Research links dysregulated brain regions to higher BMI, indicating reduced appetite control

04 Sep 2023 --- Impaired connections in obese people between the dorsolateral hippocampus (dlHPC) and the lateral hypothalamus (LH) may impact their ability to control or regulate eating habits or emotional responses when anticipating rewarding meals or treats, according to a new study.

The disrupted connections between memory and appetite-regulating brain circuits were increased in people with a higher body mass index (BMI) and patients who suffer from disorders or overeating that can lead to obesity, such as binge eating disorder (BED). 

While earlier research suggested a connection between the hippocampus and managing hunger and appetites, studying the link in humans is challenging as it requires significant brain surgery. The current study could verify the connection in human tissue for “the first time” by studying patients under observation in Penn Medicine’s Epilepsy Monitoring Unit. 

“These findings underscore that some individual’s brains can be fundamentally different in regions that increase the risk for obesity,” senior author Casey Halpern, MD, an associate professor of neurosurgery and chief of stereotactic and functional neurosurgery at Penn Medicine at the University of Pennsylvania, tells Nutrition Insight. 

“Conditions like disordered eating and obesity are much more complicated than managing self-control and eating healthier. What these individuals need is not more willpower, but the therapeutic equivalent of an electrician that can make right these connections inside their brain.”

Health benefits 
The hippocampus has never been targeted to treat obesity, nor the disordered eating that can sometimes cause obesity, explains Halpern. 

“We hope to be able to use this research to both identify which individuals are likely to develop obesity later in life and to develop novel therapies – both invasive and not – to help improve the function of this critical circuit that seems to go awry in patients who are obese.”  

The identified impaired connections may impact people’s ability to control or regulate eating habits.He continues: “There is a lot of press about drugs to help with weight loss, but we still need to increase our understanding of the brain mechanisms that make a person more likely to develop obesity to help manage it.” 

Role of the hippocampus 
The dlHPC is located in the region of the brain that processes memory, explains Halpern, while the LH is in the area of the brain responsible for keeping the body in a stable state, called homeostasis. 

“Previous research has found an association with loss of function in the human hippocampus in individuals with obesity and related disordered eating, like BED. However, outside of imaging techniques such as magnetic resonance imaging (MRI), the role of the hippocampus has been difficult to study in humans with obesity and related eating disorders.” 

Halpern adds that in the current study, published in Nature, researchers were able to evaluate patients whose brains were already being monitored electrically in the Epilepsy Monitoring Unit. 

The research team performed an additional test on nine participants, providing a sweet-fat incentive and determining responses in the brain regions. 

“Researchers monitored brain activity as patients anticipated and then received a chocolate milkshake as a sweet treat,” explains Halpern. “They found that both the dlHPC and the LH activated simultaneously when participants anticipated receiving the rewarding meal.” 

“These researchers confirmed using stimulation techniques pioneered by co-authors Dr. Kai Miller and Dr. Dora Hermes Miller from Mayo Clinic, that this specific zone of the hippocampus, the dlHPC and LH exhibited extremely strong connectivity.” 

They also found that the functional connectivity between the dlHPC and LH area in a resting state was significantly decreased in overweight/obese compared to lean participants. 

Last month, neuroscientists from universities in Cambridge, UK, found that people with a higher BMI also have a larger hypothalamus volume, especially in the regions controlling appetite, which they suggest could contribute to eating more. 

The researchers hope to use the outcomes to identify who may develop obesity and to create new therapies.3D modeling 
To define the dlHPC region, the researchers determined where LH streamlines were more densely populated through high-resolution diffusion-MRI-based tractography – a 3D modeling technique used to represent nerve tracts using data collected by diffusion MRI visually.

The study included MRI data from two groups of people: 178 individuals from the Human Connectome Project – a project that aims to map the human brain – and 37 women prone to binge eating whom the Stanford Eating Disorders Program recruited. 

The researchers further analyzed brain tissue by stimulating receptors in the brain and through post-mortem brain clearing on one sample – rendering it transparent to enable deep imaging of tissue through microscopes. 

The technique revealed melanin-concentrating hormone (MCH), a neuropeptide known to regulate feeding behavior mainly produced in the LH. The authors only found MCH in the dlHPC and nowhere else, which confirms the link between the two regions.

As there is a growing awareness of weight loss medication such as semaglutide, researchers question their long-term use, since patients often cease treatment after two years because it is no longer cost-effective. 

Similarly, a recent report highlighted the inefficiencies in weight loss drugs, as two-thirds of obesity medication GLO-1a (glucagon-like peptide-1 agonist) consumers stop taking the medication within a year due to the high costs of the drugs. 

By Jolanda van Hal