Brain and fat are well acquainted with each other. We know, for example, that fat cells secrete hormones that signal the brain when to stop eating. This exchange of messages can be rather slow, though, as it takes time for hormones to travel from fat into the bloodstream to the brain.
A study published August 31 in Nature, however, suggests that fat may be sending much faster messages to the brain. The work provides evidence that somatosensory cells—the ones that warn us if something is cold or painful—innervate the adipose tissue of mice, hinting that these neurons may sense something in the fat, potentially prompting a reaction as fast as jerking a hand away from a hot stovetop. But what that something might be, and its effects on the brain, remain unknown for now.
This is a “really nice paper,” says University of Oxford neuroscientist Ana Domingos, who was not involved in this study. The prospect it raises of hitherto unknown biological mechanisms involved in metabolic control is almost “revolutionary,” she says, and motivates “new ways of thinking about metabolism.”
In 2015, Domingos and her colleagues reported the presence of axon terminals of sympathetic nerves in the adipose tissue in mice; those terminals send messages from brain to fat, triggering its breakdown. However, much less was known about whether a different type of nerves, sensory cells, have projections to this tissue—the phenomenon had been suggested by indirect evidence but was debated.
What are these sensory neurons sensing? What’s there to be sensed?
—Ana Domingos, University of Oxford
Li Ye, a neuroscientist at the Scripps Research Institute in San Diego and coauthor of the paper, says that while “developing large scale, whole body imaging methods” to test how the mouse brain communicates with peripherical organs in general, he and his colleagues observed fibers coming from the dorsal root ganglia, near the spinal cord, into the fat tissue. Their origin indicated these were sensory nerves. The team found this quite surprising, he says, since it was not clear, based on previous work, whether any innervation was actually occurring, nor to what extent. These initial observations prompted Ye and his colleagues to explore the issue further, while at the same time refining the methodologies needed to address it.
One of these tools was an imaging technique based on hydrogel that makes mouse tissues transparent. This enabled the team to trace fluorescent sensory nerves from their origin to the adipose tissue. This visualization of the sensory nerves in fat revealed not only that they reach this tissue, but that they do so in relatively large volumes: The magnitude of sensory innervation the team observed in fat is comparable to that of sympathetic nerves in that same tissue, and to that of sensory nerves themselves in the skin near the fat, Ye notes.
Fluorescent sensory neurons project from their origin, near the spinal cord (top), into the fat tissue (bottom) of an adult mouse.
Ye and his colleagues then asked what the function of these sensory nerves is. They first sought a way to target and remove them, engineering a viral vector to specifically kill sensory cells projecting to the fat of live mice.
Being able to target these nerves without “any collateral damage” to other types of neurons is one of the strongest achievements of this work, says Claus Brandt, a researcher at the Centre for Physical Activity Research, Rigshospitalet, in Copenhagen, who did not participate in the study.
The team measured how the destruction of these sensory neurons affected gene expression in the mouse fat pads. They found that the nerves’ loss results in an increased expression of genes involved in thermogenesis and lipid metabolism, both of which are known to be triggered by the sympathetic nerves and are related to the process of converting white fat—which primarily stores lipids—to brown fat, which burns them to generate heat. This suggests that sensory and sympathetic nerves have opposite effects on fat, although the significance of this is unclear.
In fact, experts who spoke with The Scientist about the findings all agree that they raise multiple questions. For instance, sensory nerves in muscle and skin have a fast temporal resolution for reaction, “so there must be some innervation in fat that reacts to something within milliseconds,” Brandt says. “Why would we need that time precision in terms of metabolic control?” asks Domingos.
Brandt adds that it would be “extremely interesting to see what actually activates these neurons” and to what part of the brain their signal goes. In other words, as Domingos wonders, “What are these sensory neurons sensing? What’s there to be sensed?” This is “like the million-dollar question,” Ye notes, adding he suspects it is one of the classic stimuli associated with these nerves—heat, cold, touch, chemical signals, pain—but which one is an enigma. He and his colleagues, he says, are now working on finding out.