Visceral Adiposity, Genetic Susceptibility, and Risk of Complications Among Individuals with Crohn's Disease.

INTRODUCTION: Adipose tissue in mesenteric fat plays a key role in systemic and luminal inflammation. However, little is known about the role of visceral adipose tissue (VAT) and its interaction with genetic predisposition in Crohn's disease (CD) progression. METHODS: Our study population included patients with CD enrolled in Prospective Registry in Inflammatory Bowel Disease Study at Massachusetts General Hospital (PRISM). VAT volume was measured from computed tomography using Aquarius 3D. We used logistic regression models to estimate the multivariable-adjusted odds ratio and 95% CI. We tested for effect modification by genetic predisposition using the log likelihood ratio test. RESULTS: Among 482 patients with CD with available data on VAT, 174 developed penetrating disease, 132 developed stricturing disease, 147 developed perianal disease, and 252 required surgery. Compared with individuals in the lowest quartile of VAT volume, the multivariable-adjusted odds ratio of surgery among individuals in the highest quartile was 2.02 (95% CI, 1.09-3.76; Ptrend = 0.006). Similarly, the risk of penetrating disease seemed to increase with greater VAT volume (Ptrend = 0.022) but not stricturing or perianal disease (all Ptrend > 0.23). The associations between VAT volume and CD complications were not modified by genetic predisposition (all Pinteraction > 0.12). CONCLUSIONS: Visceral adiposity as measured by VAT volume may be associated with a significant increase in the risk of penetrating disease and surgery in CD. Our data suggest that visceral adiposity as measured by VAT may negatively impact long-term progression of CD regardless of genetic predisposition.

Tropomyosin and Profilin Cooperate to Promote Formin-Mediated Actin Nucleation and Drive Yeast Actin Cable Assembly.

Tropomyosins comprise a large family of actin-binding proteins with critical roles in diverse actin-based processes [1], but our understanding of how they mechanistically contribute to actin filament dynamics has been limited. We addressed this question in S. cerevisiae, where tropomyosins (Tpm1 and Tpm2), profilin (Pfy1), and formins (Bni1 and Bnr1) are required for the assembly of an array of actin cables that facilitate polarized vesicle delivery and daughter cell growth. Formins drive cable formation by promoting actin nucleation and by accelerating actin filament elongation together with profilin [2]. In contrast, how tropomyosins contribute mechanistically to cable formation has been unclear, but genetic studies demonstrate that Tpm1 plays a more important role than Tpm2 [3, 4]. Here, we found that loss of TPM1 in strains lacking BNR1, but not BNI1, leads to severe defects in cable formation, polarized secretion, and cell growth, suggesting that TPM1 function is required for proper Bni1-mediated cable assembly. Furthermore, in vitro total internal reflection fluorescence (TIRF) microscopy demonstrated that Tpm1 strongly enhances Bni1-mediated, but not Bnr1-mediated, actin nucleation without affecting filament elongation rate, whereas Tpm2 has no effects on Bni1 or Bnr1. Tpm1 stimulation of Bni1-mediated nucleation also requires profilin and its interactions with both G-actin and formins. Together, these results demonstrate that yeast Tpm1 works in concert with profilin to promote formin-dependent nucleation of actin cables, thus expanding our understanding of how specific tropomyosin isoforms influence actin dynamics.