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Developmental biology - Brown Fat|
Brown fat flexes its muscle
Here's how brown fat works: When the body senses cold, our brain releases norepinephrine, which is detected by a receptor on brown fat cells. This triggers a cascade of biochemical signals leading to production of a protein called Uncoupling Factor-1 also known as Mitochondrial uncoupling protein (UCP1). UCP1 then fuses into the mitochondria within brown fat cells.
In a normal cell, mitochondria act much like batteries. They convert nutrients from our diet into energy and then store it, primarily, in ATP molecules. But in brown fat cells, UCP1 creates heat instead of ATP. With UCP1 made active in mitochondria, brown fat cells soak up fat and sugars to burn for heat.
Previous research found brown fat shares some characteristics of muscle, particularly in the myosin proteins, which act like little motors. In muscle, myosin contracts the muscle cells, but what myosin did in brown fat cells was unknown. So researchers stimulated brown fat and measured how much the cell flexed by measuring the tension of the cell wall. Cell walls became roughly twice as stiff when stimulated. But, when researchers disabled myosin they found brown fat cells reduced stiffness by a factor of about two significantly softer.
"Our finding that the muscle-like myosin is responsible for stiffening brown fat cells was really unexpected, no one has ever observed that before."
The study found that UCP1's activity is directly tied to the increase in cell tension. When that tension in activated brown fat cells caused a 70 percent reduction in UCP1 — and generated less heat. Researchers were then able to identify the molecules in the cell that respond to increased tension which triggers activation of UCP1. In experiments in mice, they disrupted these molecules to find that brown fat cells lose their function and physically look more like white fat cells, where excess energy is stored.
"Now that we better understand how brown fat cells work, we can think about ways to stimulate muscle-like myosin in brown fat to increase thermogenesis and burn calories," Stahl said. "Drugs to stimulate muscle-like myosin in existing brown fat would probably create more active brown fat cells in adults."
"This study offers a remarkable example of how mechanical and other physical forces can influence physiology and disease in powerful, unexpected ways," explains Sanjay Kumar, Berkeley professor of bioengineering and a co-author of the study. "We hope that our work will aid in the design of therapeutic biomaterials and other technologies geared towards enhancing brown fat function."
• BAT adrenergic stimulation induces an actomyosin-based mechanical response
• Modulation of actomyosin responses alters oxidative metabolism in adipocytes
• Thermogenic gene expression in adipocytes is in part regulated by YAP/TAZ
The activation of brown/beige adipose tissue (BAT) metabolism and the induction of uncoupling protein 1 (UCP1) expression are essential for BAT-based strategies to improve metabolic homeostasis. Here, we demonstrate that BAT utilizes actomyosin machinery to generate tensional responses following adrenergic stimulation, similar to muscle tissues. The activation of actomyosin mechanics is critical for the acute induction of oxidative metabolism and uncoupled respiration in UCP1+ adipocytes. Moreover, we show that actomyosin-mediated elasticity regulates the thermogenic capacity of adipocytes via the mechanosensitive transcriptional co-activators YAP and TAZ, which are indispensable for normal BAT function. These biomechanical signaling mechanisms may inform future strategies to promote the expansion and activation of brown/beige adipocytes.
Authors: Kevin M. Tharp, Michael S. Kang, Greg A. Timblin, Jon Dempersmier, Garret E. Dempsey, Peter-James H. Zushin, Jaime Benavides, Catherine Choi, Catherine X. Li, Amit K. Jha, Shingo Kajimura, Kevin E. Healy, Hei Sook Sul, Kaoru Saijo, Sanjay Kumar and Andreas Stahl.
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Illustration of a brown/beige adipose tissue (BAT) cell metabolism - and the induction
of uncoupling protein 1 (UCP1). Image; University of California Berkeley.