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Aging and disease    2020, Vol. 11 Issue (3) : 575-587     DOI: 10.14336/AD.2019.0810
Orginal Article |
Aging-Induced Brain-Derived Neurotrophic Factor in Adipocyte Progenitors Contributes to Adipose Tissue Dysfunction
Song Hyun-Doo1, Kim Sang Nam2, Saha Abhirup2, Ahn Sang-Yeop1, Akindehin Seun1, Son Yeonho2, Cho Yoon Keun2, Kim MinSu2, Park Ji-Hyun2, Jung Young-Suk3, Lee Yun-Hee2,*
1College of Pharmacy, Yonsei University, Incheon, Republic of Korea.
2College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea.
3College of Pharmacy, Pusan National University, Busan, Republic of Korea.
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Abstract  

Aging-related adipose tissue dysfunction contributes to the progression of chronic metabolic diseases. We investigated the role of age-dependent expression of a neurotrophin, brain-derived neurotrophic factor (BDNF) in adipose tissue. Pro-BDNF expression was elevated in epididymal white adipose tissue (eWAT) with advanced age, which was associated with the reduction in sympathetic innervation. Interestingly, BDNF expression was enriched in PDGFRα+ adipocyte progenitors isolated from eWAT, with age-dependent increase in expression. In vitro pro-BDNF treatment caused apoptosis in adipocytes differentiated from C3H10T1/2 cells, and siRNA knockdown of sortilin mitigated these effects. Tamoxifen-inducible PDGFRα+ cell-specific deletion of BDNF (BDNFPdgfra KO) reduced pro-BDNF expression in eWAT, prevented age-associated declines in sympathetic innervation and mitochondrial content in eWAT, and improved insulin sensitivity. Moreover, BDNFPdgfra KO mice showed reduced expression of aging-induced inflammation and senescence markers in eWAT. Collectively, these results identified the upregulation of pro-BDNF expression in adipocyte progenitors as a feature of visceral white adipose tissue aging and suggested that inhibition of BDNF expression in adipocyte progenitors is potentially beneficial to prevent aging-related adipose tissue dysfunction.

Keywords BDNF      adipose tissue      sympathetic innervation      adipocyte progenitors      aging     
Corresponding Authors: Lee Yun-Hee   
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These authors contributed equally to this work.

