Evidence for activation of inflammatory lipoxygenase pathways in visceral adipose tissue of obese Zucker rats.

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.

• 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)

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

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)