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Further validation for a role in LOX pathway
Further validation for a role in 12/15-LOX pathway in mediating adipocyte function comes from studies revealing a regulatory role of lipocalin-2 on 12/15-LOX activity. Lipocalin-2, a glycoprotein member of the lipocalin superfamily, is a novel abundant adipokine implicated in obesity-mediated inflammation and insulin resistance. Reports demonstrate that lipocalin-2 α-Amanitin is increased and correlates with increased inflammation in visceral adipose tissue from obese patients and obese rodent models [81], [82], [83]. Lipocalin-2 directly regulates adipose inflammation by activating 12/15-LOX activity [84]. Law and colleagues demonstrated that epididymal adipose tissue from lipocalin-2 deficient mice placed on a high-fat diet exhibited decreased macrophage infiltration, markers of oxidative stress, inflammatory markers, including TNF-α and MCP-1, with marked improvement in insulin action with increased insulin-stimulated glucose uptake compared to control C57BL6/J mice on a high-fat diet [84]. This protection correlated with decreased expression of 12/15-LOX and its primary metabolite, 12(S)-HETE, and decreased metabolism of its main substrate, arachidonic acid, in adipose tissue. Addition of cinnamyl-3,4-dihydroxy-α-cyanocinnamate (CDC; 12-LOX inhibitor) prevented lipocalin-2 induction of TNF-α and ensuing insulin resistance in adipose tissue of normal C57BL6/J mice fed a high-fat diet. Interestingly lipocalin-2 appears to exert adipose-specific effects on 12/15-LOX as expression of the latter was not altered and insulin sensitivity did not differ in other tissues examined between wild-type and lipocalin-2 deficient mice. Thus, these studies provide additional evidence implicating a critical role for 12/15-LOX in modulating adipocyte dysfunction with significant whole-body consequences. Less investigation has been devoted to the role of epidermal- and platelet-12-LOX in obesity-induced adipocyte dysfunction. However, a recent paper from our lab has demonstrated that platelet-12-LOX is upregulated in adipocytes from C57BL6/J mice fed a Western diet for 12weeks, and interestingly treatment with an angiotensin type 1 receptor (AT1R) blocker, valsartan, can abolish this effect [85]. It would be of interest to follow-up whether 12/15-LOX is also regulated by the renin-angiotensin system (RAS) in adipose tissue, as much evidence reveals that LOX products upregulate RAS components and in turn can be regulated by the RAS in several cell types [85]. A more detailed evaluation of the role of 12/15-LOX-derived products in adipocytes was performed by Chakrabarti and colleagues [76]. 12(S)-HETE and 12(S)-HPETE were added directly to differentiated 3T3-L1 adipocytes and shown to increase inflammatory cytokine expression of TNF-α, MCP-1, IL-6, and IL-12p40, and to decrease the expression of the anti-inflammatory adipokine, adiponectin. In addition, these products induced insulin resistance as measured by a decrease in insulin-mediated activation of key insulin-signaling proteins, such as Akt and IRS-1 (insulin receptor substrate-1). Furthermore, a free fatty acid component of high-fat diets, palmitic acid, was able to induce 12/15-LOX expression in 3T3-L1 adipocytes. These results demonstrate that products of 12/15-LOX pathway can directly impair adipocyte function in a fatty-acid surplus environment. A model for a proposed role of leukocyte 12-LOX (12/15-LOX) in adipose tissue inflammation is shown in Fig. 3. When this tissue is stressed, such as under diet-induced obesity, the adipocytes no longer function properly, and this leads to significant inflammatory consequences. Leukocyte-12-LOX appears to greatly contribute to this local and systemic decline (Fig. 3). Thus further dissecting the role and regulation of leukocyte-12-LOX in adipose tissue will be of utmost importance and could lead to the development of novel therapeutic agents to reduce complications associated with obesity.