What does it mean to be hungry? It might seem obvious: when your stomach feels empty. But how much of that ‘feeling’ comes directly from an empty stomach, and how much from the brain’s electrical signals?
“The way we feed is controlled at multiple levels,” said Weiping Han, Director of the Neurometabolism in Health and Diseases scientific programme at A*STAR’s Institute of Molecular and Cell Biology (IMCB). “There’s homeostatic eating: when our bodies need energy, they signal our brains to seek food. But we’re also motivated by pleasure eating: despite a full stomach, we might still feel like having a slice of chocolate cake, as the brain’s reward centres might crave the boost.”
The complex chemical interplay between our bodies and brains—what’s known as our neurometabolism—is a subject of increasing interest in biomedical research, as evidence mounts that imbalances therein drive many significant health disorders such as diabetes and obesity.
Understanding that interplay could also help treat those disorders. In 2012, a newly launched drug, semaglutide, would tap into the brain-body connection to treat patients with type 2 diabetes (T2D). By mimicking a naturally occurring hormone, glucagon-like peptide-1 (GLP-1), semaglutide activates receptors in the pancreas and brain that prompt the body to produce more insulin—lowering blood sugar levels, as well as suppressing appetite and triggering a feeling of ‘fullness.’
Semaglutide rose to both commercial success and related controversy as a ‘miracle weight-loss drug’, with popular demand leading to supply shortages. However, despite the unintended buzz, for Han and others in the neurometabolic research community, the drug’s scientific basis represents a step towards a whole-body approach to health and disease.
“There’s a lot more to uncover about both sides of neurometabolism: how our brains’ neural circuits affect the health of our bodies, and how our bodies’ metabolic states affect our brain functions,” said Han.
Across A*STAR, researchers from IMCB and various institutes are collaborating with external partners to untangle these mysteries, hoping to identify new potential targets and brain-body relationships that could be harnessed to tackle the century’s evolving health challenges.
Linking brain and body expertise
IMCB’s neurometabolism programme was established to build a holistic, two-way understanding of brain-body interactions by bringing together physiologists like Han, neuroscientists, geneticists and other experts.
“There’s been a lot of work on how neurones regulate our systematic metabolism; how the brain controls appetite, feeding and energy expenditure. But that’s one half of the story,” said Han. “The other half—how metabolic changes impact our neurones, brains and cognition—is less studied but deserves equal emphasis.”
In 2021, not long after the IMCB programme’s initiation, A*STAR launched the Brain-Body Initiative (BBI): a cross-council, multidisciplinary strategic research programme that harnesses the agency’s ecosystem to support highly collaborative projects that focus on improving population health.
“To that end, BBI integrates A*STAR’s diverse capabilities in neuroscience, metabolism, social sciences, data science and advances in technology,” said Sze Wee Tan, Assistant Chief Executive of A*STAR’s Biomedical Research Council. “As populations age, we want to explore how the interconnectedness of brain and body could support not just longer, but healthier lives overall.”
Co-led by Han and Michael Meaney, Director of the Translational Neurosciences programme at A*STAR’s Singapore Institute of Clinical Sciences (SICS), BBI works with multiple institutes of higher learning and public sector agencies such as the National University of Singapore (NUS), Republic Polytechnic, the Institute of Mental Health and the Early Child Development Agency to translate key findings to real-world applications.
A keystone project behind much of BBI’s work is the Growing Up in Singapore Towards healthy Outcomes (GUSTO) project: a robust long-term birth cohort study with 1,200 mothers and their children that began in 2009 and continues today. Based at SICS, GUSTO represents a pool of data from the most deeply studied individuals in the world, shedding light on neurometabolic development from prenatal to adolescent phases of life, said Meaney.
“The data include extensive analyses of metabolic and brain functions, including magnetic resonance imaging (MRI),” Meaney added. “No other programme in the world offers a comparable ability to study how our brain-body interactions change over time.”
GUSTO’s comprehensive 15-year data are publicly available to researchers and used extensively in many BBI studies. To manage such large amounts of data, BBI works with A*STAR’s Bioinformatics Institute (BII) and the Institute for High Performance Computing (IHPC) to develop the necessary data infrastructure. IHPC and the Institute for Infocomm Research (I2R) also aid BBI in developing new biosensors and monitoring methods for improved data collection.
