Humans and Mice Display Opposing Patterns of “Browning” Gene Expression in Visceral and Subcutaneous White Adipose Tissue Depots

Abstract As research into the adipocyte microenvironment has advanced, it is becoming more widely accepted that the extracellular matrix (ECM) contributes to adipocyte dysfunction. The majority of current published work focuses on the role of collagens in metabolic disease while less emphasis has been placed on the contribution of laminins, an important component of the adipocyte basement membrane. Laminins are trimeric ECM proteins composed of α, β, and γ chains. The α chains contain sites which can interact with cell surface receptors and is considered the driver of tissue-specific expression and specialized signaling. Our group has shown that the laminin-α4 (LAMA4) chain, which is highly expressed in mature adipocytes, plays a role in adipocyte function and thermogenesis in mice (1). In this study we investigate the relationship between laminin α chain expression and obesity by assessing gene expression of LAMA1-5 in subcutaneous white adipose tissue (sWAT) from mice fed chow (RCD) and 45% high fat diet (HFD) for 8 weeks. Expression of LAMA2 and LAMA4 was significantly increased in the HFD sWAT compared to chow (6.1 fold, p=0.01 and 4.9 fold, p=0.001 respectively), however LAMA4 displayed a much stronger positive correlation with weight (R2=0.697) than did LAMA2 (R2=0.382). In order to validate the relevance of these findings in human models of obesity, we evaluated gene expression of LAMA2, LAMA4, and LAMA5 in sWAT biopsies from non-diabetic adult females with obesity (class II or higher). sWAT samples from obese subjects exhibited 4.5 fold higher LAMA4 expression (p=0.0089) than samples from non-obese control subjects, suggesting that the LAMA4 chain may play an important role in human obesity. Lastly we examined changes in sWAT LAMA4 expression following a period of weight loss in obese mice and in human subjects after bariatric surgery, and found that LAMA4 expression levels remain largely unchanged in both cases. In this study we demonstrate the relationship between LAMA4 expression and obesity and present findings that can be extended to human models of obesity. Reference: (1) Vaicik et al., Endocrinology. 2018 Jan;159(1):356–67.

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Adipocyte deletion of the RNA binding protein HuR induces cardiac hypertrophy and fibrosis

10.1101/2021.01.19.425776 ◽

2021 ◽

Author(s):

Adrienne R. Guarnieri ◽

Sarah R. Anthony ◽

Anamarie Gozdiff ◽

Lisa C. Green ◽

Sam Slone ◽

...

Keyword(s):

Gene Expression ◽

Adipose Tissue ◽

Cardiac Hypertrophy ◽

White Adipose Tissue ◽

Rna Binding ◽

Binding Protein ◽

Rna Binding Protein ◽

Rna Seq ◽

Subcutaneous White Adipose Tissue ◽

Specific Deletion

ABSTRACTAdipose tissue continues to gain appreciation for its broad role as an endocrine organ, and disruptions in adipose tissue homeostasis plays a central role in cardiovascular physiology. We have previously shown that expression of the RNA binding protein HuR in adipose tissue mediates energy expenditure, but the potential cardiovascular impacts of this finding have not been explored. We show here that adipose tissue-specific deletion of HuR (Adipo-HuR-/-) is sufficient to induce the spontaneous development of cardiac hypertrophy and fibrosis. Hearts from Adipo-HuR-/- mice have increased left ventricular (LV) ejection fraction, rate of pressure generation, and LV posterior wall thickness that is accompanied by an increase in LV/body weight ratio and hypertrophic gene expression. Furthermore, Adipo-HuR-/- hearts display increased fibrosis by picrosirius red staining and periostin expression. To identify underlying mechanisms, we applied both RNA-seq and weighted gene co-expression network analysis (WGCNA) to define HuR-dependent changes in gene expression as well as significant relationships between adipose tissue gene expression and LV mass. RNA-seq results demonstrate a significant increase in pro-inflammatory gene expression in the subcutaneous white adipose tissue (scWAT) from Adipo-HuR-/- mice that is accompanied by an increase in serum levels of both TNF-α and IL-6. WGCNA identified a significant enrichment in inflammation, apoptosis/cell death, and vesicle-mediated transport genes among those whose expression most significantly associated with CVD in Adipo-HuR-/-. In conclusion, we demonstrate that the loss of HuR expression in adipose tissue promotes the development of cardiac hypertrophy and fibrosis, potentially through modulation of inflammation and vesicle-mediated transport in scWAT.NEW AND NOTEWORTHYThis work demonstrates the spontaneous development of cardiac hypertrophy and fibrosis upon adipose tissue-specific deletion of the RNA binding protein HuR that appears to be mechanistically driven by HuR-dependent changes in inflammatory and extracellular vesicle transport mediating genes in the subcutaneous white adipose tissue. These results suggest that loss of HuR expression in adipose tissue in obesity, as demonstrated in mouse and humans by our group and others, may contribute to obesity-mediated CVD.

