The involvement of neuroimmune cells in adipose innervation

Abstract

53Innervation of adipose tissue is essential for the proper function of this critical metabolic 54 organ. Numerous surgical and chemical denervation studies have demonstrated how 55 maintenance of brain-adipose communication through both sympathetic efferent and 56 sensory afferent nerves helps regulate adipocyte size, cell number, lipolysis, and 57 'browning' of white adipose tissue. Neurotrophic factors are growth factors that promote 58 neuron survival, regeneration and outgrowth of neurites from adult nerves. Peripheral 59 blood immune cells have been shown to be a source of neurotrophic factors in humans 60 and mice. Although a number of these immune cells also reside in the adipose stromal 61 vascular fraction (SVF), it has remained unclear what roles they play in adipose 62 innervation. We have demonstrated that adipose resident myeloid lineage immune cells 63 secrete brain derived neurotrophic factor (BDNF) and that deletion of this neurotrophic 64 factor from the myeloid lineage led to a 'genetic denervation' of inguinal subcutaneous 65 adipose tissue, thereby causing decreased energy expenditure and increased adipose 66 mass. AAV-BDNF intra-adipose injections resulted in an increase in markers of 67 innervation in two models with demonstrated adipose neuropathy. We and others have 68 previously shown that noradrenergic stimulation via cold exposure increases adipose 69 innervation in the inguinal depot. Here we have identified a subset of myeloid cells that 70 are Cx3cr1+ monocytes/macrophages expressing adrenergic receptors. The quantity of 71 these mobile immune cells increased in adipose tissue upon cold stimulation, fitting with 72 their function to hone to sites of tissue injury and repair, and these cells also expressed 73 BDNF. We propose that these cold induced neuroimmune cells (CINCs) are key players 74 in maintaining adipose innervation as well as promoting adipose nerve remodeling 75 under adrenergic stimuli such as cold exposure. 76 resulted in an obesity phenotype due to hyperphagic behavior [15]. Obesity is 102 associated with lower serum levels of BDNF in humans, and animal studies have shown 103 that central and peripheral administration of BDNF reduced food intake and 104 hyperglycemia, and increased energy expenditure, via CNS mediated mechanisms [16-105 18]. As review by Xu and Xie, genetic mutations in human BDNF and its receptor TrkB 106 result in morbid early-onset obesity [19]; furthermore, genome wide associated studies 107 (GWAS) have identified single nucleotide polymorphisms (SNPs) in or near BDNF to be 108 associated with increased BMI [19]. 109Despite these strong correlations between altered function of BDNF and its 110receptor TrkB with obesity, this growth factor has been predominately studied only in 111 the CNS. A few studies have clearly shown that NFs, including BDNF, are present in 112 adipose tissue [20][21][22], but the cellular source of BDNF in adipose had not been 113 determined. In adipose specific (FABP4-Cre) knock-outs of BDNF or TrkB, only CNS 114 effects...

The Presence of Myelinated Nerves and Schwann Cells in White Adipose Tissue: Proximity to Synaptic Vesicle Containing Nerve Terminals and Potential Role in BTBR ob/ob Demyelinating Diabetic Neuropathy

“…SOX10+ cells contributed to most of the DAPI labeled nuclei within and around each nerve bundle (Figure 3B, nerve bundle, cross-section). The remainder of the nuclei associated with each bundle are speculated to be neuroimmune cells, based on prior data [13]. The second greatest proportion of SOX10+ cells were observed in contact with the nerves innervating tissue vasculature (Figure 3B, neurovascular), and relatively few SOX10+ cells were observed in the parenchyma around adipocytes (Figure 3B, parenchymal).…”

“…Small fiber peripheral neuropathy is common with altered metabolic disease states such as diabetes or aging, and these may involve demyelinating neuropathies or reduced axon outgrowth due to impaired SC function in nerve repair and regeneration [14]. From our prior work, small fiber innervation in scWAT may be particularly important for metabolic control [13].…”

“…We previously demonstrated that aging leads to peripheral neuropathy in scWAT [11], and that in obese and diabetic BTBR mice homozygous for the spontaneous Lep ob mutation (BTBR ob/ob ) [12] the peripheral neuropathy also extended to metabolically-relevant tissues like adipose and muscle [11]. Deletion of brain derived neurotrophic factor (BDNF), a neurotrophic factor implicated in human obesity, from myeloid-lineage neuroimmune cells also causes a ‘genetic denervation’ of adipose tissue [13] that is accompanied by worsened metabolic phenotype. Small fiber peripheral neuropathy is common with altered metabolic disease states such as diabetes or aging, and these may involve demyelinating neuropathies or reduced axon outgrowth due to impaired SC function in nerve repair and regeneration [14].…”

Neuroimmune regulation of white adipose tissues

“…Conversely, cold exposure or exercise leads to increased nerve density [12,37–39] visualized within the whole tissue [39]. The innervation is potentially influenced by the neurotrophic factors including nerve growth factor (NGF) [39] and brain‐derived neurotrophic factor (BDNF) [40]. Blockage of NGF through neutralization antibody or pharmacological inhibition of the receptor tyrosine kinase (RTK) for NGF (TrkA) impairs the axonal outgrowth process [39].…”

“…Blockage of NGF through neutralization antibody or pharmacological inhibition of the receptor tyrosine kinase (RTK) for NGF (TrkA) impairs the axonal outgrowth process [39]. BDNF functions in distinct cell types located in the central nervous system and the periphery [36,40]: Deletion of BDNF in the paraventricular nucleus of the hypothalamus blunts the leptin‐induced sympathetic re‐innervation in the ob/ob mice [36]; deletion of BDNF from LyzM + myeloid cells results in a decrease in total innervation of the iWAT [40].…”