Brain imaging identifies satiety signaling pathway with potential to improve weight loss drugs’ efficacy

28 Nov 2023 --- Novel brain imaging shows brain cells signal the body to stop eating in response to the taste of food sent from the mouth rather than the fullness of the stomach. The brain cells reached through taste are the same ones targeted by Glucagon-like peptide 1 (GLP1) weight loss drugs, meaning the findings are pertinent to the continued development of effective weight loss treatments.

“We want to understand how food intake produces satiety and leads to the termination of a meal,” Dr. Zachary Knight, study lead and professor of physiology in the Kavli Institute for Fundamental Neuroscience at the University of California San Francisco, US, tells Nutrition Insight. 

“This is one of the most basic questions in physiology and, of course, has relevance to treating obesity. It is also of great personal interest to many people since most of us have had the experience of trying to lose weight, and so would like to better understand what makes us hungry or satiated.”

The study published in the journal Nature included the first-ever imaging and recording of the caudal nucleus of the solitary tract (cNTS) — a brainstem structure critical for feeling full — in an awake, active mouse. The technique was used to look at two types of neurons long known to have a role in food intake — prolactin-releasing hormone (PRLH) and GCG neurons.

“If we can figure out how sensory filtering works and block it — so that PRLH neurons respond to gut signals during normal ingestion — this would potentially create a potent inhibition of food intake and could be a new strategy for treating obesity. We are working on this now,” Knight states.

he aim of the study was to find out how cNTS processes ingestive feedback.Brain responses to gut and mouth 
The cNTS is described as the site in the brain where many meal-related signals are first sensed and integrated. The aim of the study was to find out how cNTS processes ingestive feedback. 

“There are neurons in the brainstem that respond to signals of food ingestion from the stomach and intestines and trigger meal termination. While this has been known for decades, the activity of these neurons had never been observed in an animal eating a meal due to technical challenges associated with brainstem imaging,” Knight explains.

“Surprisingly, we found that many of these cells respond to different signals and control feeding in different ways than was widely assumed. In particular, the finding that these neurons respond to taste was completely unexpected and challenges the textbook model of how food intake is controlled by the brain.” 

Knight adds that the researchers discovered there are two parallel pathways in the brainstem — one that restrains how fast people eat and another that limits how much. 

“We found that the first pathway — which controls how fast you eat and involves PRLH neurons — is unexpectedly activated by the taste of food. This was surprising because we all know that tasty food causes us to eat more.”

Controlling satiety
Knight’s team describes that when food is placed directly into a mouse’s stomach, its PRLH brain cells — a type of cNTS that promote non-aversive satiety — are regulated by the gut.

“It was widely assumed that the PRLH neurons would be activated by signals from the stomach and intestine following food ingestion,” he says. “We found that PRLH neurons can respond to these gut signals when food is infused into the stomach but, surprisingly, they do not when the same food is ingested by the mouth. Instead, they toggle to a new mode of activity that tracks only food tastes, ignoring the signals from the gut.”

Knight explains that his team’s findings reveal that food tastes also function to limit the pace of ingestion through a brainstem pathway that likely functions beneath the level of our conscious awareness. “There has been very little research into how such a pathway might work, and so this opens the door to study of a new aspect of food intake regulation.”

The brainstem circuits that control satiety were shown to selectively attend to certain sensory cues over others, which is of high relevance to treating obesity.He argues that this reveals that the brainstem circuits that control satiety can selectively attend to certain sensory cues over others, depending on the state of the animal. 

“This is analogous to the ’cocktail party effect,’ where you can ignore all of the background noise until the moment you hear your name mentioned across the room. Our findings reveal that the sensory system that monitors the inside of our body is able to do the same thing.”

Weight loss medicine application 
Knight says that there are two ways in which his findings could potentially shed light on how GLP1 weight loss drugs work and how this knowledge can be leveraged to enhance such medicine’s effectiveness.

“First, it is widely believed that GLP1 drugs inhibit food intake by activating neurons in the cNTS. Our paper describes methods that have enabled, for the first time, the recording of the activity of neurons in the cNTS in an awake animal. We now have the capability to use this approach to study how GLP1 drugs work in vivo. We are doing this.”

“Second, GCG is the other cell type that we investigate in this study and is the primary source of GLP1 in the brain. Thus, activating these cells mimics some of the effects of GLP1 drugs. 

He adds that the research shows that artificially activating these GCG neurons causes an unusual, long-lasting satiety. “This long-lasting effect is likely part of the reason why GLP1 drugs are so effective. We are trying now to understand how this long-lasting satiety works.” 

A recent international clinical trial also found that a treatment with semaglutide, a GLP-1 receptor agonist medication, reduced cardiovascular events by 20% in overweight and obese patients who do not have diabetes. 

GLP-1 weight loss medicine can be an important aid for people suffering with obesity, however, for experts recommend natural weight loss management for most other people looking to lose weight.

By Milana Nikolova