New Publication: Metabolic–Epigenetic Control of Macrophage Healing Is Disrupted in Obesity

We are excited to share our recent publication in The FASEB Journal:

📄 Read the full article

Overview

Macrophages play a central role in resolving inflammation and promoting tissue repair. Their ability to adapt to local microenvironments—particularly hypoxia—is essential for proper healing. However, how metabolic signals integrate with epigenetic regulation to control macrophage function has remained unclear.

Key Findings

Our study identifies a metabolic–epigenetic axis that governs macrophage adaptation and healing:

• Hypoxia induces H3K4me3, a histone modification associated with active transcription

• This epigenetic program promotes lactate accumulation, a key metabolic intermediate

• Lactate drives histone lactylation and pro-resolving gene expression

• Together, this axis enables efficient efferocytosis, a critical process for clearing apoptotic cells and resolving inflammation

In contrast, diet-induced obesity disrupts this pathway, leading to:

• Reduced H3K4me3 induction

• Impaired lactate accumulation and histone lactylation

• Defective efferocytosis

• Delayed wound healing and persistent inflammation 

Conceptual Advance

This work supports a broader conceptual framework:

Metabolites function as signaling molecules that regulate immune cell behavior through epigenetic mechanisms.

Importantly, we demonstrate that these defects are imprinted in hematopoietic stem and progenitor cells (HSPCs), linking metabolic disease to long-term reprogramming of the innate immune system (central trained immunity).

Disease Relevance

These findings provide new insight into:

• Chronic inflammation in obesity

• Impaired wound healing

• Metabolic regulation of immune function

They also suggest potential therapeutic strategies targeting metabolite availability and epigenetic regulation to restore macrophage function.

Funding

This work was supported by the National Institutes of Health, including funding from NIDDK.