Research Paper Volume 15, Issue 2 pp 542—552

Metformin increases bone marrow adipose tissue by promoting mesenchymal stromal cells apoptosis

Wu Duan1, , Huajie Zou2, , Nan Zang1, , Dongxia Ma3, , Bo Yang4, , Lin Zhu5, ,

  • 1 Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China
  • 2 Department of Endocrinology, The Affiliated Hospital of Qinghai University, Xining 810000, China
  • 3 Department of Allergy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
  • 4 Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
  • 5 Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China

Received: December 29, 2020       Accepted: October 27, 2022       Published: January 14, 2023      

https://doi.org/10.18632/aging.204486
How to Cite

Copyright: © 2023 Zhu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Bone marrow adipose tissue (MAT) has the potential to exert both local and systemic effects on metabolic homeostasis. As a first-line drug used to treat type 2 diabetes mellitus, metformin has conflicting effects on MAT and bone marrow mesenchymal stem cell (BM-MSC) differentiation. Through a series of experiments in vivo and in vitro, we found that except improving the glucose and lipid metabolism disorder in ob/ob mice, 200 mg/kg metformin increased MAT in mice tibia, and prompted osteogenic genes (RunX2, OPN, OCN) and lipogenic genes (Ppar-γ, Cebpα, Scd1) expression in mice bone marrow. However, metformin promoted osteogenesis and inhibited lipogenesis of MSC in vitro, which is inconsistent with the results in vivo. Given MAT being considered the “filler” of the space after the apoptosis of bone marrow stroma, the effect of metformin on MSC apoptosis was examined. We discovered that metformin induces MSC apoptosis in vivo and in vitro. Therefore, we speculated that the increased MAT in mice tibia may be attributed to the filling of adipose tissue after apoptosis of bone marrow stromal cells induced by metformin. The increased MAT may be involved in the regulation of metformin on glucose, lipid, and bone metabolism in diabetic mice, providing a new way to understand the metabolic regulation of metformin. While increased MAT-associated insulin resistance and metabolic disorders may account for the poorer clinical benefits in patients with intensive glucose control.

Abbreviations

BAT: Bone marrow adipose tissue; BM-MSC: bone marrow mesenchymal stem cells; T2DM: type 2 diabetes mellitus; RunX2: runt-related transcription factor 2; Bsp: bone sialo protein; OPN: osteopontin; PPAR: peroxisome proliferator-activated receptors; C/EBP: CAAT/enhancer binding proteins; Enos: endothelial nitric oxide synthase; AMPK: activating Adenosine 5′-monophosphate-activated protein kinase; GSK3β: glycogen synthase kinase 3 beta; hAMSCs: human amnion-derived MSCs; Ocn: osteocalcin; TG: triglyceride; TC: total cholesterol; HDL-C: high-density lipoprotein cholesterol; LDL-C: low-density lipoprotein cholesterol; Scd1: Stearyl CoA desaturase 1; Bcl-2: B-cell lymphoma-2; Bax: Bcl-2-associated X protein; Bad: Bcl-2-associated agonist of cell death; IGF-1: insulin-like growth factor; SDF-1: stromal-derived factor.