Science of Sucralose: Can it Cause Weight Gain?
Looking at the figure below, there seems to be a direct correlation between the number of products containing artificial sweeteners and BMI. This article will explain the chemistry of one of the most popular artificial sweeteners and what to be aware of when consuming it.
[caption id="attachment_54780" align="aligncenter" width="577"] Source: Yale Journal of Biology and Medicine June 8, 2010: v83(2)[/caption]
Sucralose (marketed as Splenda) is a zero-calorie, chemically altered sucrose molecule, containing 3 Chlorine atoms in place of hydroxyl (OH) group. What this essentially does in dramatically change the polarity of the molecule, which in turn allows it to bind more tightly to your taste bud receptors.
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For example, this small chemical change to the molecule makes sucralose 600X sweeter than sugar. This is because sucralose forms key molecular interactions with your taste bud receptors that sucrose does not. 
These receptors are called chemoreceptors which means that when a molecule like sucralose binds, it triggers the brain to send a signal to the pathways that control different bodily functions, like hunger and release of dopamine. 
Since sucrose and sucralose are both disaccharides (two sugar molecules chemical bound, see figure below), they are susceptible to breaking down into two individual sugar molecules in the body which can raise insulin levels. This process is known as hydrolysis. The chemical changes in sucralose also slow down the reaction of hydrolysis 60x vs normal sucrose, which results in a much lower spike in insulin. 
This may be one of the reasons that sucralose has not been shown to increase post-prandial (post food consumption) insulin, ghrelin, or glucagon-like peptide-1 levels in multiple studies. 
However, since sucralose cannot be metabolized and broken down for energy in the body, many people use it as a way to satisfy a ?sweet tooth? craving without the calories of sugar. But is this a solid practice, especially if you?re trying to lose weight?
Artificial Sweeteners for Weight Loss?There have been a ton of studies examining the effects of non-calorie sweeteners and food consumption/energy regulation. One of the biggest paradoxes is that how can something with no calories cause weight gain in so many studies.
The answer is more in-depth than you think.
Sucralose and Energy RegulationYou see, your brain tightly regulates and correlates sweetness of food with the amount consumed. This is a learned behavior based on your body?s experiences with associating the consumption certain food with the amount consumed to prepare for the appropriate post-ingestive physiologic response. When sugar is substituted with sucralose, it alters your brain?s perception of food intake and energy regulation.
Repeated exposure to low-energy foods containing sucralose may lead to a non-cognitive expectation that their consumption would not contribute much caloric energy to the diet.
Thus, if presented with the same amount of food but with real sugar, your brain will rely on past consumption history instead of actual energy value, which can trick your body into eating more to satisfy its perceived caloric value.  This is one theory on how zero-calorie sweeteners have been contributing to weight gain and obesity in recent years.
Sucralose and Gut MicrobiotaAnother possible mechanism for the association between sucralose (and other artificial sweeteners) and weight gain is the possibility of negatively altering the gut microbiota. Studies have shown that changes in the type of bacteria in your gut can activate pro-inflammatory cytokines than can promote insulin resistance, fat storage, and weight gain.
A 12-week study in rats treated with Splenda (containing glucose and maltodextrin as fillers) significantly decreased beneficial fecal microflora (a 37-67.5% decrease in ?good bacteria? such as lactobacilli, bifidobacteria, and Bacteroids), as well as increases to the pH of fecal matter and body weight all at the lowest Splenda dose. 
Sucralose and the Brain's Pleasure-Reward CenterThere is also conflicting data on whether sucralose can affect the brain?s pleasure-reward system. This is the part of the brain where dopamine is released due to a behavioral pleasantness response.
In a 2007 study in 12 healthy women, subjects were given either a sucrose or sucralose solution and researchers measured brain taste pathway and downstream reward system for each group. While both groups exhibited a reward response, the sucrose group had more areas of the brain activated in a dose-dependent manner.
These findings suggest that sucrose may act on more taste receptors (despite sucralose being sweeter and binding more tightly) vs sucralose. One interesting finding was while the absolute brain response after sucralose was lower, the recruitment of related brain regions is stronger. This may be a reason for why sucralose has been shown to elicit a ?wanting? more feeling while clearly activating the brain?s reward system. 
Sweeteners and Hidden CaloriesOne final thing that applies to all commercially-available artificial sweeteners is that they all contain hidden carbs/calories when not consumed in their raw form.
Most people don't realize this, but each 1g packet contains about 50mg of sweetener and 950mg of fillers like dextrose and maltodextrin. Because of food labeling laws, anything containing less than 1g of carbs companies can list this as a zero-calorie food, despite there being calories.
For example, if you were to use 10 packets of Splenda a day, that's roughly 10g of carbs and 80kcal of fillers. These calories contribute nothing, as they don't contain and micronutrients or vitamins of any kind. These carbs/calories can be significant to someone who is dieting for a show or follows a low carb or ketogenic diet, as these are sugars that can affect insulin levels.
This does not pertain to companies using the raw form of sucralose as a flavoring agent. Your pre-workout or protein powder doesn't contain these hidden calories, only in the packet form.
Final ThoughtsIn summation, while Splenda may satisfy the sweet tooth craving you get when dieting, overuse of Splenda may hinder your weight loss goals via several mechanisms. Sucralose has been shown to induce a false sense of hunger, negatively alter your gut microbiota, and disrupt your brain?s pleasure-reward taste pathway.
Lastly, beware of hidden calories, carbs and fillers in those ?calorie free? packets of Splenda on the restaurant counter, as they may unknowingly disrupt your daily macros without offering any benefits.
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