You may have heard online chatter about protein being the best food group to keep you feeling full and satisfied after a meal. Beijing brain boffins challenged themselves to find out- is this fact or just a gut feeling? Surprisingly they discovered that not only does the protein make you less hungry, but brains have specific neurons that track how much protein we’re eating.
Your Brain on Insulin
We know that dietary proteins promote insulin secretion, and the suppressive effect of insulin on food intake has been long documented.1, 2 What we didn’t know until now, was what this elevated insulin was doing… Why would Protein be triggering insulin- the hormone that controls our blood sugar?
This may be surprising if you have only heard about insulin in the context of blood glucose levels (e.g. in diabetes), but insulin also acts on our brains. 3 In fact, our braincells can make insulin too. Because a brain is so busy, it needs fast access to energy and to be able to control sugar levels very precisely. Neurons don’t have time to wait for insulin to make it’s way up from our pancreas in our blood if they need a boost.
Researchers based at Beijing’s Chinese Academy of Sciences teamed up with colleagues at the University of California San Francisco and Johns Hopkins Medical School to find out why and how our bodies respond differently to a plate of steak than to a plate of fries.
By taking a look into the brain circuitry of fruit flies, these researchers discovered that a specific pair of protein intake-activated neurons tells the brain when it’s time to stop eating more protein.1 Preventing these two neurons from activating, blocked the appetite supressing effects of protein, suggesting that these neurons were controlling the flies’ hunger pangs.
Unravelling the Mystery
The takeaway? Brain-derived insulin signals triggered by protein consumption do result in protein-specific feeding inhibition.1 That is, eating protein makes you less hungry. It all comes down to a single pair of neurons, tritocerebrum 1-dopaminergic neurons (T1-DANs).
By feeding fruit flies different types of diet and then closley examing their brains, the researchers were able to construct a map of the processes in the brain that go on when the flies ate a lot of protein.
The researchers discovered that eating protein triggered insulin-producing cells in the brain to activate appetite-suppressing neurons via a chemical signal known as DILP2.1 When they compared the reponses of the neurons to protein or to a sugar-based diet, they found that these neurons were only detecting signals from insulin triggered by protein.1
Blocking these neurons only affected flies that ate protein, flies eating sugar kept mucnhing away.
The T1-DANs then communicated with another set of neurons located in a specific area of the fruit fly brain, the protocerebral bridge, sending off a ‘feeding termination’ signal that tells the fly to stop eating. 1
Here Comes The Science Part
So how did they get from feeding protein to a little fruit fly, to mapping the brain circuitry that controls appetite? To help you understand how scientists are able to come to these types of conclusions, we’re going to walk through the experiments they did step-by-step.
The researchers were able to figure out this process by starting with what they knew, forming a hypothesis, and asking questions based on the data they were generating.
They guesed that dopaminergic neurons were somehow stimulated by protein and involved in generating ‘I’m full’ signals, but they didn’t know how and through which specific groups of dopaminergic neurons.
What’s Going on In Your Head?
Ever wished you could see what’s going on inside someone’s head? Turns out molecular biologists can do just that.
To watch what was happening in a fly’s brain, they labelled the different groups of neurons in the live flies using molecular tags. This allowed the resaerchers to tell groups of neurons and individual brain cells apart using a microscope. It also made it easy for them to target indivdual cells. They were able to inactivate individual neurons one at a time to see what happened to the fly’s eating habits.
The scientists would switch off the neurons, flood the fly with fly-insulin and see whether the the fly changed it’s behaviour. By doing this to each dopaminergic neuron in turn, and observing if there was a corresponding appetite-suppressing response, they were able to identify the specific neurons involved, the T1-DANs.
Well, that was the researchers providing an insulin signal themselves. They then wondered wanted if this same activation could be achieved on its own through diet.
Probing with Protein
The scientists compared a protein and sugar-based diet and found that the T1-DAN neurons were only activated by protein feeding.