BBI partnerships also extend beyond Singapore’s shores. “BBI has served as a point of contact for international collaborations with the University of California at Los Angeles, Stanford, Cornell, McGill and Harvard among others,” said Meaney. “For these researchers, BBI offers a combination of unique datasets and the exceptionally broad domain expertise required to understand brain-body interactions.”
“We have resources we can rapidly mobilise: when we find an important question, we can leap to answer it with partners across A*STAR councils,” Han added.
Sounding our inner ecosystems
Under both IMCB and BBI, a multitude of research groups are delving into various aspects of neurometabolism, ranging from basic research on its fundamental systems to clinical studies for potential treatment options.
Han’s Laboratory of Metabolic Medicine works to define how specific regulators and metabolic states affect the brain and nervous system; for example, the metabolic pathways that cancer cells hijack to promote their own growth, or the chemical imbalances that stress our cells and accelerate their decline.
“Many cells are specialists that function best under certain internal and external conditions,” said Han. “For example, neurones evolved to mediate brain-body interactions by secreting neurotransmitters. But if the environment around them is out of balance—say it has an abnormal amount of sugar, as in diabetes—they’re compelled into another task that they’re less well-built for: in this case, to convert that excess for storage.”
Distracted neurones can struggle to fulfil their original roles to release neurotransmitters when prompted. If forced to keep up the multitasking over a long term, their suboptimal functioning could be fixed in stone, leading to permanent issues like the early development of dementia, Han added.
Similar discoveries have been made by teams under IMCB Principal Investigators Sarah Luo and Caroline Wee. Using a multi-model approach with rodents and zebrafish, they aim to examine how nutrients and the gut microbiome can modulate brain health and function, and how the brain in turn regulates metabolism and dietary choices.
“We’ve found recent evidence of neurodegeneration in the peripheral nervous system and in certain organs, like the liver, under conditions of metabolic stress, maternal metabolic stress and potentially ageing,” said Luo. “Through our work, we envision a future where we can exert enough neuromodulatory control to restore some of these neuronal signals, so we can maintain better long-term organ function despite the onset of old age.”
Together with colleagues from SICS, the Singapore Institute of Food and Biotechnology Innovation (SIFBI), Singapore immunology Network (SIgN) and the Genome Institute of Singapore (GIS), the team also uses a reverse translational approach to analyse multi-omics data, including neuroimaging, to identify factors associated with metabolic and brain health in children from the GUSTO cohort.
“The neuroimaging analyses build on work led by SICS’ Ai Peng Tan, showing that the size of the brain’s nucleus accumbens—critical for appetite regulation—and peripheral fat mass are highly correlated, even at birth,” commented Meaney.
Currently, the team is validating potential target factors in their respective preclinical models before reconfirming them in humans. “If we can establish a causative link between certain metabolites and neurodegeneration or brain function, then we can promote better brain health by modulating diet and nutrition,” said Wee.
The neural connection
While much work at A*STAR delves into the body’s influence on the brain, it retains strong research interests in the classic brain-to-body direction. Teams like those under IMCB Senior Principal Investigator, Yu Fu, aim to uncover new insights on the neural mechanisms behind metabolic regulation.
Fu’s group focuses on excessive feeding—particularly the overconsumption of high-sugar and high-fat foods. In a recent publication, they identified a population of neurones in the hypothalamic area of a mouse’s brain that appears to control appetite. While naturally activated by palatable food, this group of neurones can also be stimulated to drive mice to eat despite being satiated.
Currently, the team is working on a follow-up project focused on compulsive eating disorders. Using a custom-built, whole-brain neural circuit and active neurone mapping pipeline, they revealed connections between a cortical region of the brain—involved in memory, thinking, reasoning and sensory function—and a hypothalamic area. These connections are activated in response to a high-fat diet and may contribute to compulsive eating behaviour.
To move these insights from bench to bedside, the team works with SICS colleagues to analyse functional MRI (fMRI) data from GUSTO and examine if neural circuits in mice are also relevant for human food overconsumption. Early studies on the brain regions and neural connections behind anorexia nervosa are also underway, in partnership with human MRI researchers in France.
“We’re actively collaborating with clinicians to translate our animal work into human clinical studies,” shared Fu. “Conversely, findings from human studies may also help us form new ideas and hypotheses.”
