Ltb4r1 inhibitor: A pivotal insulin sensitizer? Saeed Esmaili 1, 2 and Jacob George 1 1 Storr Liver Centre, Westmead Millennium Institute and Westmead Hospital, University of Sydney, Sydney, New South Wales 2145, Australia 2 Liver and Pancreatobiliary Diseases Research Centre, Digestive Disease Research Institute, Shariati Hospital, Tehran university of Medical Sciences, Tehran, Iran The potent chemokine leukotriene B 4 (LTB4) is increased in obesity, and is associated with insulin resistance. A recent article shows that inhibition of its receptor LTB4 receptor 1 (Ltb4r1) improves insulin sensitivity in muscle and liver via cytokine-independent mechanisms, and reduces proinflammatory immune cell infiltration in the adipose tissue. Insulin resistance (impaired insulin action), a cardinal feature of obesity and type 2 diabetes is accompanied by chronic low-grade inflammation evidenced by the accumu- lation of immune cells in insulin target tissues such as adipose, muscle and liver. The effect of this inflammatory response in reducing insulin sensitivity is well known. Li. et al., [1] now suggest that leukotriene B 4 (LTB4) is a key lipid mediator that drives insulin resistance following a high fat diet (HFD) by promoting both inflammation-asso- ciated insulin resistance as well as reducing insulin sensi- tivity directly in muscle and liver. Importantly for translational medicine, the results of this relatively ‘clean’ study suggests that pharmacologic inhibition of the LTB4 receptor 1 (Ltb4r1)- a G protein-coupled receptor, protects mice from HFD-induced insulin resistance. Adipocytes do not express Ltb4r1 and thus the beneficial effect on adipose tissue insulin sensitivity was through inhibition of inflam- mation and monocyte recruitment. By contrast, in muscle and liver cells that do express Ltb4r1, the inhibitor im- proved insulin action independent of LTB4-Ltb4r1-medi- ated recruitment of inflammatory cells. In muscle, LTB4 inhibits insulin-stimulated phosphorylation of Akt, trans- location of Glut4 and glucose uptake by augmenting serine phosphorylation of insulin receptor substrate 1 (Irs1). These effects were blunted by pertussis toxin that inhibits Gai (to which Ltb4r1 couples), or by c-Jun N-terminal kinase (JNK) small interference RNA (siRNA), or an in- hibitor of JNK activity, implying a Gai-Jnk pathway to insulin resistance. In primary hepatocytes likewise, LTB4 enhanced hepatic glucose production (HGP) through Gai, pJNK and serine phosphorylation of Irs2. Unexpectedly, Ltb4r1 KO hepatocytes were resistant to the effects of glucagon in promoting HGP; the mechanism is unknown. Overall, the Ltb4r1 inhibitor improved glucose tolerance, reduced the levels of insulin and plasma free fatty acids, and reversed hepatic steatosis (Figure 1). Although LTB4 levels were elevated in adipose tissue, muscle, and liver of mice fed the HFD, it is not clear if LTB4 levels were higher in HFD fed mice treated with the Ltb4r1 inhibitor. Importantly, despite the proinflammatory role of LTB4 through binding to Ltb4r1, intracellular LTB4 is an agonist for PPAR-a which has anti-inflammatory effects [2]. Spite et al., [3] have shown that Ltb4r1 KO mice express higher levels of PPARa. Thus, the finding that Ltb4r1 inhibitor administration to normal chow fed WT or Ltb4r1 KO mice does not further improve insulin sensitiv- ity, strengthens the likelihood that LTB4 in combination with Ltb4r1 inhibition is required for improving insulin sensitivity. LTB4 stimulation of intraperitoneal macrophages pro- moted phosphorylation of JNK, the degradation of IkB, and increased expression of proinflammatory cytokines. By contrast, Ltb4r1 inhibitor abrogated the chemotaxis of macrophages towards condition media of 3T3-L1 adipo- cytes containing LTB4. Likewise, in vivo, Ltb4r1 KO mono- cytes injected to WT mice fed a HFD did not recruit to adipose tissue, compared to their WT counterparts. Nagar- eddy et al., [4] have previously demonstrated that hypergly- cemia increases monocytosis and recruitment of monocytes to atherosclerotic lesions. Hence, beside the inhibitory effect of the Ltb4r1 inhibitor on chemotaxis, it could potentially have reduced recruitment of monocytes to adipose tissue by increasing insulin sensitivity and lowering blood glucose levels. Li et al., [1] also demonstrated higher expression by adipose tissues in vivo of anti-inflammatory genes associ- ated with an M2 like macrophage phenotype including interleukin 10 (IL-10), macrophage galactose-type C-type lectin 1 (Mgl1), C-type lectin domain family 7 member A (Clec7a), mannose receptor, C type 1 (Mrc1), and IL-4. Spite et al., [3] have reported similar increases in M2 like macrophages in Ltb4r1 KO mice fed a HF diet. M2 macrophages promote insulin sensitivity in metabolic tissues like liver and fat, while M1 macrophages induce insulin resistance, as reviewed elsewhere [5]. Interestingly, although the Ltb4r1 inhibitor in vivo increased the number of M2 like macrophages, in vitro it did not affect anti-inflammatory gene expression (despite a reduction of expression of proinflammatory genes in intraperitoneal macrophages stimulated with LTB4). This discordance suggests that merely blocking the LTB4-Ltb4r1 interac- tion on macrophages is insufficient for induction of an M2 phenotype. Thus, it is possible that the metabolic Spotlight 1043-2760/ ß 2015 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tem.2015.03.007 Corresponding authors: Esmaili, S. (saeed.esmaili@sydney.edu.au); George, J. (jacob.george@sydney.edu.au). Keywords: obesity; inflammation; leukotriene B4; leukotriene B4 receptor; insulin sensitivity. TEM-1026; No. of Pages 2 Trends in Endocrinology and Metabolism xx (2015) 1–2 1