothesis. Increased lipid in the muscle is likely a result of reduced fatty acid oxidation, or impairment in the ability of ER-alpha−deficient muscle to metabolize fat. Because fatty acid oxidation occurs in the mitochondria, the lab’s focus turned to these organelles, which are the power houses of the cell.
Work from other groups demonstrated that the mitochondrial life cycle includes a dynamic fission-fusion process. During fission, two daughter mitochondria are produced. In many cases, one of these mitochondria has a normal membrane potential and can integrate back into the mitochondrial network, but the other is depolarized and is either segregated into a solitary period of repair, or if irreparable damage has occurred, destroyed by mito-specific autophagy called mitophagy.
Further experiments determined that ER-alpha is involved in maintaining mitochondrial function and health, and these processes are important for insulin action in skeletal muscle. Hevener and colleagues, including Korach and NIEHS senior biologist Sylvia Hewitt, published the findings online April 13 in Science Translational Medicine.
Hevener said future work will focus on whether maintaining or increasing ER-alpha levels produces a way to protect against chronic diseases associated with metabolic dysfunction.
"For those of you interested in maintaining fitness, the upregulation of ER-alpha in skeletal muscle is also part of the adaptation to endurance training and is critical for promoting the health benefits of exercise," Hevener said.
Citation: Ribas V, Drew BG, Zhou Z, Phun J, Kalajian NY, Soleymani T, Daraei P, Widjaja K, Wanagat J, de Aguiar Vallim TQ, Fluitt AH, Bensinger S, Le T, Radu C, Whitelegge JP, Beaven SW, Tontonoz P, Lusis AJ, Parks BW, Vergnes L, Reue K, Singh H, Bopassa JC, Toro L, Stefani E, Watt MJ, Schenk S, Akerstrom T, Kelly M, Pedersen BK, Hewitt SC, Korach KS, Hevener AL. 2016. Skeletal muscle action of estrogen receptor alpha is critical for the maintenance of mitochondrial function and metabolic homeostasis in females. Sci Transl Med 8(334):334ra54.