Just Accepted Date: 14 August 2019   Issue Date: 13 May 2020
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Song Hyun-Doo
Kim Sang Nam
Saha Abhirup
Ahn Sang-Yeop
Akindehin Seun
Son Yeonho
Cho Yoon Keun
Kim MinSu
Park Ji-Hyun
Jung Young-Suk
Lee Yun-Hee
Cite this article:   
Song Hyun-Doo,Kim Sang Nam,Saha Abhirup, et al. Aging-Induced Brain-Derived Neurotrophic Factor in Adipocyte Progenitors Contributes to Adipose Tissue Dysfunction[J]. Aging and disease, 2020, 11(3): 575-587.
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http://www.aginganddisease.org/EN/10.14336/AD.2019.0810     OR
Figure 1.  BDNF expression was upregulated in epididymal adipose tissue with advanced age, but not in brown adipose tissue and inguinal white adipose tissue. (A-D) Immunoblot analysis of BDNF and senescence marker expression in supra-scapular brown adipose tissue (BAT), epididymal white adipose tissue (eWAT), and inguinal white adipose tissue (iWAT) of mice at the indicated ages. N= 4, mean ± S.E.M, p value was calculated by t-test (Full length blots in supplementary Fig. 2).
Figure 2.  Age-dependent increase in pro-BDNF expression was associated with reduction in sympathetic innervation and mitochondrial activity in eWAT. (A) Immunoblot analysis of BDNF, TH and p-HSL expression in epididymal white adipose tissue (eWAT) of mice at the indicated ages. (n = 4, mean ± S.E.M, **p<0.01, ***p<0.001). (B, C) quantitative PCR analysis. (n = 4, mean ± S.E.M, *p<0.05, **p<0.01, ***p<0.001). (D) Analysis of oxygen consumption rate (OCR) of eWAT obtained from 2, 12 and 18-month old mice with a series of treatments of indicated drugs (oligomycin, carbonyl cyanide-4(trifluoromethoxy)phenylhydrazone (FCCP), and potassium cyanide (KCN)) (n = 3, mean ± S.E.M, *p<0.05, **p<0.01, ***p<0.001). (E) MitoTracker Red CMXRos staining in adipocytes differentiated from PDGFRα+ cells of eWAT of 2, 12, and 18-month-old mice.
Figure 3.  Upregulation of pro-BDNF expression by 12 weeks of HFD feeding (A) Immunoblot analysis of BDNF, TH and p-HSL expression in epididymal white adipose tissue (eWAT) mice fed with high fat diet and chow diet for 12 weeks. (n = 6, mean ± S.E.M, *p<0.05, **p<0.01).
Figure 4.  The major cellular source of pro-BDNF expression in eWAT is PDGFRα+ adipocyte progenitors. (A) quantitative PCR analysis of Bdnf expression in adipocytes and PDGFRA+ cells isolated from eWAT of mice at the indicated ages (n = 3, mean ± S.E.M, ***p<0.001). Plin1 and Pdgfra expressions were used as specific markers for adipocytes and progenitor cells, respectively. (B) Immunoblot analysis of BDNF expression in adipocytes and PDGFRA+ cells isolated from eWAT of mice at the indicated ages (n = 3, mean ± S.E.M, ***p<0.001). Full images of Western blots are shown in supplementary Fig. 4.
Figure 5.  proBDNF treatment-induced apoptosis/necroptosis of adipocytes required sortilin expression. (A) Immunoblot analysis of sortilin expression and apoptosis/necroptosis markers in adipocytes differentiated from C3H10T1/2 cells. (B) Immunoblot analysis of sortilin in adipocytes differentiated from C3H10T1/2 treated with siRNA or scrambled sequence controls (negative controls) (mean ± SEM; n = 4, *** p < 0.001). (C) Immunoblot analysis of cell surface protein detection in adipocytes differentiated from C3H10T1/2 cells treated with vehicle or pro-BDNF (10ng/ml) for 24 h (n = 4, means ± SEM, *** p < 0.001). Full images of Western blots are shown in supplementary Fig. 5.
Figure 6.  PDGFRα+ cell-specific KO reduced inflammatory and senescence marker expression in eWAT and insulin resistance of mice with advanced age. (A) Immunoblot analysis of BDNF and TH expression in epididymal white adipose tissue (eWAT) of BDNFpdgfra KO and WT mice at the indicated ages. (n = 5 per condition, mean ± S.E.M, *p<0.05, **p<0.01, *** p < 0.001). (B) Quantitative PCR analysis of eWAT of BDNFpdgfra KO and WT mice at the indicated ages. (n = 5, mean ± S.E.M, *p<0.05, **p<0.01, ***p<0.001). (C) Immunoblot analysis of mitochondrial makers involved in mitochondrial oxidative phosphorylation. (D) BODIPY staining of adipocytes differentiated from PDGFRα+ cells that were isolated from eWAT of BDNFpdgfra KO and WT mice (n = 4, mean ± S.E.M, **p<0.01). (E) Measurement of glucose tolerance test (GTT) in WT and BDNFpdgfraKO mice and the area under the curve of GTT plots. N = 5, mean ± S.E.M, **p<0.01. Full images of Western blots are shown in supplementary Fig. 6.
Figure 7.  PDGFRα+ cell-specific KO reduced apoptosis and necroptosis in eWAT of mice with advanced age. (A) Quantitative PCR analysis of eWAT of BDNFpdgfra KO and WT mice at the indicated ages. (n = 5, mean ± S.E.M, *p<0.05, **p<0.01, ***p<0.001). (B) Immunostaining of F4/80 in paraffin sections of eWAT of BDNFpdgfra KO and WT mice. DAPI was used as a nuclear counterstain. (C) Immunoblot analysis of apoptosis/necroptosis makers in eWAT of BDNFpdgfra KO and WT mice. (D) Immunoblot analysis of sortilin expression in plasma membrane fractions of eWAT of WT and BDNFpdgfra KO mice (n = 5, means ± SEM). Full images of Western blots are shown in supplementary Fig. 7.
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