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Dysregulation of subcutaneous white adipose tissue inflammatory environment modelling in non-insulin resistant obesity and responses to omega-3 fatty acids – a double blind, randomised clinical trial

Dysregulation of subcutaneous white adipose tissue inflammatory environment modelling in non-insulin resistant obesity and responses to omega-3 fatty acids – a double blind, randomised clinical trial
Dysregulation of subcutaneous white adipose tissue inflammatory environment modelling in non-insulin resistant obesity and responses to omega-3 fatty acids – a double blind, randomised clinical trial
Background: Obesity is associated with enhanced lipid accumulation and the expansion of adipose tissue accompanied by hypoxia and inflammatory signalling. Investigation in human subcutaneous white adipose tissue (scWAT) in people living with obesity in which metabolic complications such as insulin resistance are yet to manifest is limited, and the mechanisms by which these processes are dysregulated are not well elucidated. Long chain omega-3 polyunsaturated fatty acids (LC n-3 PUFAs) have been shown to modulate the expression of genes associated with lipid accumulation and collagen deposition and reduce the number of inflammatory macrophages in adipose tissue from individuals with insulin resistance. Therefore, these lipids may have positive actions on obesity associated scWAT hypertrophy and inflammation.

Methods: To evaluate obesity-associated tissue remodelling and responses to LC n-3 PUFAs, abdominal scWAT biopsies were collected from normal weight individuals and those living with obesity prior to and following 12-week intervention with marine LC n-3 PUFAs (1.1 g EPA + 0.8 g DHA daily). RNA sequencing, qRT-PCR, and histochemical staining were used to assess remodelling- and inflammatory-associated gene expression, tissue morphology and macrophage infiltration.

Results: Obesity was associated with scWAT hypertrophy (P < 0.001), hypoxia, remodelling, and inflammatory macrophage infiltration (P = 0.023). Furthermore, we highlight the novel dysregulation of Wnt signalling in scWAT in non-insulin resistant obesity. LC n-3 PUFAs beneficially modulated the scWAT environment through downregulating the expression of genes associated with inflammatory and remodelling pathways (P <0.001), but there were altered outcomes in individuals living with obesity in comparison to normal weight individuals.

Conclusion: Our data identify dysregulation of Wnt signalling, hypoxia, and hypertrophy, and enhanced macrophage infiltration in scWAT in non-insulin resistant obesity. LC n-3 PUFAs modulate some of these processes, especially in normal weight individuals which may be preventative and limit the development of restrictive and inflammatory scWAT in the development of obesity. We conclude that a higher dose or longer duration of LC n-3 PUFA intervention may be needed to reduce obesity-associated scWAT inflammation and promote tissue homeostasis.

Clinical Trial Registration: www.isrctn.com, identifier ISRCTN96712688.
1664-3224
Fisk, Helena L.
2483d346-75dd-41b3-a481-10f8bb39cd9f
Childs, Caroline E.
ea17ccc1-2eac-4f67-96c7-a0c4d9dfd9c5
Miles, Elizabeth A.
20332899-ecdb-4214-95bc-922dde36d416
Ayres, Robert
da3a1f2b-432f-46f8-857f-ceae18ce7b40
Noakes, Paul S.
239467df-a79c-4761-802d-131c341abcae
Paras Chavez, Carolina
f0170853-485a-4ef7-bc03-727884b13dbd
Antoun, Elie
10fc5678-b33c-4410-977d-b11234031791
Lillycrop, Karen A.
eeaaa78d-0c4d-4033-a178-60ce7345a2cc
Calder, Philip C.
1797e54f-378e-4dcb-80a4-3e30018f07a6
Fisk, Helena L.
2483d346-75dd-41b3-a481-10f8bb39cd9f
Childs, Caroline E.
ea17ccc1-2eac-4f67-96c7-a0c4d9dfd9c5
Miles, Elizabeth A.
20332899-ecdb-4214-95bc-922dde36d416
Ayres, Robert
da3a1f2b-432f-46f8-857f-ceae18ce7b40
Noakes, Paul S.
239467df-a79c-4761-802d-131c341abcae
Paras Chavez, Carolina
f0170853-485a-4ef7-bc03-727884b13dbd
Antoun, Elie
10fc5678-b33c-4410-977d-b11234031791
Lillycrop, Karen A.
eeaaa78d-0c4d-4033-a178-60ce7345a2cc
Calder, Philip C.
1797e54f-378e-4dcb-80a4-3e30018f07a6

