How the Fly Brain Knows When to Release Insulin

When lipid biologist Usha Acharya at the National Cancer Institute (NCI) tinkered with lipid breakdown pathways in Drosophila melanogaster, she observed something intriguing. Blocking a biochemical reaction led to a lipid molecule accumulating to levels high enough to activate stress responses in the flies. Despite this, the insects survived.

While exploring how the flies adapted to such conditions, Acharya found increased levels of an enzyme—CG8093—in their guts.¹ Curious, the team decided to dig deeper and study the enzyme, a lipase that breaks down fat. 

Now, her team has identified that the lipase is synthesized in the gut of Drosophila. In response to fatty foods, it travels from the gut to the brain to influence insulin production.² The results, published in Nature Communications, describe a molecular link between dietary fat and insulin secretion in the brain.

“We know that there are a lot of peptides and hormones in the gut that are released and their primary role is to affect physiology and behavior,†said Meet Zandawala, a Drosophila neuroendocrinologist at the University of Nevada, Reno and University of Würzburg, who wasnâ€t involved with the study. “But this is a different class of signaling molecules.â€

To investigate CG8093, Usha Acharyaâ€s team generated a fly line that expressed a green fluorescent protein-tagged version of the molecule in the gut. Using fluorescence microscopy, they tracked the glowing molecule all the way to the brain, where it was abundantly expressed in the pars intercerebralis, a region that contains insulin-producing cells. When the researchers analyzed gene expression maps of CG8093, they observed negligible levels in the brain and central nervous system compared to the gut, suggesting that CG8093 was synthesized in the gut before moving into the brain. 

The tradition of naming Drosophila genes after their functions inspired Usha Acharya to call the enzyme Vaha. “Vaha is the Sanskrit word for movement.â€

These findings indicate that Vaha can cross the blood-brain barrier (BBB), said Kandahalli Venkataranganayaka  Abhilasha, a lipid biologist in Acharyaâ€s team and coauthor of the study. The BBB allows only select molecules to access the brain, one of which is lipid transfer particle (LTP), he added.³ When they knocked down the gene encoding LTP, they observed a reduction in Vaha accumulation in the brain, confirming that LTP facilitates the lipaseâ€s movement into the brain. 

Although they identified the inter-organ crosstalk, it wasnâ€t immediately clear what prompted the production and transport of Vaha. The intestine perceives dietary information, so the team wondered whether nutrients influenced the lipaseâ€s expression in the gut. They increased either the fat or glucose content of the flies†diet by adding either a little coconut oil or sucrose to their food.⁴ Flies that consumed a high-fat diet showed increased Vaha gene expression and protein synthesis in the gut, as well as increased Vaha accumulation in insulin-producing cells in the brain. 

Focusing in on these cells, the researchers sought to understand how Vaha affected their production of peptides. Genetic deletion of Vaha resulted in reduced secretion of insulin-like peptide in the fly brain. 

This had downstream effects, causing elevated glucose and triglyceride levels, which decreased on supplementing the flies with Vaha. The Vaha mutants also exhibited altered metabolic pathways for glucose, a hallmark of a diabetic pathophysiology.⁵

In vitro assays solidified the lipaseâ€s role as a key mediator of insulin signaling. The researchers found that Vaha breaks down diacylglycerol, a lipid containing two fatty acid chains, into a monoacylglycerol, containing one fatty acid chain, and free fatty acids. When they supplemented these lipids in the flies†diet, they observed an increase in the release of insulin-like peptide in the brains. 

The finding that a lipase can detect local information, travel to another organ, and convey the information to modulate a response is amazing, said Jairaj Acharya, a lipid biologist at NCI, and a coauthor of the paper. The team was so surprised that a lipase travels from the fly gut to the brain that they spent almost two years validating this observation. “Usually in science, you see small molecules moving from one organ to another doing this communication,†Jairaj Acharya said. “But in this instance, there is actually a protein.â€

Such an inter-organ communication link between the gut and insulin-secreting pancreas likely exists in humans, Zandawala noted. He added that future work could explore whether Vaha regulates hormones other than insulin and determine whether other animals have a similar axis.

Abhilasha noted that they are already designing experiments using cocultured mouse intestinal and insulin-producing pancreatic beta cells to see if the gut secretes molecules that communicate with the pancreas.

Eventually, the research team would like to advance their experiments into organoids to test for an inter-organ crosstalk, said Usha Acharya. “But that will take us some time.â€