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Am J Physiol Endocrinol Metab (September 23, 2009). doi:10.1152/ajpendo.00320.2009
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RESEARCH ARTICLE

Glucocorticoid reamplification within cells intensifies NF{kappa}B and MAPK signaling and reinforces inflammation in activated preadipocytes

Takako Ishii-Yonemoto,1 Hiroaki Masuzaki, MD, PhD,1,* Shintaro Yasue,1 Sadanori Okada, MD,1 Chisayo Kozuka,1 Tomohiro Tanaka,1 Michio Noguchi, MD, PhD,1 Tsutomu Tomita,1 Junji Fujikura, M.D., Ph.D.,1 Yuji Yamamoto, M.D., PhD,1 Ken Ebihara,1 Kiminori Hosoda,1 and Kazuwa Nakao1

1Kyoto University Graduate School of Medicine

Submitted 18 May 2009 ; revised 24 August 2009 ; accepted in final form 16 September 2009

Increased expression and activity of the intracellular glucocorticoid-reactivating enzyme, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) contributes to dysfunction of adipose tissue. Although the pathophysiological role of 11β-HSD1 in mature adipocytes has long been investigated, its potential role in preadipocytes still remains obscure. The present study demonstrates that the expression of 11β-HSD1 in preadipocyte-rich stromal-vascular fraction (SVF) cells in fat depots from ob/ob and diet-induced obese mice was markedly elevated compared to lean control. In 3T3-L1 preadipocytes, level of mRNA and reductase activity of 11β-HSD1 was augmented by TNF-{alpha}, IL-1β and LPS, with a concomitant increase in iNOS, MCP-1 or IL-6 secretion. Pharmacological inhibition of 11β-HSD1 and RNAi against 11β-HSD1 reduced the mRNA and protein levels of iNOS, MCP-1, and IL-6. In contrast, overexpression of 11β-HSD1 further augmented TNF-{alpha}-induced iNOS, IL-6, and MCP-1 expression. Moreover, 11β-HSD1 inhibitors attenuated TNF-{alpha}-induced phosphorylation of NF{kappa}B p65 and p38-, JNK-, and ERK1/2-MAPK. Collectively, the present study provides novel evidence that inflammatory stimuli-induced 11β-HSD1 in activated preadipocytes intensifies NF{kappa}B and MAPK signaling pathways and results in further induction of pro-inflammatory molecules. Not limited to 3T3-L1 preadipocytes, we also demonstrated the notion was reproducible in the primary SVF cells from obese mice. These findings highlight an unexpected, pro-inflammatory role of re-amplified glucocorticoids within preadipocytes in obese adipose tissue.

11β-HSD1; inflammation; preadipocyte; NFkB


* Kyoto University Graduate School of Medicine hiroaki{at}kuhp.kyoto-u.ac.jp






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