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

Abstract

BackgroundObesity 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.MethodsTo 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.ResultsObesity 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.ConclusionOur 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 Registrationwww.isrctn.com, identifier ISRCTN96712688.

An Atlas of Promoter Chromatin Modifications and HiChIP Regulatory Interactions in Human Subcutaneous Adipose-Derived Stem Cells

“…Some of these were previously identified as GF-enriched markers for whole adipose tissue ( TBX15 , SHOX2 , and SFRP2 [ 13 , 27 ]). Importantly, we also identified new depot-specific marker genes that are known to influence adipose tissue function ( ZIC1 , TWIST2 , COL4A4 , APOD [ 28 , 29 , 30 , 31 ]).…”

Metabolic and histomorphological changes of adipose tissue in cachexia

“…In fact, experimental and clinical studies assessed the role of nutrients on metabolic and nutritional status in general, including omega-3 fatty acid supplementation, as well as specific amino acids, carnitine and vitamins, observing changes mainly on body weight and lean body mass [49]. However, data seem to suggest that EPA and DHA administration might modulate lipolysis and the metabolic processes involving the adipose tissue, acting on inflammatory patterns [50]. These effects on inflammation were also recently verified on tumor microenvironment after administration of oral immunonutrition among patients presenting with unvoluntary body weight loss, but effects on body composition were not available [51].…”

Omega-3 Lipid Mediators: Modulation of the M1/M2 Macrophage Phenotype and Its Protective Role in Chronic Liver Diseases

“…Also, it was found, in clinical trial analysis, that EPA plus DHA can decrease lipogenesis and liver steatosis [53,54]. Additionally, EPA and DHA being both preventive and therapeutic protective factors related to immunity and particularly macrophages anti-inflammatory balances, as shown in Table 1 [55][56][57][58][59][60][61][62][63][64][65][66][67]. The Table 1 presents a comprehensive summary of the effects of EPA/DHA on different mechanisms and models (clinical trials and animal studies).…”