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Scientists shed new light on how our bodies adapt to lack of food

New findings in mice reveal how the receptor ALK7 controls the tissue responsible for heat production in humans and other mammals, helping our bodies respond appropriately to stress such as fasting and exposure to cold temperatures.
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New insight on the biological process that allows humans and other mammals to adapt to nutritional stress such as fasting and exposure to cold temperatures has been published today in eLife.

A type of fat in our body called brown adipose tissue, or brown fat, is crucial for turning our food into body heat. The study in mice suggests that an activin receptor called ALK7 controls how brown fat adapts to nutritional stress by preventing the overactivation of signalling pathways caused by fasting, allowing for a more appropriate response to lack of food. These findings could inform the development of novel strategies for treating metabolic disorders such as obesity and type 2 diabetes.

The ability of humans and other mammals to adapt to food availability is crucial for our survival. We are able to produce our own body heat well when food is plentiful. When food is lacking, mammals such as mice can reduce their internal heat production as an adaptive, energy-saving mechanism by entering a resting state known as torpor.

“When a lack of food is combined with living in cold temperatures, mammals must balance the needs of their organs that demand high levels of energy, such as the brain, with the need to maintain body temperature,” explains co-author Patricia Mármol Carrasco, a postdoctoral researcher in senior author Carlos Ibáñez’s lab at Karolinska Institute, Stockholm, Sweden. “However, our understanding of the mechanisms that control this balance is limited.”

Previous studies have shown that, in rodents as well as humans, the activin receptor ALK7 is expressed in tissues that are important for the regulation of energy, including adipose tissue. The research team set out to discover what role ALK7 might play in the ability of brown adipose tissue to adapt to nutrient availability in mice.

To do this, they studied two groups of mice: those with normal levels of ALK7 in their brown adipocytes (cells that make up brown fat) and those engineered to lack ALK7 in these cells. In the mice lacking ALK7, the team found that protein molecules from their food were excessively broken down by brown adipocytes after overnight fasting, leaving the tissue energetically unable to cope with the demands imposed by low temperatures. On the other hand, in the mice with normal levels of ALK7, the team found that this excessive activity in brown adipocytes was limited, enabling the animals to respond more appropriately to the nutrient and temperature stress.

Further experiments revealed a high expression of genes that are responsive to nutrient stress, including KLF15, POX and ATGL, in the brown fat of mice lacking ALK7, compared to the animals with normal levels of ALK7. These results highlight the key role of the receptor in suppressing POX and KLF15 expression in both mouse and human brown adipocytes, thereby avoiding the excessive breakdown of protein molecules during a period of fasting in cold temperatures.

“Our work reveals for the first time a key role for ALK7, as well as a novel signalling pathway involving KL15, POX and other genes, in allowing brown fat to adapt correctly to variations in nutritional status,” says co-author Favio Krapacher, also a postdoctoral researcher in Ibáñez’s lab at Karolinska Institute.

“Further studies are now needed to gain a better understanding of the mechanisms by which brown fat responds to fluctuations in nutrient availability,” concludes senior author Ibáñez, Professor at Karolinska Institute. “This could be important for developing new methods to harness energy expenditure in brown fat to help treat metabolic disorders such as obesity and type 2 diabetes.”

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    eLife
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