The impact of metabolic endotoxaemia on the browning process in human adipocytes

Farah Omran; Alice M. Murphy; Awais Z. Younis; Ioannis Kyrou; Jana Vrbikova; Vojtech Hainer; Petra Sramkova; Martin Fried; Graham Ball; Gyanendra Tripathi; Sudhesh Kumar; Philip G. McTernan; Mark Christian

doi:10.1186/s12916-023-02857-z

The impact of metabolic endotoxaemia on the browning process in human adipocytes

Farah Omran
, Alice M. Murphy
, Awais Z. Younis
, Ioannis Kyrou
, Jana Vrbikova
, Vojtech Hainer
, Petra Sramkova
, Martin Fried
, Graham Ball
, Gyanendra Tripathi
, Sudhesh Kumar
, Philip G. McTernan
, Mark Christian

University of Nottingham
University Hospitals Coventry and Warwickshire NHS Trust
Aston University
Institute of Endocrinology
Anglia Ruskin University
University of Derby
Nottingham Trent University
OB CLINIC Inc.
University of Warwick

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

18 Citations (Scopus)

58 Downloads (Pure)

Abstract

Background: Dysfunctional adipose tissue (AT) is known to contribute to the pathophysiology of metabolic disease, including type 2 diabetes mellitus (T2DM). This dysfunction may occur, in part, as a consequence of gut-derived endotoxaemia inducing changes in adipocyte mitochondrial function and reducing the proportion of BRITE (brown-in-white) adipocytes. Therefore, the present study investigated whether endotoxin (lipopolysaccharide; LPS) directly contributes to impaired human adipocyte mitochondrial function and browning in human adipocytes, and the relevant impact of obesity status pre and post bariatric surgery. Methods: Human differentiated abdominal subcutaneous (AbdSc) adipocytes from participants with obesity and normal-weight participants were treated with endotoxin to assess in vitro changes in mitochondrial function and BRITE phenotype. Ex vivo human AbdSc AT from different groups of participants (normal-weight, obesity, pre- and 6 months post-bariatric surgery) were assessed for similar analyses including circulating endotoxin levels. Results: Ex vivo AT analysis (lean & obese, weight loss post-bariatric surgery) identified that systemic endotoxin negatively correlated with BAT gene expression (p < 0.05). In vitro endotoxin treatment of AbdSc adipocytes (lean & obese) reduced mitochondrial dynamics (74.6% reduction; p < 0.0001), biogenesis (81.2% reduction; p < 0.0001) and the BRITE phenotype (93.8% reduction; p < 0.0001). Lean AbdSc adipocytes were more responsive to adrenergic signalling than obese AbdSc adipocytes; although endotoxin mitigated this response (92.6% reduction; p < 0.0001). Conclusions: Taken together, these data suggest that systemic gut-derived endotoxaemia contributes to both individual adipocyte dysfunction and reduced browning capacity of the adipocyte cell population, exacerbating metabolic consequences. As bariatric surgery reduces endotoxin levels and is associated with improving adipocyte functionality, this may provide further evidence regarding the metabolic benefits of such surgical interventions.

Original language	English
Article number	154
Number of pages	17
Journal	BMC Medicine
Volume	21
Issue number	1
Early online date	19 Apr 2023
DOIs	https://doi.org/10.1186/s12916-023-02857-z
Publication status	E-pub ahead of print - 19 Apr 2023

Bibliographical note

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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence 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.

Funder

Farah Omran was a recipient of the University of Warwick CARA Scholarship. Alice Murphy was supported via funding from a research fellowship from Nottingham Trent University. Awais Younis was supported via funding as a postdoctoral researcher from Nottingham Trent University. Mark Christian was supported by BBSRC grant BB/P008879/2. This study was also supported by the EFSD through the New Horizons Collaborative Research Initiative (EFSD New Horizons research grant).

Funding

Farah Omran was a recipient of the University of Warwick CARA Scholarship. Alice Murphy was supported via funding from a research fellowship from Nottingham Trent University. Awais Younis was supported via funding as a postdoctoral researcher from Nottingham Trent University. Mark Christian was supported by BBSRC grant BB/P008879/2. This study was also supported by the EFSD through the New Horizons Collaborative Research Initiative (EFSD New Horizons research grant).

