Evidence for activation of inflammatory lipoxygenase pathways in visceral adipose tissue of obese Zucker rats.
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.
Strelitz Diabetes Center, Eastern Virginia Medical School, Norfolk, VA, USA.
Swarup K
SK
Chakrabarti
Yeshao
Y
Wen
Anca D
AD
Dobrian
Banumathi K
BK
Cole
Qian
Q
Ma
Hong
H
Pei
Michael D
MD
Williams
Melissa H
MH
Bevard
George E
GE
Vandenhoff
Susanna R
SR
Keller
Jiali
J
Gu
Jerry L
JL
Nadler
D041721:3T3-L1 Cells; D058927:5-Lipoxygenase-Activating Proteins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001092:Arachidonate 12-Lipoxygenase / Q000235:genetics / Q000378:metabolism*; D001094:Arachidonate 5-Lipoxygenase / Q000235:genetics / Q000378:metabolism*; D001095:Arachidonic Acids / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D018836:Inflammation Mediators / Q000378:metabolism*; D050152:Intra-Abdominal Fat / Q000166:cytology / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D009765:Obesity / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D010431:Pentoxifylline / Q000031:analogs & derivatives / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011924:Rats, Zucker; D050797:STAT4 Transcription Factor / Q000378:metabolism
D058927:5-Lipoxygenase-Activating Proteins; C548594:Alox5ap protein, rat; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001095:Arachidonic Acids; D016207:Cytokines; D018836:Inflammation Mediators; D012333:RNA, Messenger; D050797:STAT4 Transcription Factor; D001092:Arachidonate 12-Lipoxygenase; D001094:Arachidonate 5-Lipoxygenase; C025189:lisofylline; D010431:Pentoxifylline