Glutamate is an amino acid with very different functions. In the pancreas, it modulates the activity of the pancreatic ß-cells responsible for insulin production, whereas in the brain it is the main excitatory neurotransmitter. In recent years, it has been suspected to play an additional role in the functioning of the brain. In the brain, glutamate is predominantly derived from glucose catabolism and subsequent TCA cycle metabolism. The latter provides substrates for glutamate dehydrogenase (GDH), an essential enzyme connecting glucose and glutamate metabolism.
In the CNS, glutamate dehydrogenase is predominantly expressed in astrocytes, an alternative pathway to glutamate-glutamine cycling that provides neurotransmitter precursors for glutamatergic neurons. Therefore, it has long been theorised that the brain uses the excitory neurotransmitter glutamate as a source of energy. Now, a study from researchers at the University of Geneva (UNIGE) has verified that the brain uses glutamate to produce energy and has highlighted unexpected links with the rest of the body. The opensource study is published in the journal Cell Reports.
Previous studies show that unlike other organs, the brain cannot draw its energy from lipids, an energy resource widely present in the body. The blood-brain barrier, which protects it from the pathogens and toxins circulating in the blood, indeed limits the passage of these lipids. Moreover, while most of the organs in the human body have the ability to store glucose by increasing their mass, the brain cannot count on these variations in volume. Unable to store its food, the brain depends on sugar supplied in real-time by the rest of the body, whose distribution of energy is controlled by the liver. Glutamate is the most abundant excitatory neurotransmitter and, besides glucose, may also contribute to sustain brain energy homeostasis. As glutamate can be oxidized by astrocytes at higher rate than glucose, the group decided to verify if glutamate was indeed an energy source for the brain.
The current study analyzed the role of the glutamate dehydrogenase enzyme, which is encoded by the Glud1 gene and responsible for glutamate metabolism in the brain. The lab suppressed the Glud1 gene in the brain of mice and found that in the absence of glutamate dehydrogenase the brain was no longer able to convert glutamate into energy, even though the amino acid was present in the brain. Results show that when the brain is devoid of the energy supplied by cerebral glutamate, it sends signals to the liver to acquire glucose, at the expense of the rest of the body.
Data findings also show that the transgenic mice showed a growth deficit and muscle atrophy due to this ‘acquiring’ of glucose from the rest of the body. The team state that this clearly shows how the brain works in a just-in-time manner and that each percent of energy resources is essential for its proper functioning. They go on to add that if part of this energy disappears, the brain serves itself first and the rest of the body suffers. Results show that the liver must then make more glucose by drawing upon muscle protein, resulting in loss of muscle mass. The group conclude that knowing that the brain uses glutamate as an energy resource allows researchers to reflect on other ways to overcome a potential shortfall.
The team surmise that in mutant form the glutamate dehydrogenase enzyme is responsible for a congenital hyperinsulinism syndrome, a severe disease affecting the endocrine pancreas, the liver and the brain. They go on to add that individuals affected by this syndrome suffer from intellectual disability and have a high risk of epilepsy, and that the global medical community also suspect a correlation between the Glud1 gene and schizophrenia. For the future, the researchers are introducing in mice the same Glud1 mutation detected in epileptic patients and will also be assessing how schizophrenic patients brain’s use glutamate.
Source: University of Geneva (UNIGE)
Michelle Petersen is the founder of Healthinnovations, having worked in the health and science industry for over 21 years, which includes tenure within the NHS and Oxford University. Healthinnovations is a publication that has reported on, influenced, and researched current and future innovations in health for the past decade.
Michelle has been picked up as an expert writer for Informa publisher’s Clinical Trials community, as well as being listed as a blog source by the world’s leading medical journals, including the acclaimed Nature-Springer journal series.
Healthinnovations is currently indexed by the trusted Altmetric and PlumX metrics systems, respectively, as a blog source for published research globally. Healthinnovations is also featured in the world-renowned BioPortfolio, BioPortfolio.com, the life science, pharmaceutical and healthcare portal.
Most recently the Texas A&M University covered The Top 10 Healthinnovations series on their site with distinguished Professor Stephen Maren calling the inclusion of himself and his team on the list a reflection of “the hard work and dedication of my students and trainees”.
Michelle Petersen’s copy was used in the highly successful marketing campaign for the mega-hit film ‘Jumanji: The Next Level, starring Jack Black, Karen Gilian, Kevin Hart and Dwayne ‘The Rock’ Johnson. Michelle Petersen’s copywriting was part of the film’s coverage by the Republic TV network. Republic TV is the most-watched English language TV channel in India since its inception in 2017.
An avid campaigner in the fight against child sex abuse and trafficking, Michelle is a passionate humanist striving for a better quality of life for all humans by helping to provide traction for new technologies and techniques within healthcare.