When Energy Runs Short: How Brown Fat “Turns White” — and What It Tells Us About Resilience

A recent study in Nature Metabolism (Kaul et al., 2025) gives us a close look at how our cells respond when their mitochondria — the “power plants” of the cell — begin to fail. The researchers examined brown adipose tissue (BAT), a fat type known for burning calories and producing heat through uncoupled mitochondrial respiration. This high-energy state is one reason brown fat is often called “good fat.”

But under stress, brown fat doesn’t stay brown.

The Molecular Cascade: From Brown to White

When the mitochondrial protease CLPP is missing, mitochondria develop defects in respiratory complex I, disrupting the flow of electrons and ATP production. Even though the cell tries to compensate by making more mitochondria, the imbalance creates an energy stress signal.

Here’s what happens next:

• PHGDH activation and d-2-hydroxyglutarate buildupThe serine synthesis enzyme PHGDH becomes hyperactive, generating excess d-2-hydroxyglutarate (d-2HG) — a metabolite often linked to cancer biology.

• Epigenetic remodelingd-2HG blocks α-ketoglutarate–dependent dioxygenases, enzymes that normally remove methyl marks from DNA and histones. The blockade leads to increased H3K4me3 histone methylation, especially at promoters of lipid and adipogenic genes such as SREBP1/2 and C/EBPβ. This chromatin reprogramming shifts the cell’s transcriptional program away from thermogenesis toward lipid storage.

• Lipid droplet (LD) expansionAs metabolic priorities change, lipid droplets enlarge. Rather than a simple failure of fat burning, this LD growth acts as a protective buffer, reducing lipotoxic stress and sequestering excess substrates.

• Nuclear softeningThe accumulation of d-2HG also alters nuclear mechanics. The nucleus becomes softer and more deformable, partly due to changes in cholesterol metabolism. Supplementing cholesterol rescues stiffness, while statins (cholesterol synthesis inhibitors) make it worse. This reveals a direct tie between mitochondrial dysfunction, metabolite signaling, and nuclear architecture.

From an ERM Perspective: Energy Stress as Adaptive Reprogramming

The Exposure-Related Malnutrition (ERM) framework proposes that under chronic stress, cells reallocate resources: short-term survival is prioritized, while long-term resilience declines. This study provides a clear molecular example:

• Energy stress → metabolite buildup (d-2HG)

• Metabolite signaling → epigenetic shifts

• Epigenetic shifts → functional reprogramming

• Functional reprogramming → BAT whitening (high-burn → low-burn state)

In essence, the cell trades a metabolically expensive thermogenic identity for a cheaper, storage-focused one. It’s like a city during an energy crisis: shutting down power-hungry industries, re-wiring governance, and stockpiling resources — ensuring survival at the cost of growth and flexibility.

Why It Matters

This discovery adds mechanistic detail to the idea that energy stress reshapes our biology through metabolite-driven epigenetics. It reinforces ERM’s central claim: many early “malnutrition-like” changes in chronic disease are not simply nutrient deficiencies, but adaptive reallocations under stress.

The takeaway is profound: what looks like a loss of function (brown fat whitening) is in fact an adaptation to preserve survival. The danger comes when this adaptive mode becomes chronic, locking cells — and whole tissues — into a low-resilience state.