Study confirms 20 year-old hypothesis on the brain using lactate for energy.


In comparison to other organs, the human brain has the highest energy requirements. The supply of energy for nerve cells and the particular role of lactic acid (lactate) has been a matter of intense research for many years. A hypothesis from the 1990’s postulates, that a well-orchestrated collaboration between two cell types, astrocytes and neurons, is the basis of brain energy metabolism.

It is known that astrocytes produce lactate, which flows to neurons to cover their high energy needs. However, due to a lack of experimental techniques, it remained unclear whether an exchange of lactate existed between astrocytes and neurons.  Now, a study from researchers at the University of Zurich has confirmed the 20-year old hypothesis by showing that nerve cells cover their high energy demand with glucose and lactate. The team state they have shown for the first time in the intact mouse brain evidence for an exchange of lactate between different brain cells. The opensource study is published in the journal Cell Metabolism.

Previous studies show that the energy demand of mammalian brain tissue is met mainly by degradation of blood-borne glucose, with classical experiments suggesting two separate tricarboxylic acid cycles via a ‘large’ and a ‘small’ compartment, which were assigned to neurons and astrocytes. The concept of compartmentation in brain energy metabolism gained new momentum with the postulation of the astrocyte neuron lactate shuttle model (ANLS).  The ability of neurons to take up lactate is an important prerequisite for the use of lactate as an energy substrate as suggested by the ANLS.  In the classical version of this hypothesis, glutamate transients are linked to a cellular compartmentation of lactate. Glutamate released from active neurons activates astrocytic glycolysis leading to production of lactate, which serves as an energy source for neurons.  Increased brain lactate levels upon neuronal activation have been observed in several studies via different techniques.  However, the cellular origin of lactate released during increased activity and its significance as an energy substrate or signaling molecule remains largely unclear.  The current study shows that there is a significant concentration gradient of lactate between astrocytes and neurons and uncovers it mechanism.

The current shows that by increasing the extracellular pyruvate concentration, outward transport of lactate is stimulated. Results show that lactate levels only changed in astrocytes and not in neurons; based on this finding and on results from several control experiments, a clear lactate gradient between astrocytes and neurons was confirmed.  Data findings show that lactate transport by monocarboxylate transporters (MCTs) is a passive transport, such a concentration difference is a necessary condition for a lactate flux to be present.

The lab explain that entry and exit of lactate into and out of cells of the body is concentration dependent and is mediated by the specific lactate transporter, MCT. They go on to add that a typical property of certain transporter proteins is called trans-acceleration, with MCTs being imagined as revolving doors which turn faster when more people enter or exit; they made use of this property and accelerated the ‘revolving doors’.

The group validated this by using a novel fluorescent protein that binds lactate, thereby changing the amount of light released by the fluorescent molecule, this way the lactate concentration could be measured in single cells.  To achieve this the researchers expressed the lactate sensor in astrocytes or neurons in the brain of anesthetized mice and measured the fluorescence changes with a special two-photon microscope.

The team surmise that more than 20 years after the formulation of the hypothesis that neurons metabolize lactate, the researchers have made an important step closer to final proof of this hypothesis.  For the future, the researchers state that numerous brain diseases have been associated with metabolic deficits and their findings underlines the importance of an accurate understanding of the processes contributing to brain energy metabolism at the cellular level.

Source:  University of Zurich

Investigating lactate dynamics in brain tissue is challenging, partly because in vivo data at cellular resolution are not available. We monitored lactate in cortical astrocytes and neurons of mice using the genetically encoded FRET sensor Laconic in combination with two-photon microscopy. An intravenous lactate injection rapidly increased the Laconic signal in both astrocytes and neurons, demonstrating high lactate permeability across tissue. The signal increase was significantly smaller in astrocytes, pointing to higher basal lactate levels in these cells, confirmed by a one-point calibration protocol. Trans-acceleration of the monocarboxylate transporter with pyruvate was able to reduce intracellular lactate in astrocytes but not in neurons. Collectively, these data provide in vivo evidence for a lactate gradient from astrocytes to neurons. This gradient is a prerequisite for a carrier-mediated lactate flux from astrocytes to neurons and thus supports the astrocyte-neuron lactate shuttle model, in which astrocyte-derived lactate acts as an energy substrate for neurons.  In Vivo Evidence for a Lactate Gradient from Astrocytes to Neurons.  Weber et al 2015.

Investigating lactate dynamics in brain tissue is challenging, partly because in vivo data at cellular resolution are not available. We monitored lactate in cortical astrocytes and neurons of mice using the genetically encoded FRET sensor Laconic in combination with two-photon microscopy. An intravenous lactate injection rapidly increased the Laconic signal in both astrocytes and neurons, demonstrating high lactate permeability across tissue. The signal increase was significantly smaller in astrocytes, pointing to higher basal lactate levels in these cells, confirmed by a one-point calibration protocol. Trans-acceleration of the monocarboxylate transporter with pyruvate was able to reduce intracellular lactate in astrocytes but not in neurons. Collectively, these data provide in vivo evidence for a lactate gradient from astrocytes to neurons. This gradient is a prerequisite for a carrier-mediated lactate flux from astrocytes to neurons and thus supports the astrocyte-neuron lactate shuttle model, in which astrocyte-derived lactate acts as an energy substrate for neurons. In Vivo Evidence for a Lactate Gradient from Astrocytes to Neurons. Weber et al 2015.

One comment

  • This is a very strange press release. The transport of lactate by MCTs has been known for at least 40 years. The fact that neurons and indeed all mammalian cells utilize lactate after conversion to pyruvate has been known for even longer. The fact that lactate distributes evenly in brain tissue because of the near-equilibrium LDH enzymes is eqially canonic knowledge. The fact that lactate is transported passively along concentration gradients is an integral part of the standard description of neurochemistry. So what is really new here? And what does it have to do with the cartoon concept of the ANLS hypothesis?

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