Caloric Restriction Alters Bone Marrow Adiposity And Energy Metabolism

Abstract

BACKGROUND: Bone marrow adipose tissue (bMAT) refers to mesenchymal stem cell-derived adipocytes located within the bone marrow cavity. In adult humans, bMAT comprises ~15% of total body adiposity and is primarily located throughout the appendicular skeleton. bMAT is an extremely ‘plastic’ depot that rapidly responds to fluctuations in nutrient sensing and energetic homeostasis. Paradoxically, bMAT levels increase during both obesity and caloric restriction (CR); however, it is unclear whether the qualitative phenotype of bMAT differs under these conditions. PURPOSE: To identify obesity- and CR-induced alterations in bMAT lipid composition, transcriptional profile, and metabolic signature. METHODS: Male 6-week-old genetically obese ob/ob mice (leptin deficient) were housed at 32°C (thermoneutral) for 10 weeks. One group of mice was fed ad libitum (AL; N=9) for the study duration, while a second group was calorically restricted (CR; N=9) to ~50% of the AL group to prevent excess weight gain. Femora and tibiae were collected for lipid composition (gas chromatography), gene expression analysis (qRT-PCR), and in situ metabolic phenotyping (MPLSM-FLIM). Blood was collected for assessment of circulating analytes. RESULTS: CR mice had lower body mass and blood glucose, and higher blood corticosterone compared to AL mice. CR increased femur adipocyte density and adipocyte size compared to AL. Tibia lipid composition differed between AL and CR mice (AL>CR C16:0, C:18:1n-9, C:18:1n-7, C20:4n-6; CR >AL C14:0, C16:1n-7, and C18:2n-6). CR upregulated the expression of adipokines (e.g., Adipoq, CFD), which occurred co-incidentally with elevated levels of serum adiponectin and adipsin. Transcriptional profiling revealed differential expression of genes involved in adipogenesis, lipid metabolism, mitochondrial activity, and antioxidant response (e.g., CR>AL SCD1, FASN, LIPE, LPL, KLF15, PPARGC1a, PPARa, and SOD1). MPLSM-FLIM revealed highly heterogenic metabolic phenotypes among cells within the bone marrow cavity. CONCLUSION: CR induces functional changes in bMAT that occur independent of leptin. bMAT lies at the interface of metabolic and inflammatory signaling mechanisms, and is a potential mediator of systemic metabolic and inflammatory homeostasis during health and disease.