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Taurine supplementation associated with exercise increases mitochondrial activity and fatty acid oxidation gene expression in the subcutaneous white adipose tissue of obese women

Clinical Nutrition ◽

10.1016/j.clnu.2020.09.044 ◽

2020 ◽

Author(s):

Flavia Giolo De Carvalho ◽

Camila Fernanda Cunha Brandao ◽

Gabriela Batitucci ◽

Anderson de Oliveira Souza ◽

Gustavo Duarte Ferrari ◽

...

Keyword(s):

Gene Expression ◽

Adipose Tissue ◽

Fatty Acid ◽

Fatty Acid Oxidation ◽

White Adipose Tissue ◽

Acid Oxidation ◽

Mitochondrial Activity ◽

Obese Women ◽

Taurine Supplementation ◽

Subcutaneous White Adipose Tissue

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Acceptance of Murine Islet Allografts without Immunosuppression in the Inguinal Subcutaneous White Adipose Tissue Pretreated with bFGF

Diabetes ◽

10.2337/db18-32-or ◽

2018 ◽

Vol 67 (Supplement 1) ◽

pp. 32-OR

Author(s):

YUKI NAKAFUSA ◽

NAOYOSHI NITTA ◽

MASAFUNI NAKAMURA ◽

YOHICHI YASUNAMI

Keyword(s):

Adipose Tissue ◽

White Adipose Tissue ◽

Subcutaneous White Adipose Tissue ◽

Islet Allografts

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MED19 Regulates Adipogenesis and Maintenance of White Adipose Tissue Mass by Mediating PPARγ-Dependent Gene Expression

Cell Reports ◽

10.1016/j.celrep.2020.108228 ◽

2020 ◽

Vol 33 (1) ◽

pp. 108228 ◽

Cited By ~ 1

Author(s):

John M. Dean ◽

Anyuan He ◽

Min Tan ◽

Jun Wang ◽

Dongliang Lu ◽

...

Keyword(s):

Gene Expression ◽

Adipose Tissue ◽

White Adipose Tissue ◽

Tissue Mass ◽

Adipose Tissue Mass

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Metallothionein gene expression and secretion in white adipose tissue

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.2000.279.6.r2329 ◽

2000 ◽

Vol 279 (6) ◽

pp. R2329-R2335 ◽

Cited By ~ 24

Author(s):

Paul Trayhurn ◽

Jacqueline S. Duncan ◽

Anne M. Wood ◽

John H. Beattie

Keyword(s):

Gene Expression ◽

Molecular Weight ◽

Adipose Tissue ◽

White Adipose Tissue ◽

Stromal Vascular Fraction ◽

Low Molecular Weight ◽

Secretory Product ◽

Mrna Levels ◽

Gene Encoding ◽

Adrenoceptor Agonist

White adipose tissue (WAT) has been examined to determine whether the gene encoding metallothionein (MT), a low-molecular-weight stress response protein, is expressed in the tissue and whether MT may be a secretory product of adipocytes. The MT-1 gene was expressed in epididymal WAT, with MT-1 mRNA levels being similar in lean and obese ( ob/ ob) mice. MT-1 mRNA was found in each of the main adipose tissue sites (epididymal, perirenal, omental, subcutaneous), and there was no major difference between depots. Separation of adipocytes from the stromal-vascular fraction of WAT indicated that the MT gene (MT-1 and MT-2) was expressed in adipocytes themselves. Treatment of mice with zinc had no effect on MT-1 mRNA levels in WAT, despite strong induction of MT-1 expression in the liver. MT-1 gene expression in WAT was also unaltered by fasting or norepinephrine. However, administration of a β3-adrenoceptor agonist, BRL-35153A, led to a significant increase in MT-1 mRNA. On differentiation of fibroblastic preadipocytes to adipocytes in primary culture, MT was detected in the medium, suggesting that the protein may be secreted from WAT. It is concluded that WAT may be a significant site of MT production; within adipocytes, MT could play an antioxidant role in protecting fatty acids from damage.

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