Neurons that tell you to stop eating could unlock obesity treatments

Good news! This could be a breakthrough!

"... Using a new technique called spatially resolved molecular profiling, the ...  scientists were able to peer into the brainstem – which connects the brain to the spinal cord and controls vital functions – and discern the different types of cells in there, down to their molecular composition. This was previously not possible. ...

Specifically, as the researchers noted "... a population of neuropeptidergic neurons in the brainstem’s dorsal raphe nucleus (DRN)" ... "These neurons track food from sensory presentation through ingestion, integrate these signals with slower-acting humoral cues, and express cholecystokinin (CCK)," ... "These CCK neurons bidirectionally regulate meal size, driving a sustained meal termination signal with a built-in delay." ...

Those CCK neurons are activated by Exendin-4, a GLP-1 agonist. This suggests that one way GLP-1 agonists like Ozempic reduce appetite is by activating these specific CCK neurons. ..."

"... Though many feeding circuits in the brain are known to play a role in monitoring food intake, known neurons in those circuits do not make the final decision to cease eating a meal.

The newly identified neurons, a new element of these circuits, are located in the brainstem, the oldest part of the vertebrate brain. Their discovery could lead to new treatments for obesity.

“These neurons are unlike any other neuron involved in regulating satiation,”  ...

“Other neurons in the brain are usually restricted to sensing food put into our mouth, or how food fills the gut, or the nutrition obtained from food. The neurons we found are special in that they seem to integrate all these different pieces of information and more.” ..."

From the highlights and abstract:

"Highlights

• In situ molecular phenotyping of DRN at transcriptional and translational levels

• An obligate peptidergic population in the DRN is delineated by CCK expression

• CCK neurons track each bite of food to promote satiation via delayed signaling

• CCK neurons regulate satiation through multiple negative feedback loops

Summary

Hunger is evolutionarily hardwired to ensure that an animal has sufficient energy to survive and reproduce. Just as important as knowing when to start eating is knowing when to stop eating.

Here, using spatially resolved single-cell phenotyping, we characterize a population of neuropeptidergic neurons in the brainstem’s dorsal raphe nucleus (DRN) and describe how they regulate satiation.

These neurons track food from sensory presentation through ingestion, integrate these signals with slower-acting humoral cues, and express cholecystokinin (CCK). These CCK neurons bidirectionally regulate meal size, driving a sustained meal termination signal with a built-in delay. They are also well positioned to sense and respond to ingestion: they express a host of metabolic signaling factors and are integrated into an extended network known to regulate feeding.

Together, this work demonstrates how DRN CCK neurons regulate satiation and identifies a likely conserved cellular mechanism that transforms diverse neurohumoral signals into a key behavioral output."

Neurons that tell you to stop eating could unlock obesity treatments "Researchers at Columbia University Irving Medical Center have identified the specific neurons in mice brains that tell them they've eaten enough. This fascinating discovery could play a big role in the future of weight loss treatments for humans."

These Neurons Send Order to Stop Eating (original news release)

Brainstem neuropeptidergic neurons link a neurohumoral axis to satiation (no public access)

Graphical abstract

Map of human brain’s appetite centre could enable new treatments for obesity and diabetes

Good news!

"... While much of our knowledge of the hypothalamus comes from animal studies, especially in mice, translating these findings to humans has long been a challenge. HYPOMAP bridges this gap by providing an atlas of the individual cells within the human hypothalamus. This resource not only charts over 450 unique cell types but also highlights key differences between the human and mouse hypothalamus — differences that have major implications for drug development. ...

“HYPOMAP confirms the critical role of the hypothalamus in body-weight regulation and has already allowed us to identify new genes linked to obesity. ...

researchers ... used cutting-edge technologies to analyse over 400,000 cells from 18 human donors. HYPOMAP allows researchers to pinpoint specific cell types, understand their genetic profiles, and explore how they interact with neighbouring cells. This detailed cellular resolution offers invaluable insights into the circuits that regulate appetite and energy balance, as well as other functions such as sleep and stress responses. ..."