Next they looked for a chemical signal that was only released in response to protein. Humans and mammals make insulin to help us store exess blood glucose and control how we release energy when we need it. Flys don’t have the same insulin gene that we have, but they do have eight mini versions that make signals very similar to insulin with the same jobs. Like us, when a fly’s pancreas cells or other select insulin-making cells detect chemical components of sugar or protein, they make insulin-like molecules. When the researchers tested the flies for different types of insulin-like molecule, they found that DILP2, was elevated in the flies after eating protein, but not sugar consumption. DILP2 is one of eight fruit fly versions of insulin.
Bridging the gap
So how did they get from flies making a subtype of their version of insulin when they eat protein, to specialised brain cells telling you to stop eating? Were the two things linked or was it a coincidence? Could the T1-DAN neurons be being triggered directly by DILP2, or was some other process going on? Was DILP2 triggereing a complicated set of chemical responses that travelled though a whole neural pathway? Were other neurons connected to the stomach detecting the protein?
The researchers started by labelling the two T1-DAN neurons and the insulin making brain cells with fluoresent tags and looked for them with a microscope. Surprisingly, they found that the two sets of cells were geoographically located very close to each other in the fruit fly brain. Could there be some kind of direct communication between these DILP2 making cells and the T1-DAN neurons going on?
To confirm this, they created a sort of chemical funnel. The scientists added a toxin that prevented T1-DAN cells from talking to other neurons. This meant that they could test whether the signal to stop eating was coming from another set of neurons or whether the neurons were detecting DILP2 being pumped out by the insulin making cells. They found that when they blocked the signals from other neurons protein still triggered the T1-DAN response to stop eating, confirming that the T1-DANs were receiving the insulin-like signal directly from those cells.
Are we T1-DONE?
Kind of. At this point, the researchers wanted to know two things: what happens next and what makes this process specific to protein? The researchers found that the T1-DANs form a direct and dense connection with neurons in the protocerebral bridge, a part of the insect brain analogous to the human basal ganglia. 1
They looked at how the communication between these neurons changed under different feeding conditions (i.e. protein vs sugar) and found the brain activity in the protocerebral bridge was enhanced only after protein intake, eliciting an ‘I’m full signal’ to the fly.
What does it all mean?
Well, the research seems to suggest that the insulin system in the brain serves as a kind of ‘hub’ for food satiation for different nutrients. 1 Our brains have evolved an incredibly sophisticated system that allows the various receptors and cells involved in this process to identify and respond differently depending on what we’ve eaten.
Like a long fly-ght, it might take a while to figure out how the specifics of this system will translate in humans, but let’s enjoy a protein bar while we wait!
References
- Li X, Yang Y, Bai X, et al. A brain-derived insulin signal encodes protein satiety for nutrient-specific feeding inhibition. Cell Reports. 2024;43(6). doi:10.1016/j.celrep.2024.114282
- Rietman A, Schwarz J, Tomé D, Kok FJ, Mensink M. High dietary protein intake, reducing or eliciting insulin resistance? Eur J Clin Nutr. 2014;68(9):973–979. doi:10.1038/ejcn.2014.123
- Schur EA, Tong J. Insulin Action to Inhibit Food Intake: Is It All in Your Head? The Journal of Clinical Endocrinology & Metabolism. 2022;107 (2): e874-e876. doi:10.1210/clinem/dgab661
- Powell SK, O’Shea C, Townsley K, et al. Induction of dopaminergic neurons for neuronal subtype-specific modeling of psychiatric disease risk. Mol Psychiatry. 2023;28(5):1970–1982. doi:10.1038/s41380-021-01273-0
- Watson S. Dopamine: The pathway to pleasure. Harvard Health. Published July 20, 2021. Accessed July 8, 2024. https://www.health.harvard.edu/mind-and-mood/dopamine-the-pathway-to-pleasure
