Deficiency of plasminogen activator inhibitor‐2 impairs nutritionally induced murine adipose tissue development

Abstract

Summary. Background: A functional role for several components of the fibrinolytic (plasminogen/plasmin) system in development of adipose tissue has been demonstrated. No information is available, however, on a potential role of plasminogen activator inhibitor-2 (PAI-2) in obesity. Methods: In vitro, 3T3-F442A murine pre-adipocytes were differentiated into mature adipocytes. In vivo, 5-week-old male PAI-2-deficient (PAI-2 )/) ) mice and wild-type (WT) controls of the same genetic background (C57Bl/6) were kept on a high fat diet (HFD, caloric value of 20.1 kJ g)1 ) for 15 weeks. Results: Semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) revealed expression of PAI-2 mRNA during in vitro differentiation of pre-adipocytes and in vivo in s.c. and gonadal (GON) adipose tissues of WT mice, where it was localized both in the stromal/vascular cell fraction and in adipocytes. During HFD feeding, food intake and body weight gain were comparable for WT and PAI-2 )/) mice. Subcutaneous plus GON fat mass was, however, significantly lower in PAI-2 )/) mice (3.15 ± 0.21 vs. 3.91 ± 0.18 g; P < 0.05).Immunohistochemical analysis of adipose tissues revealed significant adipocyte hypotrophy in s.c. fat of PAI-2 )/) mice (about 25% reduction in size; P < 0.01). Blood vessel density, normalized to adipocyte number, was comparable in s.c. fat, but was lower (P < 0.05) in GON fat of PAI-2 )/) mice. Adipose tissue-associated fibrinolytic activity was not affected by PAI-2 deficiency. Conclusion: PAI-2 promotes adipose tissue development in mice via a mechanism independent of its antifibrinolytic effect.

A Western-like fat diet is sufficient to induce a gradual enhancement in fat mass over generations

“…Of note, the increased expression of the precursor Tachykinin 1 (Tac1) suggests enhanced production of substance P, which has been reported to promote proliferation of preadipocytes ( 38 ). Regarding adipocyte hypertrophy, the overexpression of PAI-2 (Serpinb2) over generations is consistent with the fact that PAI-2 Ϫ / Ϫ mice fed a high-fat diet exhibit a lower adipocyte size and higher adipocyte number than wild-type mice ( 39 ), and suggests that PAI-2 overexpression promotes excessive WAT development. Reports have implicated Wnt signaling pathway components as proteins that maintain the preadipocyte compartment and inhibit adipogenesis.…”

Spontaneous Irs1 passenger mutation linked to a gene-targeted SerpinB2 allele

“…007234, http://jaxmice.jax.org/strain/007234.html; Jackson Laboratory) has been deposited at Jackson Laboratory and has been distributed to other investigators. All subsequent studies and reports from other groups (14,15,(40)(41)(42) were confined to the 10G3 line. All animal care and experimental procedures complied with the Principles of Laboratory and Animal Care established by the National Society for Medical Research and were approved by the University of Michigan Committee on Use and Care of Animals.…”

A Physiological Function of Inflammation-Associated SerpinB2 Is Regulation of Adaptive Immunity

“…Only two phenotypes have so far been reported for SerpinB2 2/2 mice: increased susceptibility to multistage skin carcinogenesis (31) and increased adipocyte hypotrophy after a high-fat diet (9). Neither phenotype provides discernable insights into the clinical observations.…”

“…The majority of the .860 publications listed in PubMed on SerpinB2/PAI-2 have thus assumed that the principle role of this serpin is inhibition of uPA, although a number of reports have indicated that certain activities associated with SerpinB2 expression appear unrelated to uPA inhibition (2,6,9,(11)(12)(13)(14). Although SerpinB2 can inhibit uPA in vitro, the evidence that this represents a physiological function for SerpinB2 in vivo is not compelling.…”

“…SerpinB2 is induced during many inflammatory processes and infections (3)(4)(5)(6)(7) and is one of the most upregulated proteins of activated monocytes/macrophages representing up to 1% of total protein (7,8). SerpinB2 can also be induced to a lesser extent in fibroblasts and endothelial cells and is constitutively expressed by differentiating keratinocytes, placental trophoblasts (3), adipocytes (9), and a range of tumors (4,10).…”