Role of the central nervous system and adipose tissue BDNF/TrkB axes in metabolic regulation

Nakagomi, Atsushi; Okada, Sho; Yokoyama, Masataka; Yoshida, Yohko; Shimizu, Ippei; Miki, Takashi; Kobayashi, Yoshio; Minamino, Tohru

doi:10.1038/npjamd.2015.9

Cited by 55 publications

(59 citation statements)

References 53 publications

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“…Using instead an adipoqcre (mature adipocyte-speci c line) there was no obesity in a BDNF or a TrkB knock-out (KO), and the BDNF KO showed no difference in adipose BDNF levels (28). Together, these ndings suggested that mature adipocytes are not the cellular source of BDNF (28), which we have con rmed in this study by demonstrating predominance of BDNF expression in the SVF. NFs are secreted by glial cells in the brain (29) and Schwann cells in peripheral tissues (30).…”

Section: Introductionsupporting

confidence: 71%

“…A few studies have clearly shown that NFs, including BDNF, are present in adipose tissue (25)(26)(27), but the cellular source of BDNF in adipose had not been determined. In adipose speci c (FABP4-Cre) knock-outs of BDNF or TrkB, only CNS effects were apparent (not surprising given off-target brain effects of this cre line) (28). Using instead an adipoqcre (mature adipocyte-speci c line) there was no obesity in a BDNF or a TrkB knock-out (KO), and the BDNF KO showed no difference in adipose BDNF levels (28).…”

Section: Introductionmentioning

confidence: 99%

“…In adipose speci c (FABP4-Cre) knock-outs of BDNF or TrkB, only CNS effects were apparent (not surprising given off-target brain effects of this cre line) (28). Using instead an adipoqcre (mature adipocyte-speci c line) there was no obesity in a BDNF or a TrkB knock-out (KO), and the BDNF KO showed no difference in adipose BDNF levels (28). Together, these ndings suggested that mature adipocytes are not the cellular source of BDNF (28), which we have con rmed in this study by demonstrating predominance of BDNF expression in the SVF.…”

Section: Introductionmentioning

confidence: 99%

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The Involvement of Neuroimmune Cells in Adipose Innervation

Blaszkiewicz

Wood

Koizar

et al. 2020

Preprint

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Background: Innervation of adipose tissue is essential for the proper function of this critical metabolic organ. Numerous surgical and chemical denervation studies have demonstrated how maintenance of brain-adipose communication through both sympathetic efferent and sensory afferent nerves helps regulate adipocyte size, cell number, lipolysis, and ‘browning’ of white adipose tissue. Neurotrophic factors are growth factors that promote neuron survival, regeneration and plasticity, including neurite outgrowth and synapse formation. Peripheral blood immune cells have been shown to be a source of neurotrophic factors in humans and mice. Although a number of immune cells reside in the adipose stromal vascular fraction (SVF), it has remained unclear what roles they play in adipose innervation. We previously demonstrated that adipose immune cells secrete brain derived neurotrophic factor (BDNF). Methods: We now show that deletion of this neurotrophic factor from the myeloid lineage led to a ‘genetic denervation’ of inguinal subcutaneous white adipose tissue (scWAT), thereby causing decreased energy expenditure, increased adipose mass, and a blunted UCP1 response to cold stimulation. Results: We and others have previously shown that noradrenergic stimulation via cold exposure increases adipose innervation in the inguinal depot. Here we have identified a subset of myeloid cells that home to scWAT upon cold exposure and are Ly6C + CCR2 + Cx3CR1 + monocytes/macrophages that express noradrenergic receptors and BDNF. Conclusions: We propose that these cold induced neuroimmune cells (CINCs) are key players in maintaining adipose innervation as well as promoting adipose nerve remodeling under noradrenergic stimulation, such as cold exposure.

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Section: Introductionsupporting

confidence: 71%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The Involvement of Neuroimmune Cells in Adipose Innervation

Blaszkiewicz

Wood

Koizar

et al. 2020

Preprint

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“…Several cells have been shown to express BDNF, including: platelets [Yamamoto and Gurney, 1990], developing heart [Clegg et al, 1989], vascular smooth muscle cells [Clegg et al, 1989], developing intestine [Clegg et al, 1989], spleen [Yamamoto et al, 1996], T-cells, B-cells, monocytes [Kerschensteiner et al, 1999;Nakahashi et al, 2000], and skeletal muscles [Mousavi and Jasmin, 2006]. In addition, the BDNF mRNA has been detected in several tissues such as the colon, leukocytes, ovary, spleen, thymus, testis, pancreas as well as in blood Pruunsild et al, 2007;Nakagomi et al, 2015]. Interestingly, altered BDNF expression occurs in response to some events in an activity-dependent manner.…”

Section: Regulation Of Bdnf Expressionmentioning

confidence: 99%

Therapeutic Potentials of BDNF/TrkB in Breast Cancer; Current Status and Perspectives

et al. 2017

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Brain-derived neurotrophic factor (BDNF) is a potent neurotrophic factor that has been shown to stimulate breast cancer cell growth and metastasis via tyrosine kinase receptors TrkA, TrkB, and the p75 death receptor. The aberrant activation of BDNF/TrkB pathways can modulate several signaling pathways, including Akt/PI3K, Jak/STAT, NF-kB, UPAR/UPA, Wnt/β-catenin, and VEGF pathways as well as the ER receptor. Several microRNAs have been identified that are involved in the modulation of BDNF/TrkB pathways. These include miR-206, miR-204, MiR-200a/c, MiR-210, MiR-134, and MiR-191; and these may be of value as prognostic and predictive biomarkers for detecting patients at high risk of developing breast cancer. It has been also been demonstrated that a high expression of genes involved in the BDNF pathway in breast cancer is associated with poor clinical outcome and reduced survival of patients. Several approaches have been developed for targeting this pathway, for example TKr inhibitors (AZD6918, CEP-701) and RNA interference. The aim of the current review was to provide an overview of the role of BDNF/TrkB pathways in the pathogenesis of breast cancer and its value as a potential therapeutic target. J. Cell. Biochem. 118: 2502-2515, 2017. © 2017 Wiley Periodicals, Inc.

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Section: Introductionmentioning

confidence: 99%

The involvement of neuroimmune cells in adipose innervation

Blaszkiewicz

Wood

Koizar

et al. 2019

Preprint

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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...

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Role of the central nervous system and adipose tissue BDNF/TrkB axes in metabolic regulation

Cited by 55 publications

References 53 publications

The Involvement of Neuroimmune Cells in Adipose Innervation

The Involvement of Neuroimmune Cells in Adipose Innervation

Therapeutic Potentials of BDNF/TrkB in Breast Cancer; Current Status and Perspectives

The involvement of neuroimmune cells in adipose innervation

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