Mini-Review: Fight against fibrosis in adipose tissue remodeling

Adipose is a key tissue regulating energy homeostasis. In states of obesity, caloric intake exceeds energy expenditure, thereby accelerating lipid accumulation with ongoing extracellular matrix (ECM) remodeling. Excess deposition of lipids and expansion of adipocytes potentially decrease ECM flexibility with local hypoxia and inflammation. Hypoxia and chronic low-grade inflammation accelerate the development of adipose tissue fibrosis and related metabolic dysfunctions. Adipose tissue remodeling impacts localized adipose tissue metabolism, which including adipogenesis, angiogenesis, insulin sensitivity, cytokine secretion profile, and in turn alters systemic glucose and lipid homeostasis. The activation and maintenance of beige adipocyte is a potential therapeutic strategy for combating HFD-induced adipose tissue fibrosis and insulin resistance. In this review, we focused on the regulatory mechanisms and mediators in remodeling of adipose tissue fibrosis, along with their relevance to clinical manifestations.

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Adipose Tissue Remodeling as Homeostatic Inflammation

International Journal of Inflammation ◽

10.4061/2011/720926 ◽

2011 ◽

Vol 2011 ◽

pp. 1-8 ◽

Cited By ~ 42

Author(s):

Michiko Itoh ◽

Takayoshi Suganami ◽

Rumi Hachiya ◽

Yoshihiro Ogawa

Keyword(s):

Fatty Acids ◽

Adipose Tissue ◽

Inflammatory Responses ◽

Saturated Fatty Acids ◽

Tissue Remodeling ◽

Low Grade ◽

Adipose Tissue Inflammation ◽

Tissue Inflammation ◽

Adipose Tissue Remodeling ◽

Novel Therapeutic Strategies

Evidence has accumulated indicating that obesity is associated with a state of chronic, low-grade inflammation. Obese adipose tissue is characterized by dynamic changes in cellular composition and function, which may be referred to as “adipose tissue remodeling”. Among stromal cells in the adipose tissue, infiltrated macrophages play an important role in adipose tissue inflammation and systemic insulin resistance. We have demonstrated that a paracrine loop involving saturated fatty acids and tumor necrosis factor-α derived from adipocytes and macrophages, respectively, aggravates obesity-induced adipose tissue inflammation. Notably, saturated fatty acids, which are released from hypertrophied adipocytes via the macrophage-induced lipolysis, serve as a naturally occurring ligand for Toll-like receptor 4 complex, thereby activating macrophages. Such a sustained interaction between endogenous ligands derived from parenchymal cells and pathogen sensors expressed in stromal immune cells should lead to chronic inflammatory responses ranging from the basal homeostatic state to diseased tissue remodeling, which may be referred to as “homeostatic inflammation”. We, therefore, postulate that adipose tissue remodeling may represent a prototypic example of homeostatic inflammation. Understanding the molecular mechanism underlying homeostatic inflammation may lead to the identification of novel therapeutic strategies to prevent or treat obesity-related complications.

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Role of toll-like receptors and their ligands in adipocyte secretion

Annals of Proteomics and Bioinformatics ◽

10.29328/journal.apb.1001012 ◽

2021 ◽

Vol 5 (1) ◽

pp. 001-007

Author(s):

Mishra A ◽

Shestopalov AV ◽

Gaponov AM ◽

Alexandrov IA ◽

Roumiantsev SA

Keyword(s):

Adipose Tissue ◽

Energy Homeostasis ◽

Whole Body ◽

Low Grade ◽

White Adipocyte ◽

White Adipocytes ◽

Beige Adipocytes ◽

Whole Body Metabolism ◽

Significant Expression ◽

Adipose Tissue Remodeling

Background: Adipose tissue is one of the main sites of energy homeostasis that regulates whole body metabolism with the help of adipokines. Disruption in its proper functioning results in adipose tissue remodeling (primarily hypertrophy and hyperplasia) which directly influences the secretion of said adipokines. Obesity characterized as chronic low-grade inflammation of the adipose tissue is one such condition that has far reaching effects on whole body metabolism. Inflammation in turn results in immune cells infiltrating into the tissue and further promoting adipocyte dysfunction. Purpose: In our study we explored this adipose tissue-innate immunity axis by differentiating adipose tissue derived stem cells (ADSCs) into white and beige adipocytes. We further stimulated our cultures with lipopolysaccharide (LPS), flagellin, or meteorin-like, glial cell differentiation regulator (METRNL) to trigger an inflammatory response. We then evaluated Toll-like receptor (TLR) mRNA expression and secretion of interleukin (IL-6), interleukin-8 (IL-8), brain-derived neurotrophic factor (BDNF), and nerve growth factor (NGF) in these cultures. Results: We found that TLR2 is the highest expressed receptor in adipocytes. Further, LPS and METRNL are strong activators of TLR2 in white and beigeBMP7(-) adipocytes. TLR4 was not significantly expressed in any of our cultures despite LPS stimulation. TLR9 expression is upregulated in ADSCs upon LPS and METRNL stimulation. IL-6 and IL-8 secretion is increased upon LPS stimulation in white adipocytes. METRNL activates both IL-6 and IL-8 expression in adipocyte cultures. Lastly, BDNF and NGF is secreted by all adipocyte cultures with beigeBMP7(-) and beigeBMP7(+) secreting slightly higher amounts in comparison to white adipocytes. Conclusion: ADSCs and adipocytes alike are capable of expressing TLRs, but white adipocytes remain the highest expressing in both control and stimulated cultures. TLR2 is highly expressed in white and beige adipocytes whereas TLR4 showed no significant expression. LPS and METRNL trigger IL-6 and IL-8 secretion in adipocytes. Products of white adipocyte “browning” are capable of secreting higher amounts of BDNF and NGF in comparison to white adipocytes.

