Intracellular Lipid Droplets Serve As a Source of Energy Substrates to Support Osteoblast Function

Presentation Number: SAT 338
Date of Presentation: April 1st, 2017

Elizabeth Rendina-Ruedy*1, Anyonya R Guntur2, Brenda J Smith3, Michael P Czech4 and Clifford J Rosen5
1Maine Medical Center, 2Maine Medical Center, Scarborough, ME, 3Oklahoma State University, 4University of Massachsetts Medical School, Worcester, MA, 5Maine Medical Center Research Institute, Scarborough, ME

Abstract

Type 2 diabetes mellitus (T2DM) is a major public health problem that results in an ~2 fold increase in fracture risk independent of bone mineral density (BMD). While the paradoxical relationship between BMD and fracture has perplexed researchers and clinicians alike, one potential explanation is the apparent decrease in bone turnover. Specifically, the high energetic demand bone formation requires has led to a renewed interest in the intracellular metabolism of osteoblasts. Therefore, we hypothesized that the decrease in bone formation associated with T2DM is a function of impaired metabolic capacity of the osteoblast. To test this hypothesis we utilized an in vivo mouse model of diet-induced obesity to model the metabolic perturbations associated with T2DM, along with ex vivo and in vitroprimary bone marrow stromal cell cultures (BMSCs). Our results demonstrate that osteoblasts from mice on a high fat diet had lower extracellular acidification rates (ECAR) and oxygen consumption rates (OCR) compared to control osteoblasts, indicative of a more quiescent cell compared to the energetic profile from the control osteoblasts. Interestingly, we observed the accumulation of intracellular lipid droplets in bone-lining osteo-progenitor cells from mice on the high fat diet, which led us to further explore whether these lipid droplets served as a readily available metabolic substrate during osteoblast differentiation. Indeed blunting lysosomal function with bafilomycin A1 (BafA1) or chloroquine (CQ) resulted in increased accumulation of neutral lipid droplets in BMSCs. Accordingly, when either lysosomal lipolysis (BafA1 or CQ) or mitochondrial fatty acid transport (etomoxir or Eto) were impaired OCR was significantly reduced in early osteogenic cells, suggesting that intracellular lipids were capable of providing endogenous fatty acid substrates for ATP generation. Collectively, these data are the first to demonstrate that osteo-progenitor cells have the ability to store, degrade, and utilize lipid droplets. Furthermore, these data suggest that the ability for osteo-progenitor cells to mobilize fatty acids from lipid droplets is impaired during T2DM, contributing to decreased bone formation and the subsequent increase in fracture risk.

 

Nothing to Disclose: ER, ARG, BJS, MPC, CJR