When Energy Gets Stuck: What a New Lactate Study Reveals About Metabolic Balance

A breakthrough paper from Princeton redefines how our bodies keep lactate—and energy itself—in check.

In March 2025, researchers from Princeton, Penn, and ETH Zurich published a striking study in Cell Metabolism titled “Lactate homeostasis is maintained through regulation of glycolysis and lipolysis.”Their goal was simple but profound: to understand how our bodies keep blood lactate—one of the busiest molecules in metabolism—within a narrow, safe range.

We tend to associate lactate with muscle fatigue, but in reality, it’s a universal energy courier. Every minute, lactate shuttles carbon and electrons between tissues, linking glycolysis (sugar breakdown) and mitochondrial oxidation (energy release). When this flow gets disrupted, the results ripple across health—rising lactate levels can signal stress, diabetes, or even sepsis.

What the researchers found

Using advanced isotope-tracing in mice, Lee et al. uncovered four feedback loops that quietly stabilize lactate:

1. Insulin boosts lactate production by speeding up glycolysis.

2. The same insulin also accelerates lactate consumption—but indirectly, by suppressing fat breakdown (lipolysis) in adipose tissue.

3. Lactate itself can trigger its own cleanup through a receptor on fat cells called HCAR1 (GPR81), which also slows lipolysis.

4. When lactate levels climb too high, they blunt insulin signaling in muscle, dampening further glucose uptake and lactate production.

In other words, lactate and fatty acids constantly compete for mitochondrial attention. When fat supply is high, lactate burning slows; when fat drops, lactate oxidation resumes. Their mathematical model showed that this system is remarkably robust—self-correcting even when one control loop falters.

What’s really happening: the acetyl-CoA balancing act

While the paper describes this as “competition for mitochondrial oxidation,” the deeper chemistry points to a common gatekeeper: the acetyl-CoA pool.

Think of acetyl-CoA as the currency of energy metabolism. It sits at the crossroads of glycolysis and fat oxidation, deciding which fuels the mitochondria can process.

• When fatty-acid oxidation floods the mitochondria, acetyl-CoA and NADH accumulate, blocking pyruvate dehydrogenase (PDH)—the enzyme that converts lactate (via pyruvate) into mitochondrial acetyl-CoA.

• When insulin or HCAR1 signaling suppresses lipolysis, the flood recedes, PDH reopens, and lactate can once again be burned cleanly for energy.

From this perspective, the entire lactate-fat-insulin system in Lee et al. can be summarized in one phrase:

Lactate homeostasis is acetyl-CoA homeostasis.

The ERM perspective: when adaptation gets stuck

Within the Exposure-Related Malnutrition (ERM) framework, this story fits neatly into the concept of “substrate congestion”—a metabolic traffic jam that arises when energy supply overwhelms cellular demand.

During acute stress or chronic over-nutrition, mitochondria face a mixed inflow of glucose, fat, and amino acids. When they can’t choose efficiently, acetyl-CoA pools back up, and the system shifts from flexibility to friction.

The result?

• Lactate and fatty acids accumulate in the bloodstream.

• Muscles and liver slip into energy inefficiency.

• Insulin signaling falters—an early sign of the maladaptive phase of ERM.

In this sense, Lee et al. give us the experimental map of what ERM predicts conceptually: energy oversupply leading to functional undersupply.

When the cell can’t clear or redirect its acetyl-CoA, even an “energy-rich” environment behaves like starvation at the functional level.

Why it matters

This study repositions lactate not as metabolic waste, but as a feedback messenger that helps the body ration its energy flow. It also highlights why metabolic resilience depends on rhythm and recovery, as it involves the constant exchange between oxidation and restoration, between the cytosolic and mitochondrial acetyl-CoA pools.

For clinicians and patients, the message is hopeful: restoring balance doesn’t always mean “adding energy” but re-establishing flow—allowing the body’s energy currency to circulate freely again.

Take-home message

When lactate builds up, it’s not just about oxygen or exercise—it’s a signal that the acetyl-CoA gate is jammed. Releasing that congestion—through metabolic rhythm, balanced nutrition, and recovery—is how the body restores both lactate balance and resilience.

Lee, W. D., Weilandt, D. R., Liang, L., MacArthur, M. R., Jaiswal, N., Ong, O., Mann, C. G., Chu, Q., Hunter, C. J., Ryseck, R.-P., Lu, W., Oschmann, A. M., Cowan, A. J., TeSlaa, T. A., Bartman, C. R., Jang, C., Baur, J. A., Titchenell, P. M., & Rabinowitz, J. D. (2025). Lactate homeostasis is maintained through regulation of glycolysis and lipolysis. Cell Metabolism, 37(3), 758–771. https://doi.org/10.1016/j.cmet.2024.12.009