Abstract |
Central obesity is associated with low-grade inflammation that promotes type 2 diabetes and cardiovascular disease in obese individuals. The 12- and 5-lipoxygenase (12-LO and 5-LO) enzymes have been linked to inflammatory changes, leading to the development of atherosclerosis. 12-LO has also been linked recently to inflammation and insulin resistance in adipocytes. We analyzed the expression of LO and proinflammatory cytokines in adipose tissue and adipocytes in obese Zucker rats, a widely studied genetic model of obesity, insulin resistance, and the metabolic syndrome. mRNA expression of 12-LO, 5-LO, and 5-LO-activating protein (FLAP) was upregulated in adipocytes and adipose tissue from obese Zucker rats compared with those from lean rats. Concomitant with increased LO gene expression, the 12-LO product 12-HETE and the 5-LO products 5-HETE and leukotriene B4 ( LTB4) were also increased in adipocytes. Furthermore, upregulation of key proinflammatory markers interleukin (IL)-6, TNFα, and monocyte chemoattractant protein-1 were observed in adipocytes isolated from obese Zucker rats. Immunohistochemistry indicated that the positive 12-LO staining in adipose tissue represents cells in addition to adipocytes. This was confirmed by Western blotting in stromal vascular fractions. These changes were in part reversed by the novel anti-inflammatory drug lisofylline (LSF). LSF also reduced p-STAT4 in visceral adipose tissue from obese Zucker rats and improved the metabolic profile, reducing fasting plasma glucose and increasing insulin sensitivity in obese Zucker rats. In 3T3-L1 adipocytes, LSF abrogated the inflammatory response induced by LO products. Thus, therapeutic agents reducing LO or STAT4 activation may provide novel tools to reduce obesity-induced inflammation.
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Authors | Swarup K Chakrabarti, Yeshao Wen, Anca D Dobrian, Banumathi K Cole, Qian Ma, Hong Pei, Michael D Williams, Melissa H Bevard, George E Vandenhoff, Susanna R Keller, Jiali Gu, Jerry L Nadler |
Journal | American journal of physiology. Endocrinology and metabolism
(Am J Physiol Endocrinol Metab)
Vol. 300
Issue 1
Pg. E175-87
(Jan 2011)
ISSN: 1522-1555 [Electronic] United States |
PMID | 20978234
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Chemical References |
- 5-Lipoxygenase-Activating Proteins
- Alox5ap protein, rat
- Anti-Inflammatory Agents, Non-Steroidal
- Arachidonic Acids
- Cytokines
- Inflammation Mediators
- RNA, Messenger
- STAT4 Transcription Factor
- Arachidonate 12-Lipoxygenase
- Arachidonate 5-Lipoxygenase
- lisofylline
- Pentoxifylline
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Topics |
- 3T3-L1 Cells
- 5-Lipoxygenase-Activating Proteins
(genetics, metabolism)
- Animals
- Anti-Inflammatory Agents, Non-Steroidal
(pharmacology)
- Arachidonate 12-Lipoxygenase
(genetics, metabolism)
- Arachidonate 5-Lipoxygenase
(genetics, metabolism)
- Arachidonic Acids
(metabolism)
- Cytokines
(metabolism)
- Female
- Gene Expression Regulation
(drug effects)
- Inflammation Mediators
(metabolism)
- Intra-Abdominal Fat
(cytology, drug effects, metabolism, pathology)
- Mice
- Obesity
(drug therapy, metabolism, pathology, physiopathology)
- Pentoxifylline
(analogs & derivatives, pharmacology)
- Phosphorylation
(drug effects)
- RNA, Messenger
(metabolism)
- Rats
- Rats, Zucker
- STAT4 Transcription Factor
(metabolism)
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