What is the clinical evidence from this study?

Study design: Observational. Population: Type 2 diabetes mellitus (n=13). Intervention: Type 2 diabetes mellitus vs. Non-T2D controls. Primary outcome: Immunometabolic crosstalk and mitochondrial stress-clearance circuit between adipocytes and macrophages.

What does this research mean for the field?

Adipocyte mitochondrial stress and defective clearance of mitochondrial-derived vesicles by lipid-associated macrophages jointly sustain chronic metaflammation in human Type 2 diabetic subcutaneous white adipose tissue. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

What question did this study set out to answer?

This research aims to understand the maladaptive interactions between adipocytes and macrophages in T2D that maintain chronic inflammation.

June 7, 2026

2418-P: A Mitochondrial-Stress Adipocyte–Macrophage Circuit Sustaining Metaflammation in Human Type 2 Diabetic Adipose Tissue

Key Result

Type 2 diabetes scWAT (n=6) compared to non-T2D controls (n=7) exhibited an immunometabolic circuit where adipocyte mitochondrial stress and macrophage clearance defects jointly sustain metaflammation.

Key Points

This research aims to understand the maladaptive interactions between adipocytes and macrophages in T2D that maintain chronic inflammation.
Utilized single-nucleus RNA sequencing on subcutaneous white adipose tissue from 13 individuals (6 T2D, 7 non-T2D)
Performed metabolic flux inference, metabolomic profiling, and cell-state annotation
Analyzed intercellular communication and macrophage responses through ligand-receptor and pseudotime analyses
Identified a stressed adipocyte state (AD3) linked with mitophagy upregulation and inflammatory signaling.
Observed a dysfunctional LAM-ST1 macrophage subset with impaired receptor and lysosomal function for mitochondrial waste clearance.
Demonstrated communication between AD3 and LAM-ST1 that supports metaflammation, highlighting maladaptive mitochondrial stress responses.

Study Design

Type

Observational (n=13)

Structured PICO

Population

13 participants (6 with Type 2 diabetes and 7 non-T2D controls) who provided subcutaneous white adipose tissue for single-nucleus RNA sequencing.

Exposure

Single-nucleus RNA sequencing and transcriptomic analysis

Comparator

scWAT from non-T2D controls

Outcome

Immunometabolic crosstalk and mitochondrial stress-clearance circuits between adipocytes and macrophagessurrogate

Single-nucleus RNA sequencing reveals that defective macrophage clearance of stressed adipocyte mitochondria sustains metaflammation in human Type 2 diabetes.

Abstract

Introduction and Objective: Type 2 diabetes mellitus (T2D) features chronic low-grade inflammation in white adipose tissue (WAT), where adipocytes and immune cells engage in immunometabolic crosstalk. Mitochondrial damage-associated molecular patterns released from stressed adipocytes are thought to sustain metaflammation, but how they are handled by macrophages in human T2D WAT is unclear. We hypothesized that in T2D subcutaneous white adipose tissue (scWAT), the mitochondrial stress-clearance circuit between adipocytes and macrophages becomes maladaptive. Methods: Using single-nucleus RNA sequencing on scWAT from 6 T2D and 7 non-T2D controls, we integrated transcriptomes and annotated cell states. Intercellular communication was mapped via metabolic flux inference, mitochondrial-derived vesicle(MDV) and phagocytosis signatures, ligand-receptor analysis, and lipid-associated macrophage(LAM) pseudotime trajectories. Results: Macrophages and adipocytes showed the strongest T2D-associated metabolic rewiring. We identified a stressed adipocyte state (AD3) with upregulated mitophagy, MDV trafficking, and inflammatory signaling, whose mitochondrial-stress module overlapped with genes enriched in adipocyte-derived extracellular vesicles. Among LAMs, we resolved an LAM-ST1 subset with immunometabolic activation but downregulation of receptors and lysosomal programs necessary for MDV uptake and degradation. Trajectory and cell-cell communication analyses revealed that AD3 signals to LAM-ST1 via inflammatory and vesicular pathways, with LAM-ST1 constituting a terminal, clearance-defective branch on the LAM continuum, indicative of a maladaptive mitochondrial stress-clearance response. Conclusion: We delineate an immunometabolic circuit wherein adipocyte mitochondrial stress and macrophage MDV clearance defects jointly sustain metaflammation in T2D scWAT, identifying LAM-mediated mitochondrial waste handling as a target for restoring immune homeostasis. Disclosure H. Ji: None. T. Cao: None. J. Du: None. Funding National Natural Science Foundation of China (grant no. 82070273), Noncommunicable Chronic Diseases-National Science and Technology Major Project grant no. 2024ZD0527200, Jiangsu Province Capability Improvement Project through Science, Technology and Education (grant no. ZDXK202230), National Key Specialty Construction Project (grant no. CZ1320240102).

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