Researchers investigate weight management cells and molecules

09 Jun 2020 --- Research is continuing to shed light on factors that may cause people to gain or lose weight. UK researchers from the University of Warwick found that cells in the brain called tanycytes increase appetite when stimulated by light. Meanwhile, scientists from Virginia Tech, US, uncovered a small mitochondrial uncoupler, named BAM15, that decreases the body fat mass of mice without affecting food intake and muscle mass or raising body temperature. These breakthroughs could be early steps in exploring treatment pathways for obesity, which affects over 40 percent of US adults, and 13 percent of the global population.

“The link between tanycytes and feeding is complex as they activate two opposing pathways. In this study, the pathway that increases feeding ‘won.’ There may be other circumstances where this does not happen, for example, different times of day and different types of food. Therefore, we need to understand why and how tanycytes function before we can make recommendations on how this could be used to control body weight. If not, you might get completely the opposite result of what you were hoping for,” Nicholas Dale, study author and Professor at the School of Life Sciences at the University of Warwick, tells NutritionInsight.

Tanycytes are glial cells located in the middle of the brain where they line one of the fluid-filled spaces known as ventricles. Here, the tanycytes can sense or “taste” the nutrients in the cerebrospinal fluid within the ventricle. The study concluded that tanycytes also deliver signals to neurons in the brain to activate appetite.

By getting tanycytes to selectively express a light-sensitive ion channel, the scientists could activate them very specifically and show that this causes nearby neurons to become active. Moreover, the researchers looked at the identity of the activated neurons and found that the tanycytes could turn on two different pathways involved in the control of feeding.

While one pathway is associated with an increased drive to feed, the other is associated with reduced appetite and greater energy expenditure. However, this alone is not enough to know which of these two opposed pathways “wins.” However, the researchers showed it results in a short-term increase in food intake.

The image shows the tanycytes expressing the light-sensitive ion channel (green), a general tanycyte marker (vimentin, red) and a stain for the cell nucleus (blue). (Source: The University of Warwick)Multifunctional cells
Tanycytes work by responding to amino acids found in foods via the same receptors that sense the umami flavor of amino acids, which are found in the taste buds of the tongue. This then signals the feeling of being full. However, Dale explains that this is just one of many ways the brain has of seeing if the person has eaten.

“Our contribution is to work out a mechanism by which information on circulating nutrients enters into this integrative process. This is an important step to understanding how to “game” the system, but since it is so complex and has many controlling factors, a simple gaming strategy may not be enough,” he details.

Given the position of tanycytes in the brain, many have speculated that they may play a role of this sort, explains Dale. “We set out more than ten years ago to try and gain evidence for this. Our first findings were that tanycytes could sense glucose. We then found that they used taste receptors (found in taste buds) to sense glucose and amino acids in the cerebrospinal fluid and it was a natural next step to see whether they could relay this information about nutrients to neurons that could then change appetite.”

He continues that tanycytes are “fascinating cells” and multifunctional. “For example, other investigators have shown that at least some of them are neural stem cells and capable of dividing to generate new neurons. This is actually the type that we have shown in this paper.”

A “fat-burning” molecule
Meanwhile, US researchers found that in addition to decreasing body fat, mitochondrial uncoupler BAM15 also decreases insulin resistance and has beneficial effects on oxidative stress and inflammation. In the past, many anti-fat drugs would tell the body to stop eating, which would lead to patients rebounding and eating more. However, this mouse study found that animals given BAM15 ate the same amount as the control group and still lost fat mass. Another side effect of previous mitochondrial uncouplers was increased body temperature, but the mice exhibited no changes.

Additionally, BAM15 is not toxic even at high doses and it does not affect the satiety center in the brain, which tells the body if it is hungry or full. However, the half-life – meaning the length of time the drug is effective – is quite short in the mouse model. For oral dosing in humans, the optimal half-life is much longer.

Notably, this exact molecule will not necessarily be successful in humans. The researchers now plan to transition the anti-fat treatment from animal models to a treatment for humans with non-alcoholic steatohepatitis (NASH), a type of fatty liver disease that is characterized by inflammation and fat accumulation in the liver.

As global obesity cases are on the rise, COVID-19 has created a new urgency to fight this trend. Mounting evidence is pointing to a connection between obesity in patients and worse COVID-19 outcomes, with a Public Health England data review last week establishing a significant relationship between weight-related comorbidities and COVID-19 mortality in the UK.

In this space, Pharmactive Biotech Products recently released CSAT+, a bioactive blend of carob bean extracts that can support weight management. Meanwhile, supplementation with BASF Human Nutrition’s newly launched brand of 2’-FL, called Prebilac, can lead to compositional changes in the gut microbiota associated with reduced body weight.

By Katherine Durrell

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