Page 21 - Abacoa Community News - October '22

Abacoa, Page 21

Scripps Research from page 20 activated solely in the liver, only secreted proteins related “The discovery of
to that organ system were highlighted – displaying the high these neurons suggests
communication specificity of the model as well. for the first time that
with each other. “Given the central role of key secreted proteins such as your brain is actively
During exercise, for insulin, there is a great deal of interest in identifying novel surveying your fat,
example, muscles secreted proteins,” said Andrew McMahon, Ph.D., senior rather than just passively
send out signals to author of the study and chair of the Department of Stem receiving messages
fat and liver tissue to Cell Biology and Regenerative Medicine at the University about it,” says co-senior
release their energy of Southern California. “Genome studies are suggesting author Li Ye, Ph.D.,
sources. While these that many new proteins remain to be characterized. We’re the Abide-Vividion
communication looking forward to a deep dive into this area now that we Chair in Chemistry and
networks play a have validated the technology.” Chemical Biology and
critical role in our There are countless research applications for this an associate professor
bodies every day, it A novel mouse model for mapping technology, Droujinine notes. With this type of model, of neuroscience at Scripps Research. “The implications of
has been historically protein communication between scientists can start to map unexplored disease pathways and this finding are profound.”
difficult to uncover organs. Proteins are labeled by ultimately develop targeted treatments, as many diseases “This is yet another example of how important sensory
su c h p a t h wa ys. biotin and their movement in the originate in a single organ and then eventually spread neurons are to health and disease in the human body,” says
Scientists at Scripps body can be tracked. Photo credit – to others. Cancer, with its metastatic properties, is one co-senior author and professor Ardem Patapoutian, Ph.D.,
Research, University Scripps Research and University of example. For another, studies have shown that many of the who is also a Nobel laureate and a Howard Hughes Medical
of Sout he rn Southern California. health complications that arise from obesity could be due Institute investigator.
Ca l i forni a a nd to faulty organ communication, yet many of the molecular In mammals, adipose tissue stores energy in the form of
elsewhere have now successfully created a model to label mechanisms remain unknown. fat cells and, when the body needs energy, releases those
and track the protein signals that enable organ-to-organ “Any protein we discover that plays a role in disease has the stores. It also controls a host of hormones and signaling
communication. potential to be translated into a therapeutic,” adds Droujinine. molecules related to hunger and metabolism. In diseases
As the researchers described in Open Biology on Aug. 10, In addition to Droujinine and McMahon, authors of the including diabetes, fatty liver disease, atherosclerosis and
their new mouse model marks the proteins that a cell secretes study, A genetic model for in vivo proximity labelling of the obesity, that energy storage and signaling often goes awry.
and tracks their movement throughout the body. This novel mammalian secretome, include Rui Yang, Amanda S. Meyer, Researchers have long known that nerves extend into
technology could shape our molecular understanding of Jinjin Guo, Jill A. McMahon of the University of Southern adipose tissue, but suspected they weren’t sensory neurons
healthy versus diseased tissue, as well as the role that inter- California (USC); Namrata D. Udeshi, Dominique K. Carey, that carry data to the brain. Instead, most hypothesized that
organ communication plays in disease onset and progression. Charles Xu and Steven A. Carr of Broad Institute of Harvard the nerves in fat belonged mostly to the sympathetic nervous
“This new model can be likened to establishing a and MIT; Yanhui Hu, David Rocco and Norbert Perrimon system – the network responsible for our fight-or-flight
passport system in the body, as we are identifying where of Harvard Medical School; Qiao Fang of University of response, which switches on fat-burning pathways during
proteins are coming from and where they’re going,” says Toronto; Jihui Sha and James Wohlschlege of UCLA; times of stress and physical activity. Attempts to clarify the
study co-first author Ilia Droujinine, Ph.D., Scripps fellow Shishang Qin of Peking University; and Alice Y. Ting of types and functions of these neurons have been difficult;
and principial investigator in the Department of Molecular Chan Zuckerberg Biohub. methods used to study neurons closer to the surface of the
Medicine at Scripps Research. “We can finally bring these This work was supported by a NIH Transformative R01 body or in the brain don’t work well deep in adipose tissue,
interconnected communications networks to light, and then grant 5R01DK121409 to A.P.M., A.Y.T., S.A.C. and N.P., where nerves are hard to see or to stimulate.
