TARIK MOUFID

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The Truth About Lactate (Part IV)

This is part IV of a series I wrote about lactate. If you want to see the other parts:

In part I I’ve debunked some lactate myths and in part II I’ve covered lactate as a key fuel source for your cells and an important biomarker for metabolic health. In part III I’ve discussed lactate’s signalling role. In this chapter, I’ll discuss lactate’s role in the brain.

🧠 The Brain: a Unique Organ with Unique Energy Demands

The brain consumes around 20% of the body’s total energy, even though it represents just 2% of overall body weight. For this, it relies specially on glucose, consuming around 120 grams of glucose per day, accounting for approximately 60-70% of the body’s total glucose utilization at rest. This is why when we look at a Positron Emission Tomography (PET) of the whole body using radioactively labeled glucose (like FDG, or fluorodeoxyglucose) to visualize areas of high metabolic activity, the brain is always lighted up.

However, recent research challenges the view that glucose is the brain’s only significant fuel. Under certain conditions, lactate becomes an alternative or even the preferred energy source for neurons.

Whole-body PET-CT, areas with high glucose metabolism lighting up

⚖️ When the Brain Prefers Lactate

While glucose is the primary fuel source, lactate serves as an important and often underappreciated energy substrate for the brain under specific circumstances, such as: exercise, hypoxia or hypoglycemia and during neonatal development.

Astrocytes, the brain’s glial cells, play an essential role producing lactate from glucose and shuttling it to neurons, especially during periods of high energy demand, in what’s known as the astrocyte-neuron lactate shuttle (ANLS).

In these situations, lactate becomes more than just an emergency backup fuel—it takes on a central role in maintaining neuronal function, highlighting the brain’s metabolic flexibility.

The Brain Lactate Shuttle. L Felipe Barros et al. (2020)

📡 Lactate Signaling Role in the Brain

Beyond its role as a fuel, lactate also functions as a signaling molecule in the brain, influencing neuronal activity, plasticity and even mood regulation. Some key pathways include:

  • Brain-Derived Neurotrophic Factor (BDNF): Lactate has been shown to promote the expression of BDNF, a critical neurotrophin involved in neuronal growth, survival, and synaptic plasticity. BDNF plays a central role in learning and memory and is crucial for maintaining brain health across the lifespan.
  • Neurotransmitter Modulation: Lactate can influence neurotransmission by altering levels of glutamate and GABA, the brain’s primary excitatory and inhibitory neurotransmitters, respectively. Lactate increases the uptake of glutamate into astrocytes, preventing excitotoxicity (neuronal damage due to excessive stimulation) and promoting neural stability.
  • NADH Shuttle: In the mitochondria, lactate contributes to the redox balance by shuttling NADH (the reduced form of NAD+) across mitochondrial membranes, facilitating ATP production. By supporting energy metabolism it may protect neurons from oxidative stress, a key factor in neurodegenerative diseases like Alzheimer’s and Parkinson’s.
Lactate’s signalling in the brain

⚕️ Therapeutic Potential of Lactate in Brain Health

Personally, this one is the most exciting. Given lactate’s multifaceted roles, its therapeutic potential for brain health and treating neurological conditions is being investigated:

  • Neuroprotection in Stroke and Traumatic Brain Injury (TBI): Following ischemic events like stroke or TBI, the brain experiences both oxygen and glucose deprivation. Lactate supplementation in these settings has shown promise in mitigating neuronal damage by serving as an alternative fuel source and reducing the inflammatory response. This could improve recovery outcomes in patients who suffer from acute brain injuries.
  • Cognitive Enhancement: Exercise-induced lactate elevations are linked to improvements in memory and cognition, mediated by increased BDNF expression and enhanced neuroplasticity. This makes lactate an intriguing target for therapies aimed at improving cognitive function in aging populations.
  • Mood and Mental Health: There is emerging evidence suggesting that lactate may have antidepressant effects. The lactate-BDNF connection is thought to play a role in mood regulation, potentially offering new strategies for the treatment of depression and anxiety disorders. Enhancing lactate signaling through exercise or lactate supplementation could promote neurogenesis and resilience to stress.
  • Multiple Sclerosis (MS): In diseases like MS, where chronic inflammation and neurodegeneration occur, lactate’s anti-inflammatory properties (e.g., shifting macrophages to an anti-inflammatory M2 phenotype) could have neuroprotective effects, potentially slowing disease progression.
Lactate therapeutic potential in the brain

💡 The Takeaway: Lactate as a key molecule for brain health

Lactate is emerging as a vital player in brain health, far beyond its classical role as a byproduct of anaerobic metabolism. From serving as an alternative fuel during metabolic stress to acting as a neuroprotective signal, lactate supports brain function and health in numerous ways. The signaling role of lactate, particularly its influence on BDNF and neurotransmitter modulation, underscores its importance in cognitive function, neuroplasticity and mood regulation. Moreover, the potential for lactate-based therapies in conditions like stroke, TBI and neurodegenerative diseases opens up exciting avenues for future research and clinical applications.

In short, lactate is not just a metabolic byproduct—it’s a key regulator of brain function, health and resilience.

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