Funders	Funder number
Nottingham Trent University
Biotechnology and Biological Sciences Research Council	BB/P008879/2
European Foundation for the Study of Diabetes
University of Warwick

UN SDGs

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

SDG 3 Good Health and Well-being

Keywords

Obesity
Endotoxin
Adipocyte browning
Mitochondria
Lipopolysaccharide
Human adipocytes
Bariatric surgery

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10.1186/s12916-023-02857-z

PublishedFinal published version, 2.25 MBLicence: CC BY

Cite this

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title = "The impact of metabolic endotoxaemia on the browning process in human adipocytes",

abstract = "Background: Dysfunctional adipose tissue (AT) is known to contribute to the pathophysiology of metabolic disease, including type 2 diabetes mellitus (T2DM). This dysfunction may occur, in part, as a consequence of gut-derived endotoxaemia inducing changes in adipocyte mitochondrial function and reducing the proportion of BRITE (brown-in-white) adipocytes. Therefore, the present study investigated whether endotoxin (lipopolysaccharide; LPS) directly contributes to impaired human adipocyte mitochondrial function and browning in human adipocytes, and the relevant impact of obesity status pre and post bariatric surgery. Methods: Human differentiated abdominal subcutaneous (AbdSc) adipocytes from participants with obesity and normal-weight participants were treated with endotoxin to assess in vitro changes in mitochondrial function and BRITE phenotype. Ex vivo human AbdSc AT from different groups of participants (normal-weight, obesity, pre- and 6 months post-bariatric surgery) were assessed for similar analyses including circulating endotoxin levels. Results: Ex vivo AT analysis (lean \& obese, weight loss post-bariatric surgery) identified that systemic endotoxin negatively correlated with BAT gene expression (p < 0.05). In vitro endotoxin treatment of AbdSc adipocytes (lean \& obese) reduced mitochondrial dynamics (74.6\% reduction; p < 0.0001), biogenesis (81.2\% reduction; p < 0.0001) and the BRITE phenotype (93.8\% reduction; p < 0.0001). Lean AbdSc adipocytes were more responsive to adrenergic signalling than obese AbdSc adipocytes; although endotoxin mitigated this response (92.6\% reduction; p < 0.0001). Conclusions: Taken together, these data suggest that systemic gut-derived endotoxaemia contributes to both individual adipocyte dysfunction and reduced browning capacity of the adipocyte cell population, exacerbating metabolic consequences. As bariatric surgery reduces endotoxin levels and is associated with improving adipocyte functionality, this may provide further evidence regarding the metabolic benefits of such surgical interventions.",

keywords = "Obesity, Endotoxin, Adipocyte browning, Mitochondria, Lipopolysaccharide, Human adipocytes, Bariatric surgery",

author = "Farah Omran and Murphy, \{Alice M.\} and Younis, \{Awais Z.\} and Ioannis Kyrou and Jana Vrbikova and Vojtech Hainer and Petra Sramkova and Martin Fried and Graham Ball and Gyanendra Tripathi and Sudhesh Kumar and McTernan, \{Philip G.\} and Mark Christian",

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T1 - The impact of metabolic endotoxaemia on the browning process in human adipocytes

AU - Omran, Farah

AU - Murphy, Alice M.

AU - Younis, Awais Z.

AU - Kyrou, Ioannis

AU - Vrbikova, Jana

AU - Hainer, Vojtech

AU - Sramkova, Petra

AU - Fried, Martin

AU - Ball, Graham

AU - Tripathi, Gyanendra

AU - Kumar, Sudhesh

AU - McTernan, Philip G.

AU - Christian, Mark

N1 - 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence 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.