From the abstract:

"The hypothalamus is a brain region that plays a key role in coordinating fundamental biological functions. However, our understanding of the underlying cellular components and neuro circuitries have, until recently, emerged primarily from rodent studies.

Here we combine single-nucleus sequencing of 433,369 human hypothalamic cells with spatial transcriptomics, generating a comprehensive spatio-cellular transcriptional map of the hypothalamus, the ‘HYPOMAP’. Although conservation of neuronal cell types between humans and mice, as based on transcriptomic identity, is generally high, there are notable exceptions. Specifically, there are significant disparities in the identity of pro-opiomelanocortin neurons and in the expression levels of G-protein-coupled receptors between the two species that carry direct implications for currently approved obesity treatments.

Out of the 452 hypothalamic cell types, we find that 291 neuronal clusters are significantly enriched for expression of body mass index (BMI) genome-wide association study genes. This enrichment is driven by 426 ‘effector’ genes.

Rare deleterious variants in six of these (MC4R, PCSK1, POMC, CALCR, BSN and CORO1A) associate with BMI at population level, and CORO1A has not been linked previously to BMI.

Thus, HYPOMAP provides a detailed atlas of the human hypothalamus in a spatial context and serves as an important resource to identify new druggable targets for treating a wide range of conditions, including reproductive, circadian and metabolic disorders."

Map of brain’s appetite centre could enable new treatments for obesity and diabetes | University of Cambridge "Scientists have created the most detailed map to date of the human hypothalamus, a crucial brain region that regulates body weight, appetite, sleep, and stress."

A comprehensive spatio-cellular map of the human hypothalamus (open access)

Fig. 1: Integrated snRNA-seq reference atlas of the human hypothalamus.

Fig. 2: Cell-type taxonomy of the human hypothalamus.

Habit-linked brain circuits light up in people with eating disorders

Good news!

"Brain scans of people with binge-eating disorder or bulimia show altered activity in areas linked to habit formation and hint at new possibilities for eating-disorder treatments. ...

This led them to two structures: the sensorimotor putamen and the associative caudate.

Because habitual behaviours probably play a part in binge-eating disorder and bulimia nervosa, the team then examined the brains of 34 women with either of these disorders to see whether there was altered activity in the two structures.

Functional magnetic resonance imaging uncovered changes in these areas in people with eating disorders, compared with those without them. The imaging showed alterations in the structure of the grey matter and in dopamine signalling in the sensorimotor putamen in particular.

Altered connections

In people with binge-eating disorder or bulimia, the connections between some parts of the cortex and the habit-reinforcing sensorimotor putamen were much stronger than in healthy controls: connectivity to the anterior cingulate cortex was decreased, but it was increased to the orbitofrontal cortex and motor cortex. ..."

From the abstract:

"Circuit-based mechanisms mediating the development and execution of habitual behaviors involve complex cortical-striatal interactions that have been investigated in animal models and more recently in humans. However, how human brain circuits implicated in habit formation may be perturbed in psychiatric disorders remains unclear. First, we identified the locations of the sensorimotor putamen and associative caudate in the human brain using probabilistic tractography from Human Connectome Project data. We found that multivariate connectivity of the sensorimotor putamen was altered in humans with binge eating disorder and bulimia nervosa and that the degree of alteration correlated with severity of disordered eating behavior. Furthermore, the extent of this circuit aberration correlated with mean diffusivity in the sensorimotor putamen and decreased basal dopamine D2/3 receptor binding potential in the striatum, consistent with previously reported microstructural changes and dopamine signaling mediating habit learning in animal models. Our findings suggest a neural circuit that links habit learning and binge eating behavior in humans, which could, in part, explain the treatment-resistant behavior common to eating disorders and other psychiatric conditions."

Habit-linked brain circuits light up in people with eating disorders Parts of the brain associated with habit formation seem unusually active in people with eating disorders.

Human habit neural circuitry may be perturbed in eating disorders (no public access)

The putamen (highlighted green) has been associated with habit formation, following brain scans of women with binge-eating disorder or bulimia