Developmental Biology - Cell Control Over Immune Response|
New Approach Turns Up Heat In Fat Cells
New cell signaling pathway can activate thermogenic fat in humans...
Researchers have discovered a new set of signals that cells send and receive to prompt one type of fat cell to convert fat into heat.
This signaling pathway, discovered in mice, has potential implications for activating this same type of thermogenic fat in humans.
Thermogenic fat cells, also called beige fat or beige adipocytes, have gained attention in recent years for their potential to curb obesity, given their ability to burn fat. But, translating this into effective therapy has not happened, yet.
The challenge to activating beige fat in humans arises, partly because the process is regulated by adrenergic signals that use the hormone catecholamine to induce beige fat cells to burn energy.
Adrenergic signaling, however, also controls other biological functions, including regulation of blood pressure and heartbeat. Activating it in humans with agonists can potentially be dangerous.
In a new study published June 12 in the journal Developmental Cell, a team of researchers led by the University of Michigan Life Sciences Institute describe a pathway that can regulate beige fat thermogenesis independently of adrenergic signaling. Instead, it operates through a receptor protein called CHRNA2, short for Cholinergic Receptor Nicotinic Alpha 2 Subunit.
"This pathway opens a whole new direction for approaching metabolic disorders. Of course, the cholinergic pathway is also involved in other important body functions — there is still much work to do to really figure out how this might work in humans. But we are encouraged by these initial findings."
Jun Wu PhD, Assistant Professor, LSI and study senior author.
For their study, Wu and her colleagues blocked the CHRNA2 pathway only in adipocytes [fat cells] of mice. Then they were fed a high-fat diet. Without CHRNA2 receptor proteins, the mice gained weight more than normal as they couldn't activate thermogenesis as a response to eating excessive amounts of food.
These findings are particularly exciting in light of another recent research discovery. A new type of beige fat not regulated by catecholamine. This newest work by LSI indicates how this beige fat — glycolytic beige fat (or g-beige fat) — can be activated through the CHRNA2 pathway.
"Many patients with metabolic disorders have catecholamine resistance — their cells do not detect or respond to catecholamine. So even if it could be done safely, activating that adrenergic pathway would not be an effective treatment option for those patients.
This new pathway — with its new subtype of beige fat — could be the beginning of a whole new chapter in this challenge."
Jun Wu PhD, Assistant Professor, Molecular and Integrative Physiology, U-M Medical School.
• CHRNA2 signaling in adipocytes mediates systemic energy homeostasis in vivo
• Acute high fat diet feeding activates CHRNA2 signaling in beige adipocytes
• CHRNA2 signaling regulates both UCP1- and creatine-mediated pathways
• CHRNA2 signaling regulates the activation of glycolytic beige adipocytes
Heejin Jun, Yingxu Ma, YongChen, Jianke Gong, Shanshan Liu, Jine Wang, Alexander J. Knights, Xiaona Qiao, Margo P. Emont, Shawn Xu, Shingo Kajimura and Jun Wu.
Maintaining energy homeostasis upon environmental challenges, such as cold or excess calorie intake, is essential to the fitness and survival of mammals. Drug discovery efforts targeting ?-adrenergic signaling have not been fruitful after decades of intensive research. We recently identified a new beige fat regulatory pathway mediated via the nicotinic acetylcholine receptor subunit CHRNA2. Here, we generated fat-specific Chrna2 KO mice and observed thermogenic defects in cold and metabolic dysfunction upon dietary challenges caused by adipocyte-autonomous regulation in vivo. We found that CHRNA2 signaling is activated after acute high fat diet feeding and this effect is manifested through both UCP1- and creatine-mediated mechanisms. Furthermore, our data suggested that CHRNA2 signaling may activate glycolytic beige fat, a subpopulation of beige adipocytes mediated by GABP? emerging in the absence of ?-adrenergic signaling. These findings reveal the biological significance of the CHRNA2 pathway in beige fat biogenesis and energy homeostasis.
The research was supported by the National Institutes of Health, American Diabetes Association, Chinese Scholarship Council and Michigan Life Sciences Fellows program.
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Graphical Abstract of the Project: A new pathway — with a new subtype of beige fat — might be the beginning of a whole new chapter in fat burning. University of Michigan Life Sciences Institute.