Diet induced obesity is independent of metabolic endotoxemia and Tlr4 signalling, but markedly increases hypothalamic expression of the acute phase protein, SerpinA3N’

Matthew J. Dalby, Gabriella Aviello, Alexander W. Ross, Alan W. Walker, Perry Barrett, Peter J. Morgan (Corresponding Author)

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Abstract

Hypothalamic inflammation is thought to contribute to obesity. One potential mechanism is via gut microbiota derived bacterial lipopolysaccharide (LPS) entering into the circulation and activation of Toll-like receptor-4. This is called metabolic endotoxemia. Another potential mechanism is systemic inflammation arising from sustained exposure to high-fat diet (HFD) over more than 12 weeks. In this study we show that mice fed HFD over 8 weeks become obese and show elevated plasma LPS binding protein, yet body weight gain and adiposity is not attenuated in mice lacking Tlr4 or its co-receptor Cd14. In addition, caecal microbiota composition remained unchanged by diet. Exposure of mice to HFD over a more prolonged period (20 weeks) to drive systemic inflammation also caused obesity. RNAseq used to assess hypothalamic inflammation in these mice showed increased hypothalamic expression of Serpina3n and Socs3 in response to HFD, with few other genes altered. In situ hybridisation confirmed increased Serpina3n and Socs3 expression in the ARC and DMH at 20-weeks, but also at 8-weeks and increased SerpinA3N protein could be detected as early as 1 week on HFD. Overall these data show lack of hypothalamic inflammation in response to HFD and that metabolic endotoxemia does not link HFD to obesity.
Original languageEnglish
Article number15648
Pages (from-to)1-15
Number of pages15
JournalScientific Reports
Volume8
DOIs
Publication statusPublished - 23 Oct 2018

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Endotoxemia
Acute-Phase Proteins
High Fat Diet
Obesity
Diet
Inflammation
Dimenhydrinate
AIDS-Related Complex
Toll-Like Receptor 4
Microbiota
Adiposity
Weight Gain
In Situ Hybridization
Lipopolysaccharides
Body Weight
Genes

Cite this

@article{a59fc6b1687845f493665fbab3a87300,
title = "Diet induced obesity is independent of metabolic endotoxemia and Tlr4 signalling, but markedly increases hypothalamic expression of the acute phase protein, SerpinA3N’",
abstract = "Hypothalamic inflammation is thought to contribute to obesity. One potential mechanism is via gut microbiota derived bacterial lipopolysaccharide (LPS) entering into the circulation and activation of Toll-like receptor-4. This is called metabolic endotoxemia. Another potential mechanism is systemic inflammation arising from sustained exposure to high-fat diet (HFD) over more than 12 weeks. In this study we show that mice fed HFD over 8 weeks become obese and show elevated plasma LPS binding protein, yet body weight gain and adiposity is not attenuated in mice lacking Tlr4 or its co-receptor Cd14. In addition, caecal microbiota composition remained unchanged by diet. Exposure of mice to HFD over a more prolonged period (20 weeks) to drive systemic inflammation also caused obesity. RNAseq used to assess hypothalamic inflammation in these mice showed increased hypothalamic expression of Serpina3n and Socs3 in response to HFD, with few other genes altered. In situ hybridisation confirmed increased Serpina3n and Socs3 expression in the ARC and DMH at 20-weeks, but also at 8-weeks and increased SerpinA3N protein could be detected as early as 1 week on HFD. Overall these data show lack of hypothalamic inflammation in response to HFD and that metabolic endotoxemia does not link HFD to obesity.",
author = "Dalby, {Matthew J.} and Gabriella Aviello and Ross, {Alexander W.} and Walker, {Alan W.} and Perry Barrett and Morgan, {Peter J.}",
note = "The authors gratefully acknowledge Doctoral Training Partnership funding from the BBSRC (M.J.D.), MRC (GA) and funding from the Scottish Government (P.J.M., A.W.R., A.W.W. and P.B.). The authors would like to acknowledge the support of the Maxwell compute cluster funded by the University of Aberdeen. We also thank the Centre for Genome-Enabled Biology and Medicine, University of Aberdeen for performing next-generation sequencing and RNAseq, Dr Sophie Shaw, for bioinformatic analysis of the RNAseq data, and Lynn Thomson for assistance with the TLR4−/− and CD14−/− mouse study, and Dr Richard Anderson and Dana Wilson for assistance with the long term high fat diet study. Supplementary information accompanies this paper at https://doi.org/10.1038/s41598-018-33928-4.",
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T1 - Diet induced obesity is independent of metabolic endotoxemia and Tlr4 signalling, but markedly increases hypothalamic expression of the acute phase protein, SerpinA3N’

AU - Dalby, Matthew J.

