Contributions of adipose tissue architectural and tensile properties toward defining healthy and unhealthy obesity - PubMed (original) (raw)

Contributions of adipose tissue architectural and tensile properties toward defining healthy and unhealthy obesity

Denise E Lackey et al. Am J Physiol Endocrinol Metab. 2014 Feb.

Abstract

The extracellular matrix (ECM) plays an important role in the maintenance of white adipose tissue (WAT) architecture and function, and proper ECM remodeling is critical to support WAT malleability to accommodate changes in energy storage needs. Obesity and adipocyte hypertrophy place a strain on the ECM remodeling machinery, which may promote disordered ECM and altered tissue integrity and could promote proinflammatory and cell stress signals. To explore these questions, new methods were developed to quantify omental and subcutaneous WAT tensile strength and WAT collagen content by three-dimensional confocal imaging, using collagen VI knockout mice as a methods validation tool. These methods, combined with comprehensive measurement of WAT ECM proteolytic enzymes, transcript, and blood analyte analyses, were used to identify unique pathophenotypes of metabolic syndrome and type 2 diabetes mellitus in obese women, using multivariate statistical modeling and univariate comparisons with weight-matched healthy obese individuals. In addition to the expected differences in inflammation and glycemic control, approximately 20 ECM-related factors, including omental tensile strength, collagen, and enzyme transcripts, helped discriminate metabolically compromised obesity. This is consistent with the hypothesis that WAT ECM physiology is intimately linked to metabolic health in obese humans, and the studies provide new tools to explore this relationship.

Keywords: adipose inflammation; bariatric surgery; extracellular matrix; matrix metalloproteinase; type 2 diabetes mellitus.

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Figures

Fig. 1.

Fig. 1.

Apparatus for white adipose tissue (WAT) tensile strength measurement (A) and force/displacement curve example from murine retroperitoneal (RP) WAT (B). A DMT560 tissue puller with custom clamps used for measuring peak force of fresh murine RP WAT was used to measure slope, peak force, and tensile strength (see

methods

). Following peak force, the tissue begins to rupture, thus resulting in variable reductions in force/displacement, as illustrated.

Fig. 2.

Fig. 2.

Mouse RP WAT collagen (extracellular matrix) content as measured by 5-(4,6-dichlorotriazinyl) aminofluorescein (5-DTAF) staining/confocal microscopy (A and B) and Sirius red histological staining (C): collagen is stained green (5-DTAF) and adipocytes are red (Bodipy 558/568 C12). In A, the starting image illustrating the collagen sheath typical of murine RP WAT surrounding the depot is depicted; to reduce variance and provide a more uniform method that could be applied to human WAT biopsies lacking a sheath, this layer was not included in the calculations shown in B. Values are presented as means ± SE comparing wild-type (WT) and collagen 6a1 knockout (Col6a) knockout mice. *Statistically significant at P < 0.05 by Student's _t_-test. Bar, 100 μm.

Fig. 3.

Fig. 3.

Healthy and metabolic syndrome (MetS) obese human adipocyte size distribution analysis. Adipocyte area was measured from Sirius red-stained paraffin sections of omental WAT (A) and subcutaneous (sc) WAT surgical biopsies (B). Bars indicate %total cells within the specified cell area range, shown as means ± SE. There were no statistically significant differences between healthy and MetS obese within the same size category, as determined by 1-way ANOVA followed by Tukey's post hoc test. Line in histology images indicates 100 μm at ×20 magnification.

Fig. 4.

Fig. 4.

Results from partial least squares-discriminant analysis (PLS-DA) modeling of clinical and WAT phenotype variables to identify features that differentiate healthy obese and MetS obese women. A: subjects scores plot illustrating individuals from the healthy (green) and MetS (pink) cohorts, showing separation of groups along latent variable 1 dimension (_x_-axis). B: scores separation along the _x_-axis dimension in A was explained primarily by variance in features depicted in the loadings plot. HOMA-IR, homeostasis model assessment of insulin resistance; BUN, blood urea nitrogren; ALT, alanine aminotransferase; CTSS, cathepsin S; ITGAX, integrin αX; MMP-7 and -9, matrix metalloproteinase-7 and -9, respectively; WBC, white blood cell; AST, aspartate aminotransferase; BP, blood pressure; ITGAD, integrin αD; BGN, biglycan; THBS1, thrombospondin-1; QUICKI, quantitative insulin sensitivity check index; ARG2, arginase 2; ECM, extracellular matrix.

Fig. 5.

Fig. 5.

Results from PLS-DA modeling of clinical and WAT phenotype variables to identify features that differentiate healthy obese and T2DM obese women. A: subjects scores plot illustrating individuals from the healthy (green) and MetS (red) cohorts, showing separation of groups along latent variable 1 dimension (_x_-axis). B: scores separation along the _x_-axis dimension in A was explained primarily by variance in features depicted in the loadings plot. Abbreviations are defined in tables and Fig. 4 legend.

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