Fisk, Helena L., Childs, Caroline E., Miles, Elizabeth A., Ayres, Robert, Noakes, Paul S., Paras Chavez, Carolina, Antoun, Elie, Lillycrop, Karen A. and Calder, Philip C. (2022) Dysregulation of subcutaneous white adipose tissue inflammatory environment modelling in non-insulin resistant obesity and responses to omega-3 fatty acids – a double blind, randomised clinical trial. Frontiers in Immunology, 13, [922654]. (doi:10.3389/fimmu.2022.9226).

Record type: Article

Abstract

Background: Obesity is associated with enhanced lipid accumulation and the expansion of adipose tissue accompanied by hypoxia and inflammatory signalling. Investigation in human subcutaneous white adipose tissue (scWAT) in people living with obesity in which metabolic complications such as insulin resistance are yet to manifest is limited, and the mechanisms by which these processes are dysregulated are not well elucidated. Long chain omega-3 polyunsaturated fatty acids (LC n-3 PUFAs) have been shown to modulate the expression of genes associated with lipid accumulation and collagen deposition and reduce the number of inflammatory macrophages in adipose tissue from individuals with insulin resistance. Therefore, these lipids may have positive actions on obesity associated scWAT hypertrophy and inflammation.

Methods: To evaluate obesity-associated tissue remodelling and responses to LC n-3 PUFAs, abdominal scWAT biopsies were collected from normal weight individuals and those living with obesity prior to and following 12-week intervention with marine LC n-3 PUFAs (1.1 g EPA + 0.8 g DHA daily). RNA sequencing, qRT-PCR, and histochemical staining were used to assess remodelling- and inflammatory-associated gene expression, tissue morphology and macrophage infiltration.

Results: Obesity was associated with scWAT hypertrophy (P < 0.001), hypoxia, remodelling, and inflammatory macrophage infiltration (P = 0.023). Furthermore, we highlight the novel dysregulation of Wnt signalling in scWAT in non-insulin resistant obesity. LC n-3 PUFAs beneficially modulated the scWAT environment through downregulating the expression of genes associated with inflammatory and remodelling pathways (P <0.001), but there were altered outcomes in individuals living with obesity in comparison to normal weight individuals.

Conclusion: Our data identify dysregulation of Wnt signalling, hypoxia, and hypertrophy, and enhanced macrophage infiltration in scWAT in non-insulin resistant obesity. LC n-3 PUFAs modulate some of these processes, especially in normal weight individuals which may be preventative and limit the development of restrictive and inflammatory scWAT in the development of obesity. We conclude that a higher dose or longer duration of LC n-3 PUFA intervention may be needed to reduce obesity-associated scWAT inflammation and promote tissue homeostasis.

Clinical Trial Registration: www.isrctn.com, identifier ISRCTN96712688.

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Accepted/In Press date: 20 June 2022
e-pub ahead of print date: 25 July 2022

Identifiers

Local EPrints ID: 467990
URI: http://eprints.soton.ac.uk/id/eprint/467990
ISSN: 1664-3224
PURE UUID: 3ffe8901-bf19-4c77-8997-6ed0fd889b54
ORCID for Helena L. Fisk: ORCID iD orcid.org/0000-0002-9534-3246
ORCID for Caroline E. Childs: ORCID iD orcid.org/0000-0001-6832-224X
ORCID for Elizabeth A. Miles: ORCID iD orcid.org/0000-0002-8643-0655
ORCID for Karen A. Lillycrop: ORCID iD orcid.org/0000-0001-7350-5489
ORCID for Philip C. Calder: ORCID iD orcid.org/0000-0002-6038-710X

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Date deposited: 27 Jul 2022 16:55
Last modified: 30 Jul 2022 01:44

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Contributors

Author: Helena L. Fisk ORCID iD
Author: Robert Ayres
Author: Paul S. Noakes
Author: Carolina Paras Chavez
Author: Elie Antoun

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