develop treatments based on this new knowledge.” and HHMI funding to N.P. I.A.D. acknowledges support Ye and colleagues developed two new methods that
Researchers have used other methods, such as viral from the Ellen Browning Scripps Foundation. enable them to overcome these challenges. First, an
approaches, to understand protein secretion and the ways imaging approach called HYBRiD turned mouse tissues
that organs communicate with each other. While these Scripps Research transparent and allowed the team to better track the
techniques have provided invaluable insight into the paths of neurons as they snaked into adipose tissue. The
proteins expressed in an organism, they aren’t sensitive Scientists Eavesdrop On researchers discovered that nearly half of these neurons
enough to label low-abundance proteins, or the origin didn’t connect to the sympathetic nervous system, but
and ultimate destination of protein interactions. But with Communication Between Fat instead to dorsal root ganglia – an area of the brain where
this new model, scientists are now able to understand the And Brain all sensory neurons originate.
exact path a particular protein takes. To better probe the role of these neurons in adipose tissue,
In the study, the researchers used an enzyme called the group turned to a second new technique, which they
BirA*G3, which labels secreted proteins with a biotin Newly discovered sensory neurons send messages from named ROOT, for “retrograde vector optimized for organ
tag. These biotin labels were then detected in live mice fat tissue to the brain and could eventually be co-opted to tracing”. ROOT let them selectively destroy small subsets of
using a method called quantitative mass spectrometry treat obesity or metabolic disease. sensory neurons in the adipose tissue using a targeted virus
proteomics, which is used to measure proteins in a sample. What did the fat say to the brain? For years, it was and then observe what happened.
This revealed where the proteins originated from and assumed that hormones passively floating through the blood “This research was really made possible by the way these
where they traveled to in the body. were the way that a person’s fat – called adipose tissue – new methods came together,” says Yu Wang, a graduate
When BirA*G3 was broadly activated throughout the could send information related to stress and metabolism to the student in both the Ye and Patapoutian labs and first author
body, the researchers found that all secreted proteins were brain. Now, Scripps Research scientists report in Nature that of the new paper. “When we first started this project, there
successfully labeled, even low-abundance proteins with newly identified sensory neurons carry a stream of messages weren’t existing tools to answer these questions.”
hormone-like properties. Likewise, when BirA*G3 was from adipose tissue to the brain. The experiments revealed that when the brain doesn’t
receive sensory messages from adipose tissue, programs
triggered by the sympathetic nervous system – related to
the conversion of white fat to brown fat – become overly
active in fat cells, resulting in a larger than normal fat pad
with especially high levels of brown fat, which breaks down
other fat and sugar molecules to produce heat. Indeed, the
animals with blocked sensory neurons – and high levels of
sympathetic signaling – had increased body temperatures.
The findings suggest that the sensory neurons and
sympathetic neurons might have two opposing functions,
with sympathetic neurons needed to turn on fat burning and
the production of brown fat, and sensory neurons required
to turn these programs down.
“This tells us that there’s not just a one-size-fits-all
instruction that brain sends adipose tissue,” says Li. “It’s
more nuanced than that; these two types of neurons are acting
like a gas pedal and a brake for burning fat.”
The team doesn’t yet know exactly what messages the
sensory neurons convey to the brain from adipose tissue,
only that the connections and communications are key for
keeping fat healthy. They are planning future research into
what the neurons are sensing and whether other similar cells
exist in additional internal organs.
Other authors of the paper, The role of somatosensory
innervation of adipose tissue, were Yu Wang, Verina Leung,
Yunxiao Zhang, Victoria S. Nudell, Meaghan Loud, M. Rocio
Servin-Vences, Dong Yang and Kristina Wang of Scripps
Research; and Maria Dolores Moya-Garzon, Veronica L. Li,
and Jonathan Z. Long of Stanford University.
Funding was provided by the Howard Hughes Medical
Institute, the National Institutes of Health (R35 NS105067,
NIH Director’s New Innovator Award DP2DK128800,
NIDDK K01DK114165), the Whitehall Foundation, the
Baxter Foundation, a Helen Dorris Scholars fellowship,
a Damon Runyon Cancer Research Foundation Merck
fellowship (DRG-2405-20), and a Fundacion Alfonso Martin
Escudero postdoctoral fellowship.