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Adipose tissue remodeling in pathophysiology of obesity

Current Opinion in Clinical Nutrition & Metabolic Care ◽

10.1097/mco.0b013e32833aabef ◽

2010 ◽

Vol 13 (4) ◽

pp. 371-376 ◽

Cited By ~ 106

Author(s):

Mi-Jeong Lee ◽

Yuanyuan Wu ◽

Susan K Fried

Keyword(s):

Adipose Tissue ◽

Tissue Remodeling ◽

Adipose Tissue Remodeling

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Adipose Tissue Remodeling in Children: The Link between Collagen Deposition and Age-Related Adipocyte Growth

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2011-2806 ◽

2012 ◽

Vol 97 (4) ◽

pp. 1320-1327 ◽

Cited By ~ 30

Author(s):

Charmaine S. Tam ◽

Joan Tordjman ◽

Adeline Divoux ◽

Louise A. Baur ◽

Karine Clément

Keyword(s):

Adipose Tissue ◽

Tissue Remodeling ◽

Collagen Deposition ◽

Age Related ◽

Adipose Tissue Remodeling

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Evidence for the Regulatory Role of Lipocalin 2 in High-Fat Diet-Induced Adipose Tissue Remodeling in Male Mice

Endocrinology ◽

10.1210/en.2013-1289 ◽

2013 ◽

Vol 154 (10) ◽

pp. 3525-3538 ◽

Cited By ~ 33

Author(s):

Hong Guo ◽

Merlijn Bazuine ◽

Daozhong Jin ◽

Merry M. Huang ◽

Samuel W. Cushman ◽

...

Keyword(s):

Adipose Tissue ◽

High Fat Diet ◽

Adipocyte Differentiation ◽

Tissue Remodeling ◽

Peroxisome Proliferator ◽

Lipocalin 2 ◽

Peroxisome Proliferator Activated Receptor ◽

Adipose Tissue Remodeling ◽

Fat Depot

Lipocalin 2 (Lcn2) has previously been characterized as an adipokine/cytokine playing a role in glucose and lipid homeostasis. In this study, we investigate the role of Lcn2 in adipose tissue remodeling during high-fat diet (HFD)-induced obesity. We find that Lcn2 protein is highly abundant selectively in inguinal adipose tissue. During 16 weeks of HFD feeding, the inguinal fat depot expanded continuously, whereas the expansion of the epididymal fat depot was reduced in both wild-type (WT) and Lcn2−/− mice. Interestingly, the depot-specific effect of HFD on fat mass was exacerbated and appeared more pronounced and faster in Lcn2−/− mice than in WT mice. In Lcn2−/− mice, adipocyte hypertrophy in both inguinal and epididymal adipose tissue was more profoundly induced by age and HFD when compared with WT mice. The expression of peroxisome proliferator-activated receptor-γ protein was significantly down-regulated, whereas the gene expression of extracellular matrix proteins was up-regulated selectively in epididymal adipocytes of Lcn2−/− mice. Consistent with these observations, collagen deposition was selectively higher in the epididymal, but not in the inguinal adipose depot of Lcn2−/− mice. Administration of the peroxisome proliferator-activated receptor-γ agonist rosiglitazone (Rosi) restored adipogenic gene expression. However, Lcn2 deficiency did not alter the responsiveness of adipose tissue to Rosi effects on the extracellular matrix expression. Rosi treatment led to the further enlargement of adipocytes with improved metabolic activity in Lcn2−/− mice, which may be associated with a more pronounced effect of Rosi treatment in reducing TGF-β in Lcn2−/− adipose tissue. Consistent with these in vivo observations, Lcn2 deficiency reduces the adipocyte differentiation capacity of stromal-vascular cells isolated from HFD-fed mice in these cells. Herein Rosi treatment was again able to stimulate adipocyte differentiation to a similar extent in WT and Lcn2−/− inguinal and epididymal stromal-vascular cells. Thus, combined, our data indicate that Lcn2 has a depot-specific role in HFD-induced adipose tissue remodeling.

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