Murine resistin is secreted by adipocytes, whereas human resistin is secreted by mononuclear cells. Although genetic and pharmacologic studies strongly support links between resistin, obesity, and insulin resistance in mice, the role of human resistin as a modulator of metabolism in inflammatory states is not well understood. The present finding that induction of human resistin alters glucose metabolism in endotoxemia clearly links human resistin to inflammation-induced insulin resistance. Therefore, this study provides much needed insight into the pathophysiologic role of human resistin in various inflammatory states associated with insulin resistance, ranging from sepsis to type 2 diabetes and atherosclerosis. In this respect, it is noteworthy that several epidemiologic studies have recently showed close relationships between resistin and type 2 diabetes, cardiovascular disease, and inflammatory markers (17
Early stages of sepsis and experimental endotoxemia are associated with hypoglycemia through increased glucose disposal by macrophage-rich tissues as well as decreased glucose production in humans as well as animals (33
). In line with previous reports, LPS administration acutely caused hypoglycemia in Rko
mice, with similar robust increases in serum proinflammatory cytokines, which are known to cause hypoglycemia (33
). LPS increased serum leptin levels and decreased adiponectin, which can be explained by cytokine responses (39
). During acute LPS-induced hypoglycemia, however, the induction of human resistin increased hepatic glucose production and decreased glucose uptake, thereby reducing the severity of hypoglycemia. Intriguingly, mice lacking resistin are more prone to fasting-induced hypoglycemia than wild-type mice (9
), suggesting similar functions of resistin across species, albeit in different physiologic settings. Thus the human-specific expression pattern of resistin facilitates its function as a glucose counterregulatory hormone to mitigate hypoglycemia during acute endotoxemia. Of note, the metabolic effects of chronic endotoxemia in wild-type mice (31
) are likely through a resistin-independent mechanism because murine resistin is not induced by LPS (Supplementary Fig. 5A–C
), although it was recently reported to be induced by homocysteine, which is proinflammatory among other pleiotropic effects (45
Animal studies on the acute effect of LPS on insulin sensitivity have yielded conflicting results (46
). In the setting of acute endotoxemia, we found that insulin sensitivity was enhanced in liver as well as in WAT of Rko
mice and that human resistin abrogated this insulin-sensitizing effect of LPS, inducing insulin resistance. Our finding that hepatic ceramide content correlated with hepatic insulin resistance is consistent with a previous report (48
). Ceramide has been shown to induce insulin resistance by inhibiting insulin signaling. Interestingly, TNF-α can acutely stimulate the accumulation of ceramide and various ceramide metabolites (49
). Although there we did not detect differences in ceramide-related gene expression in liver of the BAC-Retn
mice, the changes of hepatic ceramide content in acute endotoxemia could be due to changes in enzyme activity or to alterations in substrate flux.
During chronic endotoxemia, induction of human resistin promoted glucose intolerance and hepatic insulin resistance, suggesting its role as a link between innate immunity, inflammation, and insulin resistance. Epidemiologic studies provide strong evidence that chronic inflammation and obesity-induced insulin resistance are closely related (50
). Experimental endotoxemia in humans, akin to states of infection and sepsis, also induces systemic insulin resistance as well as increased circulating resistin (16
). Here we found that, in mice, chronic endotoxemia robustly induced inflammation in liver and skeletal muscle and was exacerbated by induction of human resistin. Our finding that human resistin promotes insulin resistance by inducing TNF-α and upregulating G6pase and PEPCK in liver are consistent with previous reports (15
Although hepatic ceramide accumulation can at least partly explain hepatic insulin resistance in acute endotoxemia, tissue inflammation exacerbated by resistin, not hepatic ceramide, seems to be a plausible mechanism for insulin resistance in chronic endotoxemia. Recently, regulatory T-cells have been demonstrated to contribute to macrophage recruitment and adipose inflammation in obesity, and resistin has been shown to indirectly enhance regulatory T-cells (57
). Thus, T-cells, in addition to macrophages, may possibly be involved in the enhanced inflammation of the BAC-Retn
mice. It remains unanswered how resistin functions in various tissues or cells, because the receptor for resistin has not yet been uncovered.
In summary, we have demonstrated that human resistin modulates glucose homeostasis under inflammation using a humanized resistin mouse model. Human resistin is induced in response to inflammation. Resistin attenuates endotoxemia-induced hypoglycemia by inducing insulin resistance in liver and WAT and promotes hepatic insulin resistance by exacerbating inflammatory responses in chronic endotoxemia. Increased inflammation is accompanied by increased infiltration of macrophages, which can, in turn, augment resistin induction. Thus, induction of resistin is expected to be a component of the pathophysiology of inflammation-induced insulin resistance in humans. The mouse model of humanized resistin expression reported here can be used to provide a better understanding and potential amelioration of the metabolic pathology of inflammatory states in humans.