To assess physiological and pathophysiological events that involve dynamic interplay between multiple cell types, real-time, in vivo analysis is necessary. We developed a technique based on confocal laser microscopy that enabled us to analyze and compare the 3-dimensional structures, cellular dynamics, and vascular function within mouse lean and obese adipose tissue in vivo with high spatiotemporal resolution. We found increased leukocyte-EC-platelet interaction in the microcirculation of obese visceral adipose tissue in ob/ob and high-fat diet–induced obese mice. These changes were indicative of activation of the leukocyte adhesion cascade, a hallmark of inflammation. Local platelet activation in obese adipose tissue was indicated by increased P-selectin expression and formation of monocyte-platelet conjugates. We observed upregulated expression of adhesion molecules on macrophages and ECs in obese visceral adipose tissue, suggesting that interactions between these cells contribute to local activation of inflammatory processes. Furthermore, administration of anti–ICAM-1 antibody normalized the cell dynamics seen in obese visceral fat. This imaging technique to analyze the complex cellular interplay within obese adipose tissue allowed us to show that visceral adipose tissue obesity is an inflammatory disease. In addition, this technique may prove to be a valuable tool to evaluate potential therapeutic interventions.
Satoshi Nishimura, Ichiro Manabe, Mika Nagasaki, Kinya Seo, Hiroshi Yamashita, Yumiko Hosoya, Mitsuru Ohsugi, Kazuyuki Tobe, Takashi Kadowaki, Ryozo Nagai, Seiryo Sugiura
Submitter: Rebecca Robker | Rebecca.email@example.com
Authors: Prof C. Wayne Smith
School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, Australia
Published March 3, 2008
The fascinating and visually beautiful work of Nishimura et al adds a great deal to our understanding of the dynamics of immune cell infiltration into adipose tissue during obesity. They demonstrate the presence of ICAM-1 positive cells within visceral adipose tissue of obese mice, with endothelial cell expression identical to that reported by our laboratory (1) which, just to clarify, was also in obese animals not lean. We have also reported that this increased ICAM-1 expression occurs in response to a high fat diet, and in a gender-specific manner (2). What is particularly informative is that an anti-ICAM-1 antibody can block macrophage migration into epididymal adipose tissue. We reported a similar finding using ICAM-1-/- mice, a small but significant decrease in macrophage infiltration into epididymal fat pads of male ICAM-1-/- mice, but not other fat pads, i.e. peri-uterine fat of ICAM-1-/- females ((1), see Figure 5B and associated text). One of the key counter receptors for ICAM-1 is Mac-1 and although Nishimura et al did not investigate the kinetics of Mac-1+ cells in their in vivo system, we did not observe a decrease in macrophage infiltration in adipose tissue of obese Mac-1-/- mice. Therefore, ICAM-1 clearly has marked effects on aspects of inflammation within adipose tissue, presumably via mediating firm adhesion of monocytes, however our data suggests that macrophage migration at least is occurring via Mac-1 independent mechanisms. Lastly, although Nishimura et al, by blocking ICAM-1 action are able to reverse the changes in macrophage migration, hypoxia and vascular permeability observed in obese adipose tissue, it is not known whether this will have any significant effect on adipose tissue function. Our studies found that ICAM-1-/- mice have identical weight gain and epididymal fat pad weight both basally and in response to a high fat diet (manuscript in preparation). Thus, although ICAM-1 is emerging as a key player in the transformation of adipose tissue during the onset of obesity, it remains to be determined how these alterations might ultimately affect adipocytes and the manifestation of obesity. 1. Robker RL, Collins RG, Beaudet AL, Mersmann HJ, Smith CW. Leukocyte migration in adipose tissue of mice null for ICAM-1 and Mac-1 adhesion receptors. Obes Res. 2004 Jun;12(6):936-40. 2. Brake DK, Smith EO, Mersmann H, Smith CW, Robker RL. ICAM-1 expression in adipose tissue: effects of diet-induced obesity in mice. Am J Physiol Cell Physiol. 2006 Dec;291(6):C1232-9.