Single-Cell Landscape and a Macrophage Subset Enhancing Brown Adipocyte Function in Diabetes (Diabetes Metab J 2024;48:885-900)

Yea Eun Kang; Ju Hee Lee

doi:10.4093/dmj.2024.0739

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Letter Single-Cell Landscape and a Macrophage Subset Enhancing Brown Adipocyte Function in Diabetes (Diabetes Metab J 2024;48:885-900): Yea Eun Kang, Ju Hee Lee; Diabetes & Metabolism Journal 2025;49(1):160-161.
DOI: https://doi.org/10.4093/dmj.2024.0739
Published online: January 1, 2025

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Department of Internal Medicine, Chungnam National University College of Medicine, Daejeon, Korea

Corresponding author: Ju Hee Lee

Department of Internal Medicine, Chungnam National University College of Medicine, 266 Munhwa-ro, Jung-gu, Daejeon 35015, Korea E-mail: serenaj@cnu.ac.kr

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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See the reply "Single-Cell Landscape and a Macrophage Subset Enhancing Brown Adipocyte Function in Diabetes (Diabetes Metab J 2024;48:885-900)" in Volume 49 on page 162.

See the article "Single-Cell Landscape and a Macrophage Subset Enhancing Brown Adipocyte Function in Diabetes" on page 885.

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by insulin resistance, and is often linked to obesity and metabolic syndrome. This condition develops when sustained energy intake exceeds energy expenditure, resulting in excessive energy storage. These energy reserves, coupled with associated inflammatory responses, contribute to the development of metabolic syndrome and diabetes [1]. To combat obesity and T2DM, strategies focused on both enhancing energy metabolism and reducing energy intake are essential. Activating brown adipose tissue (BAT), which dissipates energy as heat through uncoupling protein 1, is a promising therapeutic approach to target metabolic diseases including T2DM [2-4]. Recent advancements in single-cell transcriptomics technologies have shed light on the heterogeneity within various adipose tissues. In BAT, a study using single-nuclei sequencing in mice and humans identified subpopulations of adipocytes exhibiting thermogenic capacity [5]. However, the heterogeneity of BAT in the context of T2DM remains unexplored.

Gu et al.’s recent study [6] employed single-cell RNA sequencing to delve into the cellular mechanisms underlying BAT dysfunction in T2DM rats. Their analysis of BAT-derived stromal vascular fraction (SVF) uncovered significant changes, including elevated inflammatory responses, enhanced angiogenesis, and altered glucose and lipid metabolism. Additionally, the study identified a shift in macrophage populations within the SVF, with retinoic acid receptor responder 2 (Rarres2)-positive macrophages emerging as potential regulators of BAT differentiation.

While Gu et al.’s study [6] provided a comprehensive analysis, the interpretation was descriptive in nature, and lacks a detailed mechanistic understanding of BAT’s contribution to T2DM pathophysiology. Notably, the most significant differences between T2DM and control mice were observed in the adipose stem/progenitor cell (ASPC) cluster. The authors identified a T2DM-specific ASPC2 cluster, further subdivided into subsets with distinct functions, including Cd163+ASPC2-s1 (involved in neutrophil chemotaxis and myeloid differentiation) and S100 calcium-binding protein A9 (S100a9)+ASPC2- s2 (linked to chronic inflammation and neutrophil chemotaxis). However, this study did not utilize neutrophil populations in single-cell RNA sequencing analysis, leaving the connection between ASPCs and neutrophils unexplored. Future research clarifying the role of neutrophil chemotaxis in chronic inflammation within the context of T2DM, as hinted at by these findings, could provide valuable insight into the disease’s underlying mechanisms. Additionally, studies on changes in ASPC clusters induced by increased neutrophil chemotaxis, as well as investigations utilizing advanced single-cell technology and neutrophil sorting to explore cell-to-cell interactions between neutrophils and ASPCs, could further enhance our understanding of these complex interactions.

In addition, Gu et al. [6] observed that the primary outgoing information flow shifted from fibroblasts (FBs) to multiple cell types, including ASPCs, smooth muscle cells, and FBs, while the dominant outgoing signaling transitioned from angiopoietin-like protein (ANGPTL) signaling to multiple pathways in diabetes. ANGPTL signaling is a critical pathway in various cancers and metabolic disorders [7,8]; however, its role in BAT remains poorly understood. Gu et al. [6] not only highlighted the upregulation of ANGPTL signaling but also demonstrated that, in T2DM, this inflammatory signaling is altered across multiple cell types, particularly in the increased population of ASPCs, in addition to FBs. These findings emphasize the importance of understanding these complex interactions and suggest the potential for targeting cell type-specific inflammatory signals in future therapeutic approaches.

While the Rarres2+ macrophage subset was decreased in the BAT-derived SVF of T2DM rats, paradoxically, the relative expression level of Rarres2 was higher in T2DM compared to normal rats within this subset. However, the absence of mechanistic studies exploring Rarres2’s functional role in BAT inflammation limits the biological interpretation of these findings. Furthermore, a difference in the Rarres2+ macrophage population was not directly observed in normal versus T2DM rat brown adipocytes, restricting the study’s ability to detect broader implications for systemic glucose metabolism.

Another limitation lies in the lack of detailed information regarding the sample size and sequencing replicates, which raises concerns about the robustness and reproducibility of the data. Explicit clarification of these aspects would strengthen the study’s credibility and provide a stronger foundation for future research.

Current therapeutic approaches for T2DM with obesity primarily focus on reducing energy intake, as effective treatments to augment energy expenditure remain elusive. This study introduces a novel perspective by emphasizing the complexity of cell-cell interactions and signaling networks within BAT in T2DM, particularly through its focus on ASPCs and macrophage subsets. Future research building on these findings could pave the way for cell type-specific therapeutic strategies targeting inflammation and energy metabolism, ultimately contributing to more effective interventions for metabolic diseases.

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CONFLICTS OF INTEREST

No potential conflict of interest relevant to this article was reported.

REFERENCES

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6. Gu J, Jin J, Ren X, Zhang X, Li J, Wang X, et al. Single-cell landscape and a macrophage subset enhancing brown adipocyte function in diabetes. Diabetes Metab J 2024;48:885-900.Article PubMed PMC PDF
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Single-Cell Landscape and a Macrophage Subset Enhancing Brown Adipocyte Function in Diabetes (Diabetes Metab J 2024;48:885-900)

Diabetes Metab J. 2025;49(1):160-161. Published online January 1, 2025

DOI: https://doi.org/10.4093/dmj.2024.0739

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Single-Cell Landscape and a Macrophage Subset Enhancing Brown Adipocyte Function in Diabetes (Diabetes Metab J 2024;48:885-900)

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Kang YE, Lee JH. Single-Cell Landscape and a Macrophage Subset Enhancing Brown Adipocyte Function in Diabetes (Diabetes Metab J 2024;48:885-900). Diabetes Metab J. 2025;49(1):160-161.

DOI: https://doi.org/10.4093/dmj.2024.0739.

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