AU - Aviello, Gabriella

AU - Ross, Alexander W.

AU - Walker, Alan W.

AU - Barrett, Perry

AU - Morgan, Peter J.

N1 - The authors gratefully acknowledge Doctoral Training Partnership funding from the BBSRC (M.J.D.), MRC (GA) and funding from the Scottish Government (P.J.M., A.W.R., A.W.W. and P.B.). The authors would like to acknowledge the support of the Maxwell compute cluster funded by the University of Aberdeen. We also thank the Centre for Genome-Enabled Biology and Medicine, University of Aberdeen for performing next-generation sequencing and RNAseq, Dr Sophie Shaw, for bioinformatic analysis of the RNAseq data, and Lynn Thomson for assistance with the TLR4−/− and CD14−/− mouse study, and Dr Richard Anderson and Dana Wilson for assistance with the long term high fat diet study. Supplementary information accompanies this paper at https://doi.org/10.1038/s41598-018-33928-4.

PY - 2018/10/23

Y1 - 2018/10/23

N2 - Hypothalamic inflammation is thought to contribute to obesity. One potential mechanism is via gut microbiota derived bacterial lipopolysaccharide (LPS) entering into the circulation and activation of Toll-like receptor-4. This is called metabolic endotoxemia. Another potential mechanism is systemic inflammation arising from sustained exposure to high-fat diet (HFD) over more than 12 weeks. In this study we show that mice fed HFD over 8 weeks become obese and show elevated plasma LPS binding protein, yet body weight gain and adiposity is not attenuated in mice lacking Tlr4 or its co-receptor Cd14. In addition, caecal microbiota composition remained unchanged by diet. Exposure of mice to HFD over a more prolonged period (20 weeks) to drive systemic inflammation also caused obesity. RNAseq used to assess hypothalamic inflammation in these mice showed increased hypothalamic expression of Serpina3n and Socs3 in response to HFD, with few other genes altered. In situ hybridisation confirmed increased Serpina3n and Socs3 expression in the ARC and DMH at 20-weeks, but also at 8-weeks and increased SerpinA3N protein could be detected as early as 1 week on HFD. Overall these data show lack of hypothalamic inflammation in response to HFD and that metabolic endotoxemia does not link HFD to obesity.

AB - Hypothalamic inflammation is thought to contribute to obesity. One potential mechanism is via gut microbiota derived bacterial lipopolysaccharide (LPS) entering into the circulation and activation of Toll-like receptor-4. This is called metabolic endotoxemia. Another potential mechanism is systemic inflammation arising from sustained exposure to high-fat diet (HFD) over more than 12 weeks. In this study we show that mice fed HFD over 8 weeks become obese and show elevated plasma LPS binding protein, yet body weight gain and adiposity is not attenuated in mice lacking Tlr4 or its co-receptor Cd14. In addition, caecal microbiota composition remained unchanged by diet. Exposure of mice to HFD over a more prolonged period (20 weeks) to drive systemic inflammation also caused obesity. RNAseq used to assess hypothalamic inflammation in these mice showed increased hypothalamic expression of Serpina3n and Socs3 in response to HFD, with few other genes altered. In situ hybridisation confirmed increased Serpina3n and Socs3 expression in the ARC and DMH at 20-weeks, but also at 8-weeks and increased SerpinA3N protein could be detected as early as 1 week on HFD. Overall these data show lack of hypothalamic inflammation in response to HFD and that metabolic endotoxemia does not link HFD to obesity.

U2 - 10.1038/s41598-018-33928-4

DO - 10.1038/s41598-018-33928-4

M3 - Article

VL - 8

SP - 1

EP - 15

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

M1 - 15648

ER -