Short ribs glazed in a sweet sticky sauce and slow-cooked to perfection, potato chips hand-fried and tossed with a generous coating of sour cream, chicken wings battered and double-fried so that they stay crispy for hours. What is it about these, and other, mouth-watering — but incredibly fatty — foods that makes us reach out, and keep coming back for more?
How they taste on the tongue is one part of the story, but to really understand what drives “our insatiable appetite for fat,” we have to examine what happens after fat is consumed, says Columbia University’s Charles Zuker, a neuroscientist and molecular geneticist who has been a Howard Hughes Medical Institute (HHMI) Investigator since 1989.
Two years ago, Zuker and his team reportedexternal link, opens in a new tab how sugar, upon reaching the gut, triggers signals that are sent to the brain, thus fueling cravings for sweet treats. Now, in an article published in Nature on September 7, 2022, they describe a similar gut-to-brain circuit that underlies a preference for fat.
“The gut is the source of our great desire for fat and sugar,” says Zuker.
The topic in question is an incredibly timely one, given the current global obesity epidemic. An estimated 13 percent of adults worldwide are obeseexternal link, opens in a new tab — thrice that in 1975. In the US, that figure is even higher — at a staggering 42 percentexternal link, opens in a new tab. “It’s a very significant and important health problem,” says Zuker.
Having a high body-mass index is a risk factor for stroke, diabetes, and several other diseases. “It’s clear that if we want to help make a difference here, we need to understand the biological basis for our strong appetite for fat and sugar,” he says. Doing so will help us design interventions in the future to “suppress this strong drive to consume” and combat obesity.
To elucidate what drives our preference for fat, Mengtong Li, a postdoctoral associate in Zuker’s lab at Columbia, led a series of experiments using mice. From various earlier studies, the researchers suspected this preference occurs after ingestion, similar to what happens with sugar.
To test their hypothesis, they offered the animals two bottles — one containing an artificial sweetener, the other containing fat. While both options were equally attractive at the start, the latter was the clear favorite 48 hours later. Because artificial sweeteners send signals to the brain only upon hitting the tongue but not after they’ve been swallowed, the mice’s behavioral switch proved the researchers’ hunch right: that fat continues to alert the brain to its presence post-ingestion even after it reaches the gut, thus driving our desire for it.
This behavioral assay was a crucial first step in the study, says Li. “Because we could then begin to dissect where the fat-sensing circuit is and to see its impact on both physiology and behavior.”
The circuit runs from the gut to the brain, as further experiments using knock-out mice and various molecule-specific inhibitors revealed. The team found that fat sensing occurs via a series of steps: upon entering the gut, fat binds to special receptors; this, in turn, transmits signals to neurons via the gut-brain axis, which then activates neurons in the brain stem. The end result is that the rest of the brain receives a message: fat has been consumed and it feels great.
Interestingly, the team identified two parallel gut-to-brain signaling pathways. One is triggered only by intestinal fat, while the other is a more generic pathway that gets activated by any of the three essential nutrients: fat, sugar, or amino acids. The latter employs the hormone cholecystokinin (CCK) as a neurotransmitter to send the signals.
“The basic biology behind fat preference that they’ve uncovered is really fascinating,” says molecular neurobiologist Stephen Liberles an HHMI Investigator at Harvard University who was not part of the new paper. Unlike our external sensing system for touch, taste, smell, and so on, interoception — how the body receives information from internal organs — is not as well understood, he says. “So, the clarification of receptors for ingested fats is a very exciting advance.”
Zuker’s group is now studying what happens to the fat-triggered signals once it reaches the brain stem. “They need to be broadcasted to the rest of the brain to ultimately activate the circuits that give you this motivation to keep consuming fat,” says Zuker.
Mengtong Li et al. “Gut-Brain Circuits for Fat Preference.” Nature. Published online September 7, 2022. doi: 0.1038/s41586-022-05266-z