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

doi:10.1038/s41598-018-33928-4

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)

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

48 Citations (Scopus)

9 Downloads (Pure)

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 language	English
Article number	15648
Number of pages	15
Journal	Scientific Reports
Volume	8
DOIs	https://doi.org/10.1038/s41598-018-33928-4
Publication status	Published - 23 Oct 2018

Bibliographical 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.

Keywords

Metabolic Endotoxemia
Hypothalamic Inflammation
Caecal Microbiota
Microbiota Composition
Arcuate Nucleus

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/s41598-018-33928-4Licence: CC BY

Diet induced obesity is independent of metabolic endotoxemia and TLR4 signalling, but markedly increases hypothalamic expression of the acute phase protein, SerpinA3N
© The Author(s) 2018. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Final published version, 2.17 MBLicence: CC BY

Centre for Genome-Enabled Biology and Medicine
Elaina Susan Renata Collie-Duguid (Manager)
School of Medicine, Medical Sciences & Nutrition
Research Facilities: Facility

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.",

keywords = "Metabolic Endotoxemia, Hypothalamic Inflammation, Caecal Microbiota, Microbiota Composition, Arcuate Nucleus",

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.",

year = "2018",

month = oct,

day = "23",

doi = "10.1038/s41598-018-33928-4",

language = "English",

volume = "8",

journal = "Scientific Reports",

issn = "2045-2322",

publisher = "Nature Publishing Group",

}

TY - JOUR

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.

KW - Metabolic Endotoxemia

KW - Hypothalamic Inflammation

KW - Caecal Microbiota

KW - Microbiota Composition

KW - Arcuate Nucleus

U2 - 10.1038/s41598-018-33928-4

DO - 10.1038/s41598-018-33928-4

M3 - Article

C2 - 30353127

SN - 2045-2322

VL - 8

JO - Scientific Reports

JF - Scientific Reports

M1 - 15648

ER -

Diet induced obesity is independent of metabolic endotoxemia and TLR4 signalling, but markedly increases hypothalamic expression of the acute phase protein, SerpinA3N

Abstract

Bibliographical note

Keywords

UN SDGs

Access to Document

Fingerprint

Equipment

Centre for Genome-Enabled Biology and Medicine

Cite this