α3(V) Collagen is critical for glucose homeostasis in mice due to effects in pancreatic islets and peripheral tissues
Guorui Huang, … , Andras Nagy, Daniel S. Greenspan
Guorui Huang, … , Andras Nagy, Daniel S. Greenspan
Published January 10, 2011
Citation Information: J Clin Invest. 2011;121(2):769-783. https://doi.org/10.1172/JCI45096.
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Research Article Metabolism

α3(V) Collagen is critical for glucose homeostasis in mice due to effects in pancreatic islets and peripheral tissues

Abstract

Collagen V, broadly expressed as α1(V)2α2(V) heterotrimers that regulate collagen fibril geometry and strength, also occurs in some tissues, such as white adipose tissue (WAT), pancreatic islets, and skeletal muscle, as the poorly characterized α1(V) α2(V) α3(V) heterotrimer. Here, we investigate the role of α3(V) collagen chains by generating mice with a null allele of the α3(V) gene Col5a3 (Col5a3–/– mice). Female Col5a3–/– mice had reduced dermal fat and were resistant to high-fat diet–induced weight gain. Male and female mutant mice were glucose intolerant, insulin-resistant, and hyperglycemic, and these metabolic defects worsened with age. Col5a3–/– mice demonstrated decreased numbers of pancreatic islets, which were more susceptible to streptozotocin-induced apoptosis, and islets isolated from mutant mice displayed blunted glucose-stimulated insulin secretion. Moreover, Col5a3–/– WAT and skeletal muscle were defective in glucose uptake and mobilization of intracellular GLUT4 glucose transporter to the plasma membrane in response to insulin. Our results underscore the emerging view of the importance of ECM to the microenvironments that inform proper development/functioning of specialized cells, such as adipocytes, β cells, and skeletal muscle.

Authors

Guorui Huang, Gaoxiang Ge, Dingyan Wang, Bagavathi Gopalakrishnan, Delana H. Butz, Ricki J. Colman, Andras Nagy, Daniel S. Greenspan

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Figure 2

WAT α3(V) expression and effects of Col5a3 ablation.

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WAT α3(V) expression and effects of Col5a3 ablation. α3(V) chains ar...
α3(V) chains are detectable in (A) wild-type but not (B) Col5a3–/– inguinal fat pads stained with DAPI (blue) and anti-α3(V) antibodies (red). Red spots in Col5a3–/– tissue are nonspecific secondary antibody deposits, also observed in controls performed without primary antibody (data not shown). (C) H&E-stained dorsal skin sections from 10-day-old mice show significantly reduced (P < 0.00005) thickness of the adipocyte-rich hypodermal layer of Col5a3–/– females (36.6 ± 6 μm, n = 6) compared with that of wild-type females (88.2 ± 11.5 μm, n = 5), with a trend toward reduced thickness of the hypodermal layer of Col5a3–/– males (41.8 ± 5.9 μm, n = 10) compared with that of wild-type males (51.1 ± 13.9 μm, n = 5) that did not achieve significance (P < 0.11). Thicknesses are in mean ± SD. A 2-headed arrow denotes the hypodermal layer of wild-type female skin. Asterisks mark 2 hair follicles. Original magnification, ×5 (A and B); ×40 (C). (D) Three-week-old wild-type (males, n = 15; females, n = 13) or Col5a3–/– (males and females each, n = 10) mice were maintained for 13 weeks on a high-fat diet and weighed each week. Average weights/week are in grams. Data are presented as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001. (E) Immunoblots are of cell layer (L) or media (M) samples from cells before (Undiff) or after (Diff) induced adipocytic differentiation. Blots were probed with anti-α3(V) or anti-α1(V) antibodies. For each blot, the thin vertical line indicates where data were spliced together from noncontiguous lanes. In each case, lanes were from the same blot, and thus represent samples run on the same gel, at the same time.