Neural regulation of bone marrow adipose tissue

Abstract

Bone marrow adipose tissue (BMAT) is an important cellular component of the skeleton. Understanding how it is regulated by the nervous system is crucial to the study of bone and bone marrow related diseases. BMAT is innervated by sympathetic and sensory axons in bone and fluctuations in local nerve density and function may contribute to its distinct physiologic adaptations at various skeletal sites. BMAT is directly responsive to adrenergic signals. In addition, neural regulation of surrounding cells may modify BMAT-specific responses, providing many potential avenues for both direct and indirect neural regulation of BMAT metabolism. Lastly, BMAT and peripheral adipose tissues share the same autonomic pathways across the central neuraxis and regulation of BMAT may occur in diverse clinical settings of neurologic and metabolic disease. This review will highlight what is known and unknown about the neural regulation of BMAT and discuss opportunities for future research in the field.

Keywords: adrenergic receptor; bone; bone marrow adipocyte; mesenchymal stem cell; nervous system; neurotransmitter.

Fig. 1.. Bone marrow adipose tissue is innervated by sympathetic and sensory nerves.

Immunostained image (left) and nerve tracing (right) showing tyrosine hydroxylase positive nerves (TH, green) coiling around a vascular canal in bone (B), which are surrounded by perilipin positive bone marrow adipocytes (PLIN1, red, arrowheads). Calcitonin gene-related peptide positive nerves (CGRP, magenta) also innervate the vascular canal and lie adjacent to the surrounding bone marrow adipocytes. DAPI nuclear staining is shown in blue. BM = bone marrow.

Fig. 2.. Bone marrow adipocytes are responsive to neurotransmitter- and hormone-induced lipolytic pathways.

Local neurotransmitters secreted by sympathetic (green) and sensory (yellow) neurons and circulating neurotransmitters and hormones from the vasculature (red) act directly on G protein-coupled receptors (GPCR) on the membrane of the bone marrow adipocytes. Depending on the summative activation of cytoplasmic G-stimulatory or G-inhibitory proteins, this has the potential to activate the cAMP/PKA signaling pathway (*), leading to the phosphorylation of lipid droplet-associated protein perilipin and a series of lipases including adipose triglyceride lipase (ATGL), hormone-sensitive lipase (HSL), and monoacylglycerol lipase (MGL) that convert triglycerides to diacylglycerol, monoacylglycerol, and eventually to fatty acids (FFA) and glycerol that can be released from the adipocyte for energy use by other cells.

Fig. 3.. The peripheral nervous system may influence bone marrow adipose tissue by directly regulating cells within the bone marrow niche.

These cells include hematopoietic cells, perivascular mesenchymal stromal cells (MSCs), and skeletal cells. The regulation of bone marrow adipocytes (BMAds) by these cells may synergize with the direct actions of neurotransmitters released by sympathetic (green) and sensory (yellow) neurons on BMAds. The sympathetic nerves innervate the perivascular MSCs around the arterioles (red), forming the neuro–reticular complex. ➀ BMAds provide energy to surrounding cells. ➁ Hematopoietic cells send signals to BMAds. ➂ Skeletal cells secrete factors to regulate BMAds. ➃ Perivascular MSCs send signals to as well as differentiate into BMAds.