Award type：Award from Japanese society, conference, symposium, etc. 

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：American Diabetes Association  

Recent evidence has shown that adipose tissue eventually develops fibrosis through complex cellular cross talk. Although advances in single-cell transcriptomics have provided new insights into cell diversity during this process, little is known about the interactions among the distinct cell types. In this study, we used single-cell analytical approaches to investigate cell-to-cell communications between macrophages and fibroblasts in the adipose tissue of diet-induced obese mice. Spatial transcriptomics was used to understand local cellular interaction within crown-like structures (CLS), a characteristic histological feature of adipose tissue in obesity driving inflammation and fibrosis. Macrophages and fibroblasts were divided into several subclusters that appeared to interact more intensely and complexly with the degree of obesity. Besides previously reported lipid-associated macrophages (LAMs), we found a small subcluster expressing macrophage-inducible C-type lectin (Mincle), specifically localizing to CLS. Mincle signaling increased the expression of oncostatin M (Osm), suppressing collagen gene expression in adipose tissue fibroblasts. Consistent with these findings, Osm deficiency in immune cells enhanced obesity-induced adipose tissue fibrosis in vivo. Moreover, OSM expression was positively correlated with MINCLE expression in human adipose tissue during obesity. Our results suggest that Osm secreted by Mincle-expressing macrophages is involved in dynamic adipose tissue remodeling in the proximity of CLS.

Article Highlights

Adipose tissue fibrosis is a complex and dynamic process that involves many cell types, such as macrophages and fibroblasts. Crown-like structures, which drive inflammation and fibrosis in obesity, are excellent targets for single-cell and spatial transcriptomics. We found novel cell-to-cell communications between macrophages and fibroblasts in adipose tissue from diet-induced obese mice, particularly during the fibrotic phase. We elucidated the role of the macrophage-inducible C-type lectin–oncostatin M axis in obesity-induced adipose tissue fibrosis.

DOI： 10.2337/db24-0762

Web of Science

Scopus

PubMed

Language：English   Publisher：Scientific Reports  

Acute kidney injury (AKI) can progress to chronic kidney disease (CKD), via a mechanism that is still largely unknown. We previously reported that glucosylceramide (GlcCer) acts as a damage-associated molecular pattern (DAMP) during AKI. Here, we demonstrate that renal GlcCer levels increase persistently during AKI, primarily due to oxidative stress-mediated downregulation of β-1,4-galactosyltransferase 5 (B4galt5) in proximal tubules. Using mass spectrometry, we showed that GlcCer specifically accumulated in damaged proximal tubules. Among the enzymes involved in GlcCer metabolism, B4galt5 was predominantly expressed in proximal tubules and its expression was consistently downregulated across multiple AKI models. Knockdown of B4galt5 alone was sufficient to increase GlcCer levels in cultured proximal tubular cells. Moreover, in vivo administration of GlcCer combined with free cholesterol triggered inflammatory responses via the innate immune receptor macrophage-inducible C-type lectin (Mincle). These inflammatory responses were almost abolished in Mincle-deficient mice, suggesting a specific GlcCer-Mincle pathway. Our findings indicate that B4galt5 plays a critical role in GlcCer accumulation in necrotic tubules following AKI. Specifically, we propose that dying proximal tubules alter their glycolipid metabolism to generate DAMPs, highlighting B4galt5 as a potential therapeutic target for preventing the AKI-to-CKD transition.

DOI： 10.1038/s41598-025-28897-4

Web of Science

Scopus

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

As obesity progresses, dynamic tissue remodeling of adipose tissue occurs over time, that is, adipocyte hypertrophy, chronic inflammation, and interstitial fibrosis. Some obese individuals exhibit healthy adipose tissue expansion, characterized by modest inflammation and fibrosis despite adipocyte hypertrophy, resulting in "Metabolically Healthy Obesity (MHO)". In this study, we investigated the effects of transient weight loss on adipose tissue remodeling during the development of obesity. Male C57BL6/J mice received various types of transient weight loss treatments during diet-induced obesity. A 2-week weight loss intervention during the inflammatory phase promoted healthy adipose tissue expansion, reduced ectopic lipid accumulation, and improved glucose metabolism. In contrast, protocols with shorter duration and delayed intervention, failed to induce MHO. Since serum concentrations of ketone bodies were elevated during weight loss, we examined the effects of hyperketonemia on obesity-induced adipose tissue remodeling. Transient treatment with 1,3-butanediol (BD), which increased serum ketone body concentrations to levels similar to those observed during weight loss, induced healthy adipose tissue expansion and reduced hepatic steatosis even during continuous high-fat diet (HFD) feeding. Ketone bodies effectively suppressed activation of adipose tissue fibroblasts in vivo and in vitro. This study provides evidence that an appropriate dietary intervention can promote healthy adipose tissue expansion in mice, even after the regaining of weight, thereby leading to MHO. As the underlying mechanism, our data revealed a key role for ketone bodies in suppressing activation of adipose tissue fibroblasts. This study paves the way for nutritional approaches to induce MHO.

DOI： 10.1096/fj.202501121R

Web of Science

Scopus

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1084/jem.20192230

Open Access

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/cas.12865

Open Access

Language：Japanese

Language：Japanese

Event date： 2025.11

Event date： 2025.10

Event date： 2025.3

Event date： 2025.2

Event date： 2024.10