bims-obesme 2025-08-24 papers

Issue of 2025–08–24
five papers selected by
Xiong Weng, University of Edinburgh

Nat Commun. 2025 Aug 16. 16(1): 7648

Genkwanin glycosides are major active compounds in Phaleria nisidai extract mediating improved glucose homeostasis by stimulating glucose uptake into adipose tissues.

Carla Horvath, Joëlle Houriet, Alexandra Kellenberger, Caroline Moser, Lucia Balazova, Miroslav Balaz, Hua Dong, Aron Horvath, Isabel Reinisch, Vissarion Efthymiou, Adriano Rutz, Laurence Marcourt, Christopher Kitalong, Bertrand Graz, Victor Yano, Emerson Ferreira Queiroz, Jean-Luc Wolfender, Christian Wolfrum.

Natural remedies are used as standalone treatments or complementary to modern medicine to control type 2 diabetes. In Palau, the traditional leaf decoction of Phaleria nisidai (PNe) is selected to treat hyperglycemia and its efficacy has been supported by a small clinical trial. As part of a reverse pharmacology approach, we here investigated the anti-diabetic potential of PNe and its bioactive compounds to alleviate insulin resistance in diet-induced obese, male mice. Dietary supplementation with PNe improves insulin sensitivity and promotes glucose uptake into adipose depots. In vitro, PNe triggers glucose disposal into murine and human adipocytes by upregulating Glut1 expression through PKC-ERK1/2 signaling. To identify active constituents in PNe, we conducted bioactivity-guided fractionations and deciphered genkwanin flavone glycosides as bioactive principles. Moreover, we demonstrate that the aglycone genkwanin (GE) improves insulin resistance to a comparable extent to the anti-diabetic drug, metformin. Our findings present GE as promising glucoregulatory phytochemical that facilitates glucose uptake into adipocytes, thereby reducing systemic glucose load and enhancing insulin sensitivity.

DOI: https://doi.org/10.1038/s41467-025-62689-8

Nat Metab. 2025 Aug 18.

Metabolic Messenger: growth differentiation factor 15.

Samuel N Breit, Vicky W Tsai.

Growth differentiation factor 15 (GDF15; also known as macrophage-inhibitory cytokine-1) is a stress-responsive cytokine that is overexpressed under a broad range of conditions. It has a role in regulating appetite and body weight and is an aetiological factor in anorexia-cachexia syndromes, as well as nausea and vomiting during pregnancy. Long after its original cloning, its receptor was identified as GFRAL, a distant member of the GDNF receptor family within the TGFβ superfamily, with RET as its co-receptor. Both of these are highly localized to specific hindbrain regions. Although many of GFRAL's metabolic changes may be linked to its effect on suppressing appetite, recent findings suggest that GDF15 also independently regulates energy expenditure and insulin sensitivity. Here, we review recent literature and provide updates on the current understanding of GDF15 biology and its therapeutic applications in health and metabolic diseases.

DOI: https://doi.org/10.1038/s42255-025-01353-3

iScience. 2025 Sep 19. 28(9): 113233

Mitochondrial hyper-acetylation induced by an engineered acetyltransferase promotes cellular senescence.

Tadahiro Shimazu, Ayane Kataoka, Takehiro Suzuki, Naoshi Dohmae, Yoichi Shinkai.

Protein acetylation plays crucial roles in diverse biological functions, including mitochondrial metabolism. Although SIRT3 catalyzes the removal of acetyl groups in mitochondria, the addition of the acetyl groups is thought to be primarily controlled in an enzyme-independent manner due to the absence of potent acetyltransferases. In this study, we developed an engineered mitochondria-localized acetyltransferase, named engineered mitochondrial acetyltransferase (eMAT). eMAT localized in the mitochondrial matrix and introduced robust global protein lysine acetylation, including 413 proteins with 1,119 target lysine residues. Notably, 74% of the acetylated proteins overlapped with previously known acetylated proteins, indicating that the eMAT-mediated acetylation system is physiologically relevant. Functionally, eMAT negatively regulated mitochondrial energy metabolism, inhibited cell growth, and promoted cellular senescence, suggesting that mitochondrial hyper-acetylation drives metabolic inhibition and cellular senescence. SIRT3 counteracted eMAT-induced acetylation and metabolic inhibition, restored cell growth, and protected cells from senescence, highlighting the contribution of SIRT3 in maintaining energy metabolism and preventing cellular senescence.

Keywords: Metabolic flux analysis; Metabolomics; Protein

DOI: https://doi.org/10.1016/j.isci.2025.113233

Autophagy. 2025 Aug 19.

Pathological aging is alleviated by neutralization of the autophagy-repressive tissue hormone DBI/ACBP.

Léa Montégut, Flavia Lambertucci, Lucas Moledo-Nodar, Isabelle Martins, Alejandro Lucia, Clea Barcena, Guido Kroemer.

DBI/ACBP (diazepam binding inhibitor, acyl CoA-binding protein) is a macroautophagy/autophagy-inhibitory tissue hormone produced by multiple cell types. The plasma levels of DBI/ACBP rise with age and disease. In centenarians living in nursing homes, DBI/ACBP concentrations are approximately threefold higher than in younger adults (30-48 years old), but these levels increase further in centenarians hospitalized due to disease exacerbation. Elevated DBI/ACBP correlates with unfavorable clinical parameters, including high Charlson Comorbidity Index, elevated neutrophil:lymphocyte ratio, and decreased renal function. In mouse models, neutralization of DBI/ACBP using monoclonal antibodies ameliorates several aging-related pathologies. In zmpste24-/- progeroid mice, anti-DBI/ACBP therapy improves posture, mobility, cutaneous and dental abnormalities, splenic atrophy, kidney function, and blood parameters. In models of renal aging induced by cisplatin or doxorubicin, DBI/ACBP neutralization suppresses renal fibrosis and cellular senescence. Similarly, in cardiac and hepatic aging models, anti-DBI/ACBP reduces expression of the senescence marker CDKN1A/p21 (cyclin dependent kinase inhibitor 1A) in cardiomyocytes and hepatocytes. Single-nucleus RNA sequencing of heart tissue revealed that anti-DBI/ACBP restores key metabolic and cardioprotective gene expression patterns suppressed by doxorubicin. Together, these findings establish DBI/ACBP as a marker and driver of pathological aging and demonstrate that its neutralization confers multi-organ anti-senescence effects. Thus, DBI/ACBP-targeting strategies hold therapeutic potential for improving healthspan.

Keywords: Chemotherapy; DNA damage; geroscience; heart failure senescence

DOI: https://doi.org/10.1080/15548627.2025.2549451

Stem Cell Res Ther. 2025 Aug 20. 16(1): 444

Multi-function of adipose-derived stem cells on gut disorder: from bench to bedside.

Jiatong Zhao, Shuzi Xin, Xiaohui Liu, Weikai Shi, Boya Wang, Hongli Wang, Yi Wang, Rongxuan Hua, Yize Li, Lei Gao, Xin Lu, Jingdong Xu.

Keywords: Adipose-derived stem cells; Anti-inflammation; Fibrosis; Immunoregulatory effects; Inflammatory bowel disease; Mesenchymal stem cells

DOI: https://doi.org/10.1186/s13287-025-04549-2