MicroRNA-29a in Osteoblasts Represses High-Fat Diet-Mediated Osteoporosis and Body Adiposis through Targeting Leptin.

Wei-Shiung Lian,Jih-Yang Ko,Shao-Yu Wang,Re-Wen Wu,Yu-Shan Chen,Holger Jahr,Feng-Sheng Wang

doi:10.3390/ijms22179135

Abstract

Skeletal tissue involves systemic adipose tissue metabolism and energy expenditure. MicroRNA signaling controls high-fat diet (HFD)-induced bone and fat homeostasis dysregulation remains uncertain. This study revealed that transgenic overexpression of miR-29a under control of osteocalcin promoter in osteoblasts (miR-29aTg) attenuated HFD-mediated body overweight, hyperglycemia, and hypercholesterolemia. HFD-fed miR-29aTg mice showed less bone mass loss, fatty marrow, and visceral fat mass together with increased subscapular brown fat mass than HFD-fed wild-type mice. HFD-induced O2 underconsumption, respiratory quotient repression, and heat underproduction were attenuated in miR-29aTg mice. In vitro, miR-29a overexpression repressed transcriptomic landscapes of the adipocytokine signaling pathway, fatty acid metabolism, and lipid transport, etc., of bone marrow mesenchymal progenitor cells. Forced miR-29a expression promoted osteogenic differentiation but inhibited adipocyte formation. miR-29a signaling promoted brown/beige adipocyte markers Ucp-1, Pgc-1α, P2rx5, and Pat2 expression and inhibited white adipocyte markers Tcf21 and Hoxc9 expression. The microRNA also reduced peroxisome formation and leptin expression during adipocyte formation and downregulated HFD-induced leptin expression in bone tissue. Taken together, miR-29a controlled leptin signaling and brown/beige adipocyte formation of osteogenic progenitor cells to preserve bone anabolism, which reversed HFD-induced energy underutilization and visceral fat overproduction. This study sheds light on a new molecular mechanism by which bone integrity counteracts HFD-induced whole-body fat overproduction.

Highlights

IntroductionBone tissue plays an endocrine role in producing a plethora of molecules, including hormones, growth factors, neuropeptides, and exosomes, regulating marrow fat homeostasis, peripheral adipose metabolism, and energy expenditure [1,2]
This study aimed to use osteoblast-specific miR-29a transgenic mice to examine whether bone mass or visceral fat mass or in vivo metabolism were affected upon high-fat diet (HFD)
Given that gain of miR-29a signaling in bone tissue reversed HFD-mediated wholebody fat production and energy metabolism dysregulation, we examined whether fat metabolism was changed in the bone microenvironment

Summary

Introduction

Bone tissue plays an endocrine role in producing a plethora of molecules, including hormones, growth factors, neuropeptides, and exosomes, regulating marrow fat homeostasis, peripheral adipose metabolism, and energy expenditure [1,2]. Osteoporosis correlates with increased fat mass in the elderly [3] and the development of abdomen adiposity [4]. Expanding evidence reveals low bone mass together with high blood glucose levels and energy metabolism in mice lacking the Wnt signaling component β-catenin in osteoblasts [5]. Mice deficient in Dickkopf-1, an inhibitor for the Wnt pathway, in osteogenic progenitor cells exhibit body overweight and increased white fat pad [6]. Mesenchymal progenitor cellspecific PPARγ knockout mice develop phenotypes with high cortical bone microstructure and low epididymal fat mass [7]

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