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Adtrp regulates thermogenic activity of adipose tissue via mediating the secretion of S100b

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Abstract

Brown and beige adipose tissues dissipate chemical energy in the form of heat to maintain your body temperature in cold conditions. The impaired function of these tissues results in various metabolic diseases in humans and mice. By bioinformatical analyses, we identified a functional thermogenic regulator of adipose tissue, Androgen-dependent tissue factor pathway inhibitor [TFPI]-regulating protein (Adtrp), which was significantly overexpressed in and functionally activated the mature brown/beige adipocytes. Hereby, we knocked out Adtrp in mice which led to multiple abnormalities in thermogenesis, metabolism, and maturation of brown/beige adipocytes causing excess lipid accumulation in brown adipose tissue (BAT) and cold intolerance. The capability of thermogenesis in brown/beige adipose tissues could be recovered in Adtrp KO mice upon direct β3-adrenergic receptor (β3-AR) stimulation by CL316,243 treatment. Our mechanistic studies revealed that Adtrp by binding to S100 calcium-binding protein b (S100b) indirectly mediated the secretion of S100b, which in turn promoted the β3-AR mediated thermogenesis via sympathetic innervation. These results may provide a novel insight into Adtrp in metabolism via regulating the differentiation and thermogenesis of adipose tissues in mice.

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Availability of data and material

The datasets or materials generated in the current study are available on reasonable request.

Abbreviations

Adtrp :

Androgen-dependent tissue factor pathway inhibitor (TFPI)-regulating protein

BAT:

Brown adipose tissue

β3-AR:

β-Adrenergic receptor

S100b :

S100 calcium-binding protein b

WAT:

White adipose tissue

Ucp1 :

Uncoupling protein-1

SNS:

Sympathetic nervous system

CAD:

Coronary artery disease

ECs:

Endothelial cells

FAHFAs:

Fatty acid esters of hydroxy fatty acids

iWAT:

Inguinal WAT

eWAT:

Epididymis WAT

GEO:

Gene Expression Omnibus

KO:

Knockout

SVF:

Stromal vascular fraction

CRISPR/Cas9:

Clustered regularly interspaced short palindromic repeats/CRISPR associated 9

SFP:

Specific pathogen-free

DEGs:

Differentially expressed genes

hTERT:

Human telomerase reverse transcriptase

DMEM:

Dulbecco’s modified Eagle’s medium

FBS:

Fetal bovine serum

TG:

Triglyceride

FFA:

Free fatty acid

RT-PCR:

Reverse transcription PCR

RT-qPCR:

Quantitative reverse transcription PCR

M-MLV:

Moloney Murine Leukemia Virus

Fabp4 :

Fatty acid-binding protein 4

Dio2 :

Deiodinase, iodothyronine, type II

Cidea :

Cell death-inducing DFFA-like effector A

Cox8b :

Cytochrome c oxidase subunit 8b

Pgc1α :

Peroxisome proliferative activated receptor, gamma, coactivator 1 alpha

Pparγ :

Peroxisome proliferator-activated receptor gamma

Prdm16 :

PR domain containing 16

GTT:

Glucose Tolerance Test

ITT:

Insulin Tolerance Test

VCO2 :

Carbon dioxide generation

VO2 :

Oxygen consumption

EE:

Energy expenditure

OCR:

Oxygen Consumption Rate

ECAR:

Extracellular Acidification Rate

FCCP:

Carbonyl cyanide-4-(trifluoromethoxy) phenylhydrazone

AA:

Antimycin A

Rot:

Rotenone

2-DG:

2-Deoxy-d-glucose

BCA:

Bicinchoninic acid

HE:

Hematoxylin and Eosin

IHC:

Immunohistochemistry

IF:

Immunofluorescence

HRP:

Horseradish Peroxidase

DAB:

3,3′-Diaminobenzidine tetra-hydrochloride

FITC:

Fluorescein isothiocyanate

Creb3 :

cAMP-responsive element-binding protein 3

IP:

Immunoprecipitation

SDS-PAGE:

Sodium Dodecyl Sulfate–Polyacrylamide Gel Electrophoresis

PVDF:

Polyvinylidene fluoride

ECL:

Enhanced chemiluminescence

Hsp90 :

Heat shock protein 90

hMSCs:

Human mesenchymal stromal cells

ADIPOQ :

Adiponectin C1Q and collagen domain containing

Gys2 :

Glycogen synthase 2

Elovl3 :

Elongase of very long chain fatty acids-3

AUC:

Area Under Curve

CMTM7 :

MARVEL transmembrane domain containing 7

TMED8 :

Transmembrane p24 trafficking protein family member 8

VTN :

Vitronectin

Clstn3β :

Calsyntenin 3β

BM-MSC:

Bone marrow MSC

HFD:

High-fat diet

ERRγ :

Estrogen-related receptor gamma

SNP:

Single-nucleotide polymorphism

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Acknowledgements

We thank professor Fazheng Ren from China Agricultural University for providing guidance for the experiments. We thank professor Nafis A Rahman from University of Turku for the language editing.

