Turning Up the Heat—Important New Insights into the Biology of Brown Fat
New discoveries about the properties of brown and beige fat could inform research to develop potential new approaches for reducing obesity and its associated diseases.
Mammals harbor different kinds of adipose (fat) tissue in various regions of the body. Calorie-storing white adipose tissue (WAT) is the most abundant, and can be found surrounding internal organs, where it is referred to as visceral or abdominal fat, and just under the skin, a location termed subcutaneous. In contrast to the fat-storing WAT, brown adipose tissue (BAT) burns calories to generate heat. The heat-generating activity of brown fat is induced by cold weather, and contributes to a phenomenon known as “non-shivering thermogenesis” in which heat is produced as a by-product of specific biochemical processes that aid mammals in staying warm during hibernation.
Recent research has identified a second type of inducible brown fat cell (alternately called beige, brite (for brown in white), or recruitable BAT cells) that exhibits some of the characteristics of classic brown fat. The beige fat cells appear within portions of white fat and muscle tissue, in response to cold or other nervous system triggers. Because of the calorie-burning capability of both types of brown fat, many scientists believe that BAT could serve as an ideal target for the development of treatment strategies for obesity in humans. However, while rodents maintain patches of brown fat near the neck throughout life, classic brown fat largely disappears after infancy in humans. Interest in the therapeutic potential of BAT has been rekindled with the discovery of alternative inducible forms of BAT present in adult humans. New reports shed important new light on the anatomy, physiology, and molecular properties of human and rodent fat tissue.
In one recent study, while investigating the molecular control of brown fat activity, researchers uncovered a novel way that mammals regulate body heat—by promoting beige fat production when classic brown fat mass is reduced. Scientists genetically modified mice to lack the protein BMPR1A in a region of the developing embryo from which the bulk of BAT arises. Removing BMPR1A in these cells dramatically reduced the size of many BAT patches (also known as BAT depots). Unexpectedly, the body temperatures of adult mice lacking BMPR1A were no different from their normal littermates. Furthermore, after prolonged exposure to cold temperatures, body temperatures initially dropped in normal and genetically modified mice, but subsequently came back to normal, presumably due to brown fat activation. While the normal mice recovered in 48 hours, the mice lacking BMPR1A also recovered but required 11 days to return to normal. This surprising result suggested that cold-inducible beige fat cells might be recruited to compensate for the loss of other BAT. Further analysis showed that beige fat was indeed induced in WAT. The researchers confirmed this finding with other mouse models in which BAT activity was disrupted. This study identified a novel and complex interplay between brown and beige fat, and suggests that this compensatory relationship must be taken into account when designing brown fat-targeted therapeutics for altering energy balance.
In another study, researchers sought to better understand if beige fat cells can respond to cold exposure directly, or, as has been previously thought, only to cold-generated signals sent from the nervous system and interpreted by WAT. The scientists used mice genetically modified to lack key proteins, called β-adrenergic receptors, that interpret signals sent from the brain in response to cold temperature. These mice were then exposed to moderately cold conditions, and different fat depots were isolated to see whether genes involved in heat production (thermogenesis) were turned on. In beige fat cells without β-adrenergic receptors, thermogenic genes were turned on, but at levels much lower than normal. Surprisingly, these genes were also turned on to a similar extent in subcutaneous WAT with and without the β-adrenergic receptors. To investigate these effects in the absence of influence from the nervous system and brain, the researchers grew isolated white fat and beige fat cells in the laboratory, exposed them to cold temperature, and found that even in isolation, specific thermogenic genes were turned on, and could be turned off again by returning the cells to normal temperature. Cellular respiration—one measure of a cell’s energy output—also increased with cold exposure. Isolated classic brown fat cells did not exhibit the same responses to direct cold exposure, suggesting that their activity is induced by indirect factors (i.e., the nervous system). While most of these experiments were done in mice or with mouse cells, the researchers also tested isolated human cells from subcutaneous fat, and found that these cells similarly turned on thermogenic genes in response to cold temperature. Together, these results reveal a previously unknown direct response to cold temperature by white and beige fat cells. Scientists will now explore the mechanism of the direct response to determine whether this system can be exploited to develop weight loss strategies.
Studies in mice have greatly illuminated the basic biology of fat tissue and how the body coordinates the thermogenic response to cold temperature. The applicability of findings from rodent models to human biology, however, is always a concern, and technical limitations have impeded progress in identifying and characterizing human BAT.
To begin to address this issue, a third study characterized the complex anatomy and molecular nature of fat tissue derived from the human neck. Scientists isolated samples of fat tissue from the necks of 31 participants who had given consent and were already undergoing surgery for other reasons. The researchers then carefully examined five different depots at progressively deeper positions within the neck. Molecular and cellular analyses revealed that broadly, the fat tissue closer to the surface exhibited properties similar to mouse WAT, whereas the deeper fat depots more closely resembled mouse BAT. Importantly, however, there was considerable variability between individuals. The researchers isolated a population of cells and, using specific conditions, induced them to become brown fat cells. These brown fat cells could indeed turn on thermogenic genes in response to a chemical that “tricks” the cells into thinking that the body was exposed to cold temperatures. Moreover, cells from the deeper fat tissues of two individuals had the capacity to burn about 100 times more calories—as determined by oxygen consumption rate—than subcutaneous fat tissue, and about half as much as mouse BAT. Together, these results suggest that adipose depots deep in the human neck most closely resemble rodent BAT in anatomy and function.
These reports greatly advance the current understanding of brown, beige, and white adipose tissues, describing novel properties and complex relationships within the heat regulation system. The detailed anatomical, molecular, and functional characterization of human neck adipose tissue will aid in the translation of findings in rodents to human biology, and provides critical new information that can potentially be used to develop therapeutic strategies to alter energy balance in people.