High-Fat Diet–Induced Obesity Promotes Expansion of Bone Marrow Adipose Tissue and Impairs Skeletal Stem Cell Functions in Mice

Abstract

Obesity represents a risk factor for development of insulin resistance and type 2 diabetes. In addition, it has been associated with increased adipocyte formation in the bone marrow (BM) along with increased risk for bone fragility fractures. However, little is known on the cellular mechanisms that link obesity, BM adiposity, and bone fragility. Thus, in an obesity intervention study in C57BL/6J mice fed with a high-fat diet (HFD) for 12 weeks, we investigated the molecular and cellular phenotype of bone marrow adipose tissue (BMAT), BM progenitor cells, and BM microenvironment in comparison to peripheral adipose tissue (AT). HFD decreased trabecular bone mass by 29%, cortical thickness by 5%, and increased BM adiposity by 184%. In contrast to peripheral AT, BMAT did not exhibit pro-inflammatory phenotype. BM progenitor cells isolated from HFD mice exhibited decreased mRNA levels of inflammatory genes (Tnfα, IL1β, Lcn2) and did not manifest an insulin resistant phenotype evidenced by normal levels of pAKT after insulin stimulation as well as normal levels of insulin signaling genes. In addition, BM progenitor cells manifested enhanced adipocyte differentiation in HFD condition. Thus, our data demonstrate that BMAT expansion in response to HFD exerts a deleterious effect on the skeleton. Continuous recruitment of progenitor cells to adipogenesis leads to progenitor cell exhaustion, decreased recruitment to osteoblastic cells, and decreased bone formation. In addition, the absence of insulin resistance and inflammation in the BM suggest that BMAT buffers extra energy in the form of triglycerides and thus plays a role in whole-body energy homeostasis. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc.

A diet high in fat and fructose adversely affects osseointegration of titanium implants in rats

“…The MAR was reduced in both intervention groups, reflecting the reduced rate of matrix production by osteoblasts. A similar high‐fat‐diet‐induced reduction in tibial and vertebral MAR and BFR has been reported in male mice (Tencerova et al, ). The BFR provides a measure of both the volume of matrix production (MAR) and the area of bone surface covered by active osteoblasts (MS/BS) and was reduced in the dHFHF group.…”

Defining osteoblast and adipocyte lineages in the bone marrow

“…The differentiation of the BMSC into a bone marrow adipocyte involves expression of key transcription factors: peroxisome proliferator-activated receptor γ (Pparγ) and CCAAT/enhancer-binding protein α (c/EBPα) (10). Bone marrow adipocytes characteristically store cytoplasmic lipid droplets and express a number of genes related to lipid storage (i.e., Cidec, Plin1), fatty acid metabolism (i.e., Fasn, lipases like ATGL and HSL), and adipocyte function (i.e., adiponectin, lepR) (11). While the roles of bone marrow adipocytes are still in question, there is evidence that these cells may serve as energy reservoirs for the bone (12).…”

“…Finally, lifestyle—including reduced mechanical loading and diet—can influence the metabolic needs of the bone as well as alter the extracellular signals that dictate BMSC fate during aging. Load-bearing exercises can reduce bone marrow adiposity (61), but both high fat and calorically restricted diets induce bone marrow fat storage and consequent bone loss (11,62). Despite this evidence, whether these cellular responses to lifestyle and diet are efforts to store excess fuel sources in the form of lipid droplets remains unclear.…”

Exercise Degrades Bone in Caloric Restriction, Despite Suppression of Marrow Adipose Tissue (MAT)

“…MAT, derived from the differentiation of mesenchymal stem cells (MSC) into adipocytes, increases in bonefragility states; however, its potential role in promoting bone formation and/or resorption has not been elucidated, despite active investigation. (2)(3)(4)(5)(6)(7)(8)(9)(10)(11) Understanding of MAT has improved with quantification methods that permit exact investigations, including magnetic resonance spectroscopy (MRS) in humans (12)(13)(14)(15) as well as osmium-μCT and MRI with advanced image processing in rodents. (16)(17)(18) Recent work established MAT to be suppressed by exercise, in rodents (16,18) and humans, (19) suggesting that MAT may function similarly to white adipose tissue in a calorie-replete state as an energy depot.…”