Funding

This study was supported by grants from the National Natural Science Foundation of China (82171854 and 31970802), Beijing Municipal Natural Science Foundation (7202099) and the Medical University of Bialystok, Poland (SUB/1/DN/20/006/1104, to Xiangdong Li).

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  1. Peng Li, Runjie Song and Yaqi Du contributed equally to this work.

Authors and Affiliations

  1. State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, 100193, China

    Peng Li, Runjie Song, Yaqi Du, Huijiao Liu & Xiangdong Li

  2. Department of Reproduction and Gynecological Endocrinology, Medical University of Bialystok, Białystok, Poland

    Xiangdong Li

  3. Department of Nutrition and Health, China Agricultural University, Beijing, 100193, China

    Xiangdong Li

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Contributions

XL designed the study concept and supervised the project and analyzed the data. PL, RS and XL interpreted the data. PL, RS and YD conducted the experiments. PL, RS and HL analyzed RNA-seq and microarray data. All authors approved the final content.

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Correspondence to Xiangdong Li.

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All animal studies were approved by the ethical committee of the China Agricultural University (No.: AW32201202-3-2).

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18_2022_4441_MOESM7_ESM.pdf

Figure S1 (A-D) The expression heatmaps of the 5 overlapping genes in cold exposure at 4°C or CL316,243 treatment in mice BAT and iWAT (GEO: GSE86338, GSE104285, GSE13432, and GSE129083). Figure S2 (A) A schematic illustration of the strategy of generating the Adtrp KO mouse with the CRISPR/Cas9 system. (B) Genotyping of the Adtrp KO mice with two pairs of primers. (C-D) RT-qPCR analysis of Adtrp in BAT and Liver of Adtrp KO and WT mice (n = 5). Error bars represent the means ± SEM of three independent experiments, ***p < 0.001. Figure S3 (A) Body weights of Adtrp KO and WT mice at the age of 14 weeks (n = 10). (B) Histopathological images of liver from Adtrp KO and WT mice at the age of 8 weeks (n = 4, Scale bars, 50 μm). (C and D) Food and water intakes of Adtrp KO and WT mice in 24 h at the age of 8 weeks (n = 6). (E and F) GTT and ITT of Adtrp KO and WT mice (n = 5). (G and H) Statistics of the OCR data of Adtrp KO and WT differentiated BAT or iWAT SVF adipocytes. (I and J) Statistics of the ECAR data of Adtrp KO and WT differentiated BAT or iWAT SVF adipocytes. Error bars represent the means ± SEM of three independent experiments. *p < 0.05, **p < 0.01, ***p < 0.001, ns: nonstatistical significance. Figure S4 (A) EE of Adtrp KO and WT mice in metabolic cages at age of 8 weeks with 16°C cold exposure (n = 6). (B and C) Food and water intake of Adtrp KO and WT mice in 24 h at the age of 8 weeks with 16°C cold exposure (n = 6). (D) Statistics of AUC data of EE about Adtrp KO and WT mice at 25°C and 16°C. (E) The core body temperatures of 7 days’ CL316,243 treated Adtrp KO and WT mice at different time points after exposure to cold at 4°C (n = 5). Error bars represent the means ± SEM of three independent experiments. *p < 0.05, **p < 0.01, ***p < 0.001, ns: nonstatistical significance. Figure S5 (A) List of the predicted interaction proteins with ADTRP. (B) IP by anti-GFP antibody bond A/G magnetic beads, and western blot analyses of Creb3 and Adtrp in 293T cells. (C and D) RT-qPCR analysis of S100b in BAT and iWAT of Adtrp KO and WT mice (n = 5). Error bars represent the means ± SEM of three independent experiments, ns: nonstatistical significance (PDF 5074 kb)

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Li, P., Song, R., Du, Y. et al. Adtrp regulates thermogenic activity of adipose tissue via mediating the secretion of S100b. Cell. Mol. Life Sci. 79, 407 (2022). https://doi.org/10.1007/s00018-022-04441-9

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