A previously unknown metabolic pathway has been found to regulate energy expenditure and heat production in fat cells. This pathway, which emerged in a new study led by scientists at the University of California, San Diego, involves the accumulation and degradation of glycogen.

The pathway surprised the scientists because the role of glycogen in fat has been a mystery. To date, glycogen has been understood as a way to package and store unneeded glucose in liver and skeletal muscle cells. But now it appears that glycogen may serve a different purpose in fat cells. Specifically, in fat cells, glycogen—or rather glycogen turnover, may serve as a kind of regulatory signal, one that can shift how energy is handled.

For example, glycogen turnover may explain the “browning” of fat cells. Humans carry at least two kinds of fat tissue: white and brown. White fat cells are essentially inert containers for energy stored in the form of a single large, oily droplet. Brown fat cells are more complex, containing multiple, smaller droplets intermixed with dark-colored mitochondria—cellular organelles that give them their color and are the “engines” that convert the lipid droplets into heat and energy. Some people also have “beige” fat cells, brown-like cells residing within white fat that can be activated to burn energy.

In recent years, there has been much effort to find ways to increase brown or beige fat cell activity, to induce fat cells, known as adipocytes, to burn energy and generate heat in a process called thermogenesis as a means to treat obesity, type 2 diabetes, and other conditions.

But the therapeutic potential of brown fat—and perhaps beige fat cells—has been stymied by the complexity of the processes involved. It wasn’t until 2009 that the existence of active brown fat cells in healthy adults was confirmed; previously it was believed they were common only in newborns.

According to the new study, the browning of fat cells depends on their ability to both make and then degrade glycogen. The turnover of glycogen sends a signal that it is safe for the cell to “uncouple” the production of ATP, the molecule that provides the energy that fuels most cellular processes.

Details about the role of glycogen turnover and the uncoupling of ATP production in fat cells appeared October 27 in Nature, in an article titled, “Glycogen metabolism links glucose homeostasis to thermogenesis in adipocytes.” The article argues that glycogen synthesis and turnover in the browning of white adipose tissue signifies a novel aspect of the regulation of energy expenditure. The article also suggests that glycogen synthesis and turnover ensures the beiging only of white adipocytes with sufficient energy to fuel thermogenesis, thus preventing the potentially toxic effects of ATP uncoupling produced by the expression of uncoupling protein 1 (UCP1).

“Assessment of mice with whole-body, adipocyte-specific, and brown and beige adipocyte-specific knockout of PTG, the key glycogen-targeting protein, revealed that glycogen metabolism is required for the induction of UCP1 by adrenergic activation both in vivo and in vitro in a cell-autonomous manner,” the article’s authors noted. “Glycogen accumulation and turnover were also required for long-term cold adaptation in these models. Both synthetic and degrading enzymes are coordinately increased by β-adrenergic activation and are high in brown adipocytes, suggesting that this isoform facilitates adrenergic activation of thermogenesis in adipocytes, leading us to speculate that both glycogen turnover and synthesis are crucial.”

In obese mice, more robust metabolic processes were associated with the burning of fat and weight loss. In humans, the genes involved in these complex processes were found to be lower in patients who were obese or prone to weight gain, suggesting that the glycogen pathway is needed in fat cells to burn off excess weight.

These findings suggest that the modulation of glycogen metabolism in fat cells could have therapeutic benefits. Specifically, the uncoupling mechanism described in the study could facilitate weight loss and lead to overall improvements in metabolic health.

“Uncoupling is a way to generate heat, and in the process, help balance energy,” said Alan Saltiel, PhD, senior of the study and director of the Institute for Diabetes and Metabolic Health at University of California, San Diego, School of Medicine. “This pathway thus ensures that only the fat cells with enough energy stores to fuel the generation of heat are allowed to do so.”

The dramatic increase in worldwide obesity—650 million people or 13%, a tripling since 1975—underscores the importance of understanding how the human body balances energy intake and expenditure.

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