Fat is often thought of as a means to store energy in the form of lipids. But this is just the role of white fat cells. The body also contains a second type of fat that burns the energy stored in nutrients to produce heat, enabling mammals to maintain their body temperature in a cold environment1. Activating this ‘thermogenic’ fat is thought to be an attractive way to combat obesity2. Writing in Nature, Chen et al.3 identify a previously uncharacterized type of thermogenic fat cell, which is derived from a hitherto unknown cell lineage and burns mainly sugar, rather than the sugar and lipid combination processed by most thermogenic fat. Its discovery could open up new therapeutic possibilities for weight loss.
Thermogenic fat cells are currently classified as either brown or beige4. Unlike brown fat, beige fat cells are found interspersed in white fat. The production of beige fat cells can be triggered in response to cold by activation of the β-adrenergic-receptor proteins on the surface of precursor cells in white-fat tissue depots. These receptors are stimulated by the β-adrenergic signalling pathway, which originates in the nervous system.
Extensive efforts have been made to target thermogenic fat for weight loss, but no successful drug has been developed so far. This is due partly to the fact that the amount of active brown fat varies between individuals, and decreases with age. In addition, current strategies to induce the formation and activation of beige fat typically involve simulating cold responses, and are thought to act through β-adrenergic signalling. This inevitably affects other organs, because the β-adrenergic receptors are widely expressed across various tissues5 — and such a lack of specificity raises safety issues. Thus, other ways of inducing the formation and activation of thermogenic fat would be very valuable.
Chen et al. set out to identify alternative pathways by which to activate thermogenic fat using a mouse model called the β-less mouse, which lacks all three β-adrenergic receptors. They confirmed previous reports6,7 that some beige fat cells were still produced under these conditions (Fig. 1).
Where do these cells come from? Chen et al. performed an in-depth characterization of gene expression in the fat tissues of the β-less mice, which revealed that genes involved in muscle development were more highly expressed in fat tissues lacking β-adrenergic receptors than in those of control animals. The authors genetically engineered mice so that cells expressing one such gene, Myod (which encodes the protein MyoD and is normally expressed in muscle-cell precursors), were indelibly labelled with a fluorescent protein. They then blocked β-adrenergic signalling using a drug and exposed the mice to mild cold, before tracking the fate of MyoD-expressing cells and their descendants. This lineage-tracing experiment revealed that some MyoD-expressing cells give rise to a subset of beige fat cells, suggesting that muscle-cell precursors can be reprogrammed to turn into specific beige fat cells.
When they analysed the gene-expression profiles of the cells, Chen et al. found that this subset of beige fat differs from that of conventional beige fat. The subset expresses higher levels of many genes involved in sugar and carbohydrate metabolism and glycolysis — the process by which energy is produced from glucose. On the basis of this profile, the authors dubbed the cells glycolytic beige fat (g-beige fat). The data indicated that the transcription factor GABPα drives the differentiation of MyoD-expressing progenitors into g-beige fat cells. The authors confirmed this supposition in vitro, showing that overexpression of GABPα in muscle progenitors leads to their differentiation into fat.
Chen et al. next demonstrated that g-beige fat has a physiological role in mice, mainly burning sugar to produce heat. G-beige fat was generated in wild-type animals subjected to prolonged, harsh cold conditions. Moreover, animals engineered so that they could not produce g-beige fat showed reduced glucose uptake and oxygen consumption in fat compared with controls; their ability to control their body temperature in response to cold was also impaired.
The authors’ findings are exciting for several reasons. First, this study reinforces the idea that mature fat is composed of various cell types8,9. It is plausible that other subpopulations of brown, beige and even white fat cells exist. These cell types might have different roles in regulating body-wide metabolism. Furthermore, it is possible that the g-beige fat cells have functions besides thermogenesis. For example, in recent years it has become evident that brown fat communicates with other tissues by secreting specific signalling molecules10 — perhaps g-beige fat similarly modulates hormone signalling in the body to promote cross-talk with other fats or other tissues.
Second, g-beige fat is induced through a previously unknown pathway, which might be targeted specifically to improve glycolytic control — a key factor in the treatment of type 2 diabetes. And if these cells are also present in humans, their characterization might pave the way for new approaches to activating thermogenic fat cells. For such approaches to be successful, researchers would first need to determine how g-beige fat is induced, including which receptors and subsequent signalling cascades trigger GABPα-mediated differentiation.
In light of the current obesity epidemic, efficient and safe approaches are required to regulate excess body weight. The discovery of g-beige fat could provide a sweet way to do just that.
Nature 565, 167-168 (2019)