Authorship：Lead author   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

Open Access

PubMed

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

Recent evidence has shown that adipose tissue eventually develops fibrosis through complex cellular crosstalk. 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 employed single-cell analytical approaches to investigate cell-tocell 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 (CLSs), 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 CLSs. 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 CLSs.

DOI： 10.2337/db24-0762

PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Center for Academic Publications Japan  

<p>Repositioning is usually used to indicate drug repositioning, or the finding of new disease applications for existing, approved drugs. Nutrients can be ingested for nutritional as well as therapeutic purposes, acting much the same as drugs. Amino acids are organic compounds that possess both amino and carboxy group functionalities and are best known as building blocks of proteins in living organisms. Recent studies of individual amino acids have revealed them to be functional ingredients of new therapeutics, promoting health in addition to nutrition. Here, we propose “nutrient-repositioning”, the discovery of effects different from the existing effects of nutrients. This review summarizes some recent discoveries of unexpected amino acid functions, especially in BCAAs, histidine and serine.</p>

DOI： 10.3177/jnsv.68.s134

Web of Science

Scopus

PubMed

CiNii Research

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

The pathophysiology of type 2 diabetes involves insulin and glucagon. Protein kinase C (Pkc)-δ, a serine–threonine kinase, is ubiquitously expressed and involved in regulating cell death and proliferation. However, the role of Pkcδ in regulating glucagon secretion in pancreatic α-cells remains unclear. Therefore, this study aimed to elucidate the physiological role of Pkcδ in glucagon secretion from pancreatic α-cells. Glucagon secretions were investigated in Pkcδ-knockdown InR1G9 cells and pancreatic α-cell-specific Pkcδ-knockout (αPkcδKO) mice. Knockdown of Pkcδ in the glucagon-secreting cell line InR1G9 cells reduced glucagon secretion. The basic amino acid arginine enhances glucagon secretion via voltage-dependent calcium channels (VDCC). Furthermore, we showed that arginine increased Pkcδ phosphorylation at Thr505, which is critical for Pkcδ activation. Interestingly, the knockdown of Pkcδ in InR1G9 cells reduced arginine-induced glucagon secretion. Moreover, arginine-induced glucagon secretions were decreased in αPkcδKO mice and islets from αPkcδKO mice. Pkcδ is essential for arginine-induced glucagon secretion in pancreatic α-cells. Therefore, this study may contribute to the elucidation of the molecular mechanism of amino acid-induced glucagon secretion and the development of novel antidiabetic drugs targeting Pkcδ and glucagon.

DOI： 10.3390/ijms23074003

Web of Science

Scopus

PubMed

Language：English  

DOI： 10.1016/j.jnutbio.2021.108811

PubMed

Language：Japanese   Publisher：(株)羊土社  

グルカゴン研究は同じ膵ホルモンであるインスリン研究と比べて遅れており、その分泌動態の詳細は不明であった。グルカゴン研究が遅れてきた原因として、正確な測定系がなかったことがある。われわれは、正確な測定系の開発と、それを用いた解析により、糖尿病病態では、分岐鎖アミノ酸(BCAAs)がグルカゴン分泌を亢進させることを明らかとしたので、グルカゴン研究の現状とともに紹介する。(著者抄録)

Language：Japanese   Publisher：(公社)日本栄養・食糧学会  

Language：Japanese   Publisher：日本アミノ酸学会