Similarly, Principal Investigator Crystal Yeo and her team at IMCB’s Translational Neuromuscular Medicine Laboratory explore the biological mechanisms behind the heterogeneity of clinical phenotypes; how neurometabolic insights can be brought to patients; and how patient needs can direct research.
“Our work cycles between bench and bedside, focusing on evolving areas of medical need,” Yeo explained. “To develop targeted biomarkers and therapies, we perform careful phenotyping of patient data, multi-omics analyses of large patient databases, clinical studies and research on patient-derived induced pluripotent stem cell (iPSC) models of neurological disease.”
In collaboration with Harvard University, Yeo’s team is studying the links between liver cells and motor neurones in spinal muscular atrophy (SMA), a disease driven by whole-body motor neurone degeneration. SMA was the leading genetic cause of infant death until recent genetic therapies were available. However, even with patients living longer, their motor functions are still abnormal, with reported cases of acute liver failure and death in young children despite treatment.
“Motor neurone loss in SMA causes skeletal muscle denervation, with systemic metabolic disturbances that could lead to fatty liver,” said Yeo. “We’ve observed SMA-related fatty liver in animal models, but it was unclear whether humans were similarly affected. It’s a poorly-studied area as patients previously rarely survived beyond infancy.”
In their study, Yeo’s team found evidence that fatty liver in both human models and human patients could be directly caused by SMA-specific genetic defects in liver cells that were not secondary to motor neurone loss.
“If so, patients may need genetic therapies which target the whole body, not just the motor neurones,” said Yeo. “There’s a need for systematic clinical surveillance and targeted treatments to ensure they have a better quality of life.”
FROM THE BRAIN-BODY INITIATIVE
REPLENISH: Research on Probiotic, Lifestyle and Nutritional Interventions to Support Brain Healthspan
IMCB, SIFBI, SICS, GIS, SigN, A*SRL1, with NUS and NNI2
Asian communities have unique neurometabolic phenotypes, gut microbiomes, diets and lifestyles, but are under-characterised in the global literature. REPLENISH will examine the gut-brain axis and its links to age-related cognitive and mental decline in Singapore’s Asian population.
Drawing over 20 collaborators across eight institutes, the programme has three aims: to show how nutrition and lifestyle factors modulate brain health over ageing; to identify the gut microbiota and immune-metabolic pathways that mediate those factors; and to identify nutrient, microbiome and immune-metabolic pathways that promote healthy lifestyle behaviours. REPLENISH is currently in planning and grant application stages.
Circulation factors in primates on high-fat diets and their role in prediabetic states
IMCB, SICS with Duke-NUS
T2D occurs naturally in cynomolgus macaques, with early metabolic symptoms similar to humans. In this study, the team used a high-fat diet to induce prediabetes in a non-human primate model and a matching mouse model. By comparing transcriptomics, translatomics and proteomics analyses, the team aims to identify primate-specific metabolic factors involved in T2D and characterise their mode of action, hoping to develop effective therapies to prevent or reverse T2D progression.
Mechanisms of stress and resilience in nursing students entering the workforce
IHPC, IMCB with NUS
This project focuses on the impact of mental wellness challenges on healthy individuals moving from schooling to working environments, with a focus on stress, burnout and resilience. The team recruited students from the NUS School of Nursing for psychological and fMRI assessments, as well as activity tracking and biomarker collection, as they enter the stresses of full-time nursing work. The team hopes to identify risk factors and coping strategies that could help Singapore’s nursing programmes and other demanding professions better support workforce resilience and long-term mental health.
Blooming into health
For researchers like Michael Meaney, the integrative approach taken by BBI embodies the necessary expertise to examine health and wellbeing as a big picture. “Many research programmes today are organised around specific organs or diseases,” said Meaney. “But health emerges from interactions across all our organs, and it’s increasingly clear the effect is bi-directional; our brains and bodies impact each other.”
Sze Wee Tan adds that collaborations with external partners are pivotal in developing a research ecosystem around the field, as they bring added diverse expertise, amplify resources, accelerate innovation and ensure broader public impact.
“A*STAR plans to advance research efforts in neurometabolism and drive scientific innovations that benefit not only the region, but also the global community,” said Tan. “We will do this by nurturing talents, fostering strategic partnerships, promoting knowledge exchange and collaborating closely with government agencies and industry partners to translate research findings into practical interventions and applications.”
