Specific collagen XVIII isoforms promote adipose tissue accrual via mechanisms determining adipocyte number and affect fat deposition

Abstract

Collagen XVIII is an evolutionary conserved ubiquitously expressed basement membrane proteoglycan produced in three isoforms via two promoters (P). Here, we assess the function of the N-terminal, domain of unknown function/frizzled-like sequences unique to medium/long collagen XVIII by creating P-specific null mice. P2-null mice, which only produce short collagen XVIII, developed reduced bulk-adiposity, hepatic steatosis, and hypertriglyceridemia. These abnormalities did not develop in P1-null mice, which produce medium/long collagen XVIII. White adipose tissue samples from P2-null mice contain larger reserves of a cell population enriched in early adipocyte progenitors; however, their embryonic fibroblasts had ∼50% lower adipocyte differentiation potential. Differentiating 3T3-L1 fibroblasts into mature adipocytes produced striking increases in P2 gene-products and dramatic falls in P1-transcribed mRNA, whereas Wnt3a-induced dedifferentiation of mature adipocytes produced reciprocal changes in P1 and P2 transcript levels. P2-derived gene-products containing frizzledlike sequences bound the potent adipogenic inhibitor, Wnt10b, in vitro. Previously, we have shown that these same sequences bind Wnt3a, inhibiting Wnt3a-mediated signaling. P2-transcript levels in visceral fat were positively correlated with serum free fatty acid levels, suggesting that collagen α1 (XVIII) expression contributes to regulation of adipose tissue metabolism in visceral obesity. Medium/long collagen XVIII is deposited in the Space of Disse, and interaction between hepatic apolipoprotein E and this proteoglycan is lost in P2-null mice. These results describe a previously unidentified extracellular matrix-directed mechanism contributing to the control of the multistep adipogenic program that determines the number of precursors committing to adipocyte differentiation, the maintenance of the differentiated state, and the physiological consequences of its impairment on ectopic fat deposition.

Parathyroid Hormone Remodels Bone Transitional Vessels and the Leptin Receptor-Positive Pericyte Network in Mice

“…The N‐terminal domain of the long isoform inhibits the wnt‐beta catenin pathway, via a Frizzle‐like sequence . In addition, lack of collagen 18 increases the number of adipocyte progenitors in the liver . Thus, collagen 18 could exert relevant functions in bone biology.…”

“…(42) In addition, lack of collagen 18 increases the number of adipocyte progenitors in the liver. (43) Thus, collagen 18 could exert relevant functions in bone biology. However, 2-and 4-weekold unchallenged Col 18 alpha1 -/mice have no obvious bone phenotype.…”

Vitamin E reduces adipose tissue fibrosis, inflammation, and oxidative stress and improves metabolic profile in obesity

“…It is mediated by fibrinolytic factors, such as plasminogen and plasmin, matrix metalloproteases (MMP), and antifibrinolytic systems like the tissue inhibitors of MMP (TIMPs), among others . Studies in individuals with obesity have reported the relation between body mass index, ECM components, and metabolic disorders in adipose tissue . Experiments in mice lacking collagen VI, the most abundant type in adipose tissue, in an ob/ob background, showed larger adipocytes and improved metabolic parameters, suggesting that collagen VI may constraint adipocytes, provoking metabolic alterations .…”

Endostatin and endorepellin: A common route of action for similar angiostatic cancer avengers

“…Indeed, aortic explants isolated from Col18a1 −/− mice show increased angiogenesis compared to wild-type mice [43]. Recently, collagen XVIII has been implicated in the pathogenesis of renal ischemia/reperfusion as a mediator of leukocytic influx [44], and in hyperlipidemia associated with fatty liver and visceral obesity, suggesting that it might play a role in the adipose tissue formation [45]. …”