Metabolic Dysregulation and Adipose Tissue Fibrosis: Role of Collagen VI
Open accessAbstract
Adipocytes are embedded in a unique extracellular matrix whose main function is to provide mechanical support, in addition to participating in a variety of signaling events. During adipose tissue expansion, the extracellular matrix requires remodeling to accommodate adipocyte growth. Here, we demonstrate a general upregulation of several extracellular matrix components in adipose tissue in the diabetic state, therefore implicating "adipose tissue fibrosis" as a hallmark of metabolically challenged adipocytes. Collagen VI is a highly enriched extracellular matrix component of adipose tissue. The absence of collagen VI results in the uninhibited expansion of individual adipocytes and is paradoxically associated with substantial improvements in whole-body energy homeostasis, both with high-fat diet exposure and in the ob/ob background. Collectively, our data suggest that weakening the extracellular scaffold of adipocytes enables their stress-free expansion during states of positive energy balance, which is consequently associated with an improved inflammatory profile. Therefore, the disproportionate accumulation of extracellular matrix components in adipose tissue may not be merely an epiphenomenon of metabolically challenging conditions but may also directly contribute to a failure to expand adipose tissue mass during states of excess caloric intake.
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IMAT is low in insulin-sensitive, endurance-trained athletes.
“Unlike intramuscular triglyceride, IMAT is low in insulin-sensitive, endurance-trained athletes (26), consistent with a negative relationship of IMAT to insulin sensitivity.”
From Intermuscular adipose tissue directly modulates skeletal muscle insulin sensitivity in humans (2019) · cites this paper as [26]
Collagen and fibronectin are especially enriched in adipose tissue and the peritoneum.
“Importantly, these two ECM components are especially enriched in adipose tissue and the peritoneum (Shibata et al., 1997; Witz et al., 2001; Khan et al., 2009; Mori et al., 2014; Lin et al., 2016).”
From Microphysiological systems as models for immunologically ‘cold’ tumors (2024) · cites this paper as Khan et al., 2009
Adipose tissue hypoxia either increases the expression of pro-fibrotic genes and leads to adipose fibrosis, or directly leads to adipose necrosis, inducing infiltration by immune cells and adipose inflammation.
“Adipose tissue hypoxia either increases the expression of pro‐fibrotic genes and leads to adipose fibrosis, or directly leads to adipose necrosis, inducing infiltration by immune cells and adipose inflammation.[ 25 ]”
From Pathogenesis of sarcopenia and the relationship with fat mass: descriptive review (2022) · cites this paper as [25]
Mice deficient in collagen VI exhibit unimpeded tissue expansion.
“Conversely, mice deficient in collagen VI exhibit unimpeded tissue expansion (49).”
From The ominous triad of adipose tissue dysfunction: inflammation, fibrosis, and impaired angiogenesis. (2017) · cites this paper as [49]
In early adipose tissue expansion, a strong ECM degradation signal promotes adipose growth and is important for whole-body metabolic homeostasis.
“Thus, in early AT expansion, there is a strong ECM degradation signal to promote AT growth, which is important for maintaining whole body metabolic homeostasis (49).”
From The ominous triad of adipose tissue dysfunction: inflammation, fibrosis, and impaired angiogenesis. (2017) · cites this paper as [49]
Several ECM components are upregulated during fat mass expansion in states of obesity.
“We and others have demonstrated that several ECM components are upregulated during fat mass expansion in states of obesity (102, 103)”
From Adipose tissue remodeling and obesity (2011) · cites this paper as [102]
Weakening of the ECM that surrounds AT by elimination of collagen VI leads to improved survival rates of adipocytes and improvements in metabolism.
“We have demonstrated that the weakening of the ECM that surrounds AT by elimination of collagen VI leads to improved survival rates of adipocytes and improvements in metabolism (102)”
From Adipose tissue remodeling and obesity (2011) · cites this paper as [102]
The ECM regulates the physiological and pathological events of AT remodeling through a variety of signaling pathways.
“but also regulates the physiological and pathological events of AT remodeling through a variety of signaling pathways (102)”
From Adipose tissue remodeling and obesity (2011) · cites this paper as [102]
The ECM provides mechanical support for a fat pad.
“The ECM not only functions to provide mechanical support for a fat pad”
From Adipose tissue remodeling and obesity (2011) · cites this paper as [102]
Collagen VI is a collagen complex that is highly enriched in the ECM of AT.
“Collagen VI, for example, is a collagen complex that is highly enriched in the ECM of AT (102)”
From Adipose tissue remodeling and obesity (2011) · cites this paper as [102]
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- Authors
- Khan, T., Muise, E. S., Iyengar, P., Wang, Z. V., Chandalia, M., Abate, N., Zhang, B. B., Bonaldo, P., Chua, S., & Scherer, P. E.
- Affiliations
- Department of Cell Biology
- Departments of Molecular Profiling
- Departments of Internal Medicine
- The University of Texas Southwestern Medical Center (US)
- Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
- University of Padua (IT)
- Albert Einstein College of Medicine (US)
- ORCID
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2009-03-01
- Volume
- 29
- Issue
- 6
- Pages
- 1575-1591
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC2648231
- OpenAlex
- W2163691580
- Cited by
- 1,053
- References
- 60
- Citations by year
- 2026: 39 · 2025: 48 · 2024: 44 · 2023: 69 · 2022: 89 · 2021: 71 · 2020: 76 · 2019: 68 · 2018: 81 · 2017: 85 · 2016: 66 · 2015: 56 · 2014: 60 · 2013: 73 · 2012: 41
- FWCI
- 20.76
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Padua Research Archive (University of Padova) (submittedVersion, other-oa)
- Funders
- University of Texas Southwestern Medical Center
- University of Glasgow
- Kementerian Pendidikan Nasional
- National Institutes of Health
- Albert Einstein College of Medicine, Yeshiva University
- National Cancer Institute (R01CA112023)
- National Institute of Diabetes and Digestive and Kidney Diseases (PL1DK081182, R01DK055758, T32DK007513)
- Topics
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Disease and Adiposity
- Keywords
- adipose tissue fibrosis, collagen VI, extracellular matrix, metabolic dysfunction, diabetes mellitus, energy homeostasis, high-fat diet, ob/ob mice, adipose tissue inflammation, positive energy balance
- MeSH terms
- Adipose Tissue, Aging, Animals, Diabetes Mellitus, Endotoxins, Extracellular Matrix, Fibrosis, Glucose, Humans, Hyperplasia, Inflammation, Insulin, Male, Necrosis, Pancreas, Adipocytes, Mice, Knockout, Collagen Type VI, Cell Size, Mice
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