Desire for dietary lipids has been traced to the taste receptors CD36 and GPR120, and these have been found to be malfunctioning in both obese animals and humans, leading to low perception of fat levels in food.
The study was published online in Cellular and Molecular Gastroenterology and Hepatology. “Ours is the first study on targeting fat taste receptors, leading to [the] activation of tongue-gut loop as a therapeutic approach, and it opens new vistas to synthesize more potent chemical compounds to decrease progressive weight gain under [high-fat diet] consumption,” the authors wrote.
The perception of fat has recently been identified as a potential sixth basic taste quality, joining sweet, sour, bitter, salt, and umami. CD36 is expressed by taste cells, where it senses dietary long-chain fatty acids (LCFAs), and its deletion led mice to ignore LCFAs and oily solutions that they would otherwise prefer. GPR120 has also been proposed as a lipid sensor.
Previous researchers had suggested that CD36 may play a role in the preference for eating fats, while GPR120 could have a role in lipid satiation following consumption. “Our team also supported these conclusions and proposed that CD36 might be involved in immediate early detection [of fat in foods], whereas GPR120 will be responsible for post-ingestive regulation of lipid food intake,” the authors wrote.
The researchers showed that lipids bind to CD36 when they are present in low concentrations, but at high concentrations they bind to GPR120, suggesting that the two receptors are nonoverlapping but nevertheless complement one another during fatty acid–mediated signaling with taste bud cells (TBC). They are also coexpressed within the same type of TBC.
Experiments in rodents suggest that obese animals have reduced capacity to sense dietary fatty acids, which drives consumption of greater amounts. Fat-rich diets can also reduce fat taste perception, and this has been shown cross-sectionally in obese human subjects, and a single nucleotide polymorphism in CD36 that leads to a reduction in expression is linked to reduced perception of dietary fatty acids.
To test the idea that altering the receptors could change behavior, the researchers synthesized two novel fat taste receptor agonists (FTAs) that are derived from the LCFA linoleic acid, which is abundant in Western diets.
Using nerve recordings, the researchers confirmed that a message from TBCs is sent to the brain via the chorda tympani nerve, and the two FTAs increased the nerve signal. The signals from LCFAs alone were boosted with the addition of the FTAs, suggesting that these molecules can be effective even in the presence of dietary lipids. They also confirmed that FTAs activate the tongue-brain-gut loop by increasing pancreato-bile secretion more than linoleic acid alone.
Given the choice between two bottles, mice preferred the one containing FTAs, and the experiments indicated that FTAs are 95-142 times more potent than natural LCFA as food attractants.
It is well known that diet and lifestyle interventions rarely result in long-term weight loss, and products designed to mimic ‘fat-like’ texture – such as maltodextrin, inulin, and plant fibers – have had limited success because they do not have a fat-like taste and can lead to gastrointestinal side effects. Agonists of CD36 and GPR120 added to low- or noncaloric foods could boost their appeal and lead to earlier satiation.
Importantly, in obese mice, both TFAs led to decreased food intake as well as reduced weight gain and fat mass, without affecting lean mass. One of the agents also promoted a higher metabolic rate through increased energy expenditure.
The researchers also examined the agents’ effects on the microbiota of the obese mice, which contain high concentrations of bacteria belonging to the Lachnospiraceae family. Both inhibitors reduced the numbers of Lachnospiraceae bacteria, and promoted other bacterial families that may contribute to an anti-inflammatory effect. Obese animals exposed to TFAs also showed improvements in dyslipidemia, and there was evidence that they could reduce liver lipid concentrations.
There was no evidence of any mutagenicity, genotoxicity, or endocrine disruption. In sum, these new agonists might enable the development of novel treatments of obesity, which would have a major impact on human health.
The authors stated that they have no financial conflicts of interest. The study received financial support from institutions including the Société d'Accélération du Transfert de Technologies and the University of Burgundy.
This article was updated 2/15/23.
