The surprising interplay between metabolism and mind

Our brain and metabolism are tightly interlinked physiologically, say scientists in Singapore who are studying the links between them — an emerging field known as neurometabolism. They are studying a wide gamut of topics, including how neurons influence overeating and how metabolic states may impact the brain.

In 2018, while neurometabolism expert Sarah Luo was completing her post-doc at Singapore’s Agency for Science, Technology and Research (A*STAR), she published a paper in Science on a discovery she had made about a new feeding regulation mechanism in the brains of mice.

Luo — who now runs a lab in the division of Neurometabolism in Health and Disease at A*STAR’s Institute of Molecular and Cell Biology (IMCB) — revealed how the hunger hormone, ghrelin, activated specific neurons in the brain’s hypothalamus, which helps regulate food intake. Activation increased the amount of food her mice ate, while deactivation reduced it¹.

The following year, her colleague, Caroline Wee, a principal scientist at A*STAR’s IMCB, examined brain-wide hunger dynamics in zebrafish, offering further insights on the modulation of hunger.

Wee’s team found that different neurons are activated when hungry zebrafish were consuming large quantities of food, as opposed to when they were fasting². “And, in general, when one group of neurons is active, the other is suppressed,” she says. “A balance between them is only achieved when the animal reaches satiety — like a swinging pendulum that finally comes to rest.”

Both researchers now work as part of the Brain-Body Initiative — a cross-disciplinary research programme that integrates research in neuroscience, metabolism, the social sciences, data science and technology across several A*STAR research institutes.

Why we overeat

According to the World Health Organization, 39% of adults aged 18 years and over were overweight in 2016. Scientists agree that far more than simply a basic need to get sufficient calories is influencing our desire to eat.

Yu Fu, senior principal scientist at A*STAR’s IMCB, and Luo’s mentor during her post-doc, is looking at these dynamics. In a recent study, he examined environmental factors that influence hunger and satiety signals in mice³. “We found that some environments associated with palatable foods can cause binge eating even if the animal isn’t hungry,” says Fu.

These findings have implications in people, and the environments where we eat, such as restaurants, he says. They may even hint that the brightly coloured and highly recognizable branding of some fast-food chains — which consumers may already associate with highly palatable foods — could trigger you to over-eat.

To dig even further into the mechanisms that drive over-eating, Wee’s team has sequenced the RNA of the hypothalamic neuron clusters in zebrafish that she previously described².

They have found several subtypes of these neurons that produce different signalling molecules and hormone receptors, one of which they have now linked to voracious feeding. Collaborative work with Luo suggests that this neuron subtype can also be found in mice.

Perusing the periphery

Luo’s team is also studying another aspect of neurometabolism: how the brain uses metabolic information from organs to drive physiological changes and behaviour.

“The peripheral nervous system directly connects various organs — such as the gut, the liver and the pancreas — to the brain,” she says. “However, the types of information conveyed to the brain and how the brain processes such information are not well understood.”

Luo, who is now a principal scientist, is studying the livers of mice, and explains that the liver sits at “the gateway from the gut into the rest of the body”, as nutrients, hormones and other signalling factors from the gut pass through the liver before reaching wider circulation.

What she is finding suggests links between the gut, liver, immune system and brain. Particularly, her team has focused on interactions between the brain and the immune system through the liver because “food might contain pathogens, and this liver-brain communication serves to alert the brain to instruct the body, including the immune system, to be ready”, says Luo.

Other pathways of connection might explain some of the influences of mental health conditions, such as depression, on the body’s metabolic functions. Luo explains that neurons linked to the liver are also found in regions of the brain involved in stress. “Mental states like chronic stress could influence liver function and exacerbate liver diseases through these brain-metabolic pathways,” she says.

Gut feelings

Weiping Han, director of the Neurometabolism division at A*STAR’s IMCB and co-programme director of the Brain-Body Initiative (see box below), has also looked at the links between metabolism and mental states. His team has recently revealed how the maternal gut and the early gut microbes of their offspring can influence the development of some brain regions in young mice⁴.

These influences were found to have a possible impact on the size of brain regions linked to conditions such as attention deficit hyperactivity disorder (ADHD), anxiety and depression, says Han.

As a result, he has hopes that the division’s insights might one-day help treat not only metabolic diseases, such as obesity, but mental health conditions too. “We are a long way from treating mental health issues, but I’m convinced that understanding the metabolic conditions in which they develop is absolutely essential to get there,” he says.

The neurometabolism teams within A*STAR’s Brain-Body Initiative are using human cohort studies and preclinical modelling to study the metabolic links to mental states and how human gut microbes and their metabolites regulate metabolic and mental function.