A research team led by Scripps Research Institute scientist Dr. Supriya Srinivasan has identified a brain hormone that appears to trigger fat burning in the gut.
Model depicting the FLP-7/NPR-22 neuroendocrine axis that underlies the 5-HTergic control of body fat loss. In the nervous system, an integrated 5-HT and octopaminergic circuit stimulates body fat loss. In this study, we report the discovery of a tachykinin signalling system that underlies the 5-HTergic control of body fat loss in C. elegans. The FLP-7 neuroendocrine peptide is secreted from the ASI neurons in response to 5-HT and Oct-mediated signalling. The nutrient sensor AAK-2/AMPK acts in the ASI neurons via the CREB co-regulator CRTC-1 to regulate FLP-7 release in response to 5-HT-encoded signals of food availability. Upon release, FLP-7 acts in the intestine via the NPR-22/NK2R receptor to stimulate the ATGL-1 lipase, which drives fat loss. The identification of FLP-7 and NPR-22 addresses a long-standing question about the molecular basis of the central effects of 5-HT on fat loss in peripheral tissues. Image credit: Lavinia Palamiuc et al, doi: 10.1038/ncomms14237.
Previous studies had shown that serotonin — a neurotransmitter involved in the transmission of nerve impulses — can drive fat loss. Yet no one was sure exactly how.
To answer that question, Dr. Srinivasan and co-authors experimented with nematode worms called Caenorhabditis elegans.
They deleted genes in the worms to see if they could interrupt the path between brain serotonin and fat burning.
By testing one gene after another, they hoped to find the gene without which fat burning wouldn’t occur.
This process of elimination led them to a gene that codes for a neuropeptide hormone they named FLP-7.
Interestingly, the team found that the mammalian version of FLP-7 (called tachykinin) had been identified 80 years ago as a peptide that triggered muscle contractions when dribbled on pig intestines.
Biologists back then believed this was a hormone that connected the brain to the gut, but no one had linked the neuropeptide to fat metabolism in the time since.
The next step in the current study was to determine if FLP-7 was directly linked to serotonin levels in the brain.
The researchers performed this task by tagging FLP-7 with a fluorescent red protein so that it could be visualized in living animals, possible because the C. elegans body is transparent.
Their work revealed that the hormone was indeed secreted from neurons in the brain in response to elevated serotonin levels.
FLP-7 then traveled through the circulatory system to start the fat burning process in the gut.
According to Dr. Srinivasan and her colleagues, the newly discovered fat-burning pathway works like this:
(i) a neural circuit in the brain produces serotonin in response to sensory cues, such as food availability;
(ii) this signals another set of neurons to begin producing FLP-7;
(iii) FLP-7 then activates a receptor in intestinal cells, and the intestines begin turning fat into energy.
Next, the researchers investigated the consequences of manipulating FLP-7 levels.
While increasing serotonin itself can have a broad impact on an animal’s food intake, movement and reproductive behavior, they found that increasing FLP-7 levels farther downstream didn’t come with any obvious side effects.
C. elegans continued to function normally while simply burning more fat.
“This finding could encourage future studies into how FLP-7 levels could be regulated without causing the side effects often experienced when manipulating overall serotonin levels,” Dr. Srinivasan said.
The research was published in the Jan. 27 issue of the journal Nature Communications.
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Lavinia Palamiuc et al. 2017. A tachykinin-like neuroendocrine signalling axis couples central serotonin action and nutrient sensing with peripheral lipid metabolism. Nature Communications 8, article number: 14237; doi: 10.1038/ncomms14237
This article is based on a press-release from the Scripps Research Institute.