PY - 2023/4/19

Y1 - 2023/4/19

N2 - Background: Dysfunctional adipose tissue (AT) is known to contribute to the pathophysiology of metabolic disease, including type 2 diabetes mellitus (T2DM). This dysfunction may occur, in part, as a consequence of gut-derived endotoxaemia inducing changes in adipocyte mitochondrial function and reducing the proportion of BRITE (brown-in-white) adipocytes. Therefore, the present study investigated whether endotoxin (lipopolysaccharide; LPS) directly contributes to impaired human adipocyte mitochondrial function and browning in human adipocytes, and the relevant impact of obesity status pre and post bariatric surgery. Methods: Human differentiated abdominal subcutaneous (AbdSc) adipocytes from participants with obesity and normal-weight participants were treated with endotoxin to assess in vitro changes in mitochondrial function and BRITE phenotype. Ex vivo human AbdSc AT from different groups of participants (normal-weight, obesity, pre- and 6 months post-bariatric surgery) were assessed for similar analyses including circulating endotoxin levels. Results: Ex vivo AT analysis (lean & obese, weight loss post-bariatric surgery) identified that systemic endotoxin negatively correlated with BAT gene expression (p < 0.05). In vitro endotoxin treatment of AbdSc adipocytes (lean & obese) reduced mitochondrial dynamics (74.6% reduction; p < 0.0001), biogenesis (81.2% reduction; p < 0.0001) and the BRITE phenotype (93.8% reduction; p < 0.0001). Lean AbdSc adipocytes were more responsive to adrenergic signalling than obese AbdSc adipocytes; although endotoxin mitigated this response (92.6% reduction; p < 0.0001). Conclusions: Taken together, these data suggest that systemic gut-derived endotoxaemia contributes to both individual adipocyte dysfunction and reduced browning capacity of the adipocyte cell population, exacerbating metabolic consequences. As bariatric surgery reduces endotoxin levels and is associated with improving adipocyte functionality, this may provide further evidence regarding the metabolic benefits of such surgical interventions.

AB - Background: Dysfunctional adipose tissue (AT) is known to contribute to the pathophysiology of metabolic disease, including type 2 diabetes mellitus (T2DM). This dysfunction may occur, in part, as a consequence of gut-derived endotoxaemia inducing changes in adipocyte mitochondrial function and reducing the proportion of BRITE (brown-in-white) adipocytes. Therefore, the present study investigated whether endotoxin (lipopolysaccharide; LPS) directly contributes to impaired human adipocyte mitochondrial function and browning in human adipocytes, and the relevant impact of obesity status pre and post bariatric surgery. Methods: Human differentiated abdominal subcutaneous (AbdSc) adipocytes from participants with obesity and normal-weight participants were treated with endotoxin to assess in vitro changes in mitochondrial function and BRITE phenotype. Ex vivo human AbdSc AT from different groups of participants (normal-weight, obesity, pre- and 6 months post-bariatric surgery) were assessed for similar analyses including circulating endotoxin levels. Results: Ex vivo AT analysis (lean & obese, weight loss post-bariatric surgery) identified that systemic endotoxin negatively correlated with BAT gene expression (p < 0.05). In vitro endotoxin treatment of AbdSc adipocytes (lean & obese) reduced mitochondrial dynamics (74.6% reduction; p < 0.0001), biogenesis (81.2% reduction; p < 0.0001) and the BRITE phenotype (93.8% reduction; p < 0.0001). Lean AbdSc adipocytes were more responsive to adrenergic signalling than obese AbdSc adipocytes; although endotoxin mitigated this response (92.6% reduction; p < 0.0001). Conclusions: Taken together, these data suggest that systemic gut-derived endotoxaemia contributes to both individual adipocyte dysfunction and reduced browning capacity of the adipocyte cell population, exacerbating metabolic consequences. As bariatric surgery reduces endotoxin levels and is associated with improving adipocyte functionality, this may provide further evidence regarding the metabolic benefits of such surgical interventions.

KW - Obesity

KW - Endotoxin

KW - Adipocyte browning

KW - Mitochondria

KW - Lipopolysaccharide

KW - Human adipocytes

KW - Bariatric surgery

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U2 - 10.1186/s12916-023-02857-z

DO - 10.1186/s12916-023-02857-z

M3 - Article

SN - 1464-2662

VL - 21

JO - BMC Medicine

JF - BMC Medicine

IS - 1

M1 - 154

ER -

The impact of metabolic endotoxaemia on the browning process in human adipocytes

Abstract

Bibliographical note

Funder

Funding

UN SDGs

Keywords

Access to Document

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