translated from Spanish: Neurosciences It’s sweet and your brain knows it

While we know that sugar is a fundamental source of energy, we also know that an excess of sugar in our diet is harmful to health, leading to diseases such as feared diabetes and widely diagnosed obesity, which, if not taking the necessary measures, can have a great negative impact on our lives. These facts should not be taken lightly, as, although there is a tendency in the country recently to opt for sweeteners as a healthier alternative, we remain one of the countries with the highest rate of obesity and per capita sugar consumption. However, if you have difficulty leaving sugar, and no matter how hard you try, sweeteners simply can’t evoke the same pleasurable feeling that sugar can cause, don’t be alarmed, you’re not alone or alone.
The truth is that, due to the high energy power of this compound, the entire animal kingdom has developed neural circuits intended to seek, recognize and motivate sugar consumption, and in most species, including humans, the recruitment of this circuitry involves brain regions that regulate not only energy consumption, but also, reward and pleasure , which is why the medical and scientific community recognizes the arduous task of limiting the consumption of this sweet sin. 

Having said that, perhaps one would think that it would only be enough to replace sugar, or, more specifically glucose, which is the main sugar within a large family of molecules, with some of its well-known alternatives, such as natural or synthetic sweeteners. However, a study by Dr. Charles S. Zuker’s research team at Columbia University in New York, USA, showed that by giving lab mice the option to consume glucose-sweetened or artificially sweetened water after 48 hours, mice prefer to consume only glucose water, even though for the first 15 hours , do not denote a preference. This observation led Dr. Zuker to think that there must be a strong reason for mice, not knowing ways to sweeten their drinking water and having access to different freshwater bottles, to continue to prefer glucose over long-term sweeteners. For this reason, they set out to investigate the ways in which our brain processes a taste or preference for different flavors or nutrients. 
Initially, they thought it could be due to caloric input, as sweeteners are not able to be processed like glucose, and end up being expelled from our body almost intact. However, when they replaced glucose with a non-metabolizable insipid analogue substitute, that is, it has a similar molecular form, capable of activating the same receptors, but that no energy can be obtained from it or has a sweet taste, they re-observed that the mice developed a strong preference for this analogue compared to sweetener. This gave researchers that the system responsible for developing this behavior recognizes the sugar molecule and not its caloric content or metabolic products.
Based on these early results, the researchers thought that for an animal to develop a preference for glucose over sweetener, it should be able to recognize and distinguish between two equally attractive sweet stimuli, so they thought that if they identified the population of neurons that selectively responded to sugar consumption, they could come close to revealing how the preference and basis of the desire for sweetness is controlled.
Gut-brain axis
In order to answer this question, they exposed the animals again to glucose, sweetener or just water, and examined, using fluorescence analysis techniques, what neurons in the brain were «on» when the mouse consumed the different options. This revealed significant activation in a region of the brain known as the lone tract nucleus (NTS) when mice consumed glucose, which was not observed when opting for water with sweetener or just water. Interestingly, with the tasteless substitute they obtained the same neural response, indicating that the taste is not really relevant to obtain the same result when developing the preference. This also led them to think that the flavor receptors present in the language were perhaps not responsible for generating this marked difference, so Ior next they did was administer directly to the stomach, using an intragastric tube, in order to avoid passage through the tongue and its flavor receptors and confirm this suspicion. In conducting this experiment, they observed the same pattern of activity as NTS neurons, showing that taste is not really relevant, but it is the sugar molecule that alone can generate the behavior of preference, and not only that, but also, when the main nerve pathway of communication between intestine and brain, the vagus nerve, or when the NTS neurons «turned off» genetically, this response ceased to be observed, realizing the uniqueness of the intestinal-brain axis and how it affects the behavior of animals. 
Once they had identified the neural pathways involved in the preferred response to glucose, the researchers wondered who was responsible at the gut level for generating this choice, or how glucose was specifically recognized in the gut. This is why they studied the sensors present in the tissue that are able to activate responses when exposed to different sugars. Within these, the molecule responsible for capturing glucose in the gut, known as SGLT1, is expressed in two types of cells, so-called enteric cells and enteroendocrine cells, which are thought to function as mediators of communication between the gastrointestinal system and the vagus nerve, as they secrete a wide variety of hormones and bioactive molecules, which are considered as «messages» within the body. Specifically, SGLT1 is able to recognize glucose and gal lactose, another type of sugar present in different foods such as dairy and legumes, and both molecules are able to activate the same NTS cells, which does not occur when mice are given other sugars that are not SGLT1 activators, such as fructose and mane, both present in fruits and vegetables, or when the action of SGLT1 prior to glucose intake is pharmacologically blocked. This tells us that this circuit is dedicated only to generating preference for glucose, and not to other sugars that can be commonly ingested in the daily diet. 
The results that Dr. Zuker and his team had obtained up to this point allowed them to describe a bowel-neural circuit in a very detailed way, which ensures that the animals so eagerly desire to consume sweet foods. Finally, they wondered whether selectively activating this circuit makes it possible to change the preference to foods other than consumer taste. To find the answer, scientists genetically modified NTS neurons, using a technique known as DREADDsmeaning «designed drug-activated receptors». This technique is very useful for investigating the communication pathways between our organs, since with it you can insert receptors into specific cells that you want to study, which can only be activated by drugs, or molecules, which are completely harmless to the body. Therefore, the researchers inserted DREADDs in the NTS neurons of mice, and then proceeded to give them two options of sweetened drinks with artificial flavorings: one very sweet and popular among mice, cherry, and another not so sweet and that, therefore, rodents did not like much, grape. Unsurprisingly, all the mice preferred the cherry drink, but when they added the molecule that activated the DREADDs present in NTS neurons, mice changed their preference, and after 48 hours, rodents consumed almost exclusively grape drink. With this end result, the researchers not only confirmed their suspicion, but were also able to Hack to the circuit.
The results obtained by Dr. Zuker’s research team describe a new communication circuit between our gut and brain and reveal that even though we limit our sugar intake to opt for a healthier life, it is very difficult to deceive the brain, although in humans it is not impossible.
So the next time you come up with that tremendous urge to eat something sweet, having been limiting your sugar intake by using artificial sweeteners, remember that it’s just your brain missing its precious delicacy.
Reference: https://www.nature.com/articles/s41586-020-2199-7
* This article arises from the agreement with the Interdisciplinary Center of Neuruniversity of Valparaiso.
 

Original source in Spanish

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