We have demonstrated that, in human macrophages, an inflammatory cascade with secretion of cytokines, including TNFα and IL-6, is sufficient and necessary for the induction of resistin. Insulin sensitizers that have anti-inflammatory properties, including a synthetic PPARγ agonist as well as aspirin, suppress macrophage resistin expression, as does direct inhibition of NF-κB. Experimental endotoxemia in healthy volunteers, based on the well-established gram-negative bacterial inflammatory response in humans [38
], induces a dramatic elevation of circulating resistin levels. Hence, resistin gene and protein expression are increased by inflammatory stimuli both ex vivo and in vivo.
In rodents, resistin is produced exclusively by adipocytes, regulates normal glucose homeostasis, and causes insulin resistance at high circulating levels [11
]. Translation of resistin's metabolic effects from rodents to humans has been problematic because peripheral blood mononuclear cells and macrophages appear to be a primary source of resistin in humans [15
]. This species difference in primary locus of expression is yet another example of the close and functionally overlapping relationship between adipocytes and macrophages [41
]. Numerous studies have reported that circulating resistin levels are increased in human obesity [20
] and diabetes [19
]. Our data suggest that, whereas hyperresistinemia in obese rodents derives directly from adipocytes, human resistin is indirectly regulated by the inflammatory internal milieu of obesity (B). Indeed, obesity is associated with elevated levels of cytokines whose systemic administration leads to impaired glucose homeostasis [36
], such as TNFα and IL-6, which we show here to mediate the inflammatory induction of human resistin. Thus, in both species, adipose tissue is an endocrine organ containing adipocytes as well as macrophages that regulates energy metabolism and glucose homeostasis through secretion of multiple factors, including inflammatory cytokines [46
Clearly the relationship between obesity, inflammation, and resistin expression is complex, and needs to be systematically studied in larger and varied patient populations. Intriguingly, we found a strong correlation between plasma levels of resistin and sTNFR2, the soluble cleavage product of the activated TNFα receptor, in diabetic patients. A comparable correlation between resistin and sTNFR2 (R = 0.31, p < 0.001) was found in a cohort of 879 non-diabetic individuals, in whom resistin levels independently correlated with coronary atherosclerotic disease (M. P. Reilly, M. Lehrke, M. L. Wolfe, A. Rohatgi, M. A. Lazar, and D. J. Rader, unpublished data).
LPS binds to pathogen-associated-molecular-pattern innate immune receptors, such as CD14 and Toll-like receptor 4, activating signal cascades involving NF-κB and MAPK [47
] and thereby inducing the transcription and secretion of early cytokines, including TNFα and IL-1 [48
]. We have shown here that these early cytokines are responsible for secondary induction or enhancement of resistin expression in macrophages. Hyperresistinemia impairs glucose homeostasis in rodents [49
], and inflammatory states are associated with insulin resistance [36
], which may serve as a physiological attempt to increase the provision of glucose to the brain under stress conditions. Indeed, induction of acute inflammation by administration of LPS causes insulin resistance in humans [37
], and here we have demonstrated the concomitant induction of resistin. Interestingly, the peak in TNFα and IL-6 levels after LPS administration to humans precedes a phase of prolonged insulin resistance that begins approximately 6 h after LPS administration [37
], closely approximating the time course of resistin induction. Hence resistin is a potential mediator of insulin resistance in humans with acute inflammation. Moreover, obesity is associated with activation of innate immunity [6
], including the inflammatory mediators that induce resistin. In this context it is intriguing that resistin levels are increased in obesity [25
] and that insulin-sensitizing agents such as aspirin and rosiglitazone, with disparate primary molecular targets, antagonize resistin induction. Indeed, thiazolidinedione suppression of resistin levels has recently been correlated with hepatic insulin sensitization [43
]. Future work will be needed to better understand the relationship between circulating resistin levels and the insulin resistance characteristic of inflammatory states, including obesity.
Why Was This Study Done?
There is a very close connection between obesity and diabetes: diabetes is more common among obese people, and people with type 2 diabetes know that weight control is an essential part of their diabetes treatment. But the link between extra body fat and diabetes remains a puzzle. Recent experiments in mice suggested that a hormone called resistin could be the missing link. One reason is that resistin levels respond to a particular class of diabetes drugs called thiazolidinediones. But studies in humans found that mice and humans are quite different when it comes to resistin. One difference is that in mice resistin is produced by fat cells, but in humans it is produced by special immune cells called macrophages that are involved inflammation. Researchers are now studying what role—if any—resistin might have in humans with obesity and diabetes and are studying the similarities in the ways in which the body reacts to obesity and inflammation.
What Did the Researchers Do?
The researchers examined what happens to resistin levels when human macrophages or human patients are exposed to substances that trigger inflammation.
What Did They Find?
The substances that trigger inflammation caused higher resistin levels, but resistin levels were lowered again by thiazolidinediones.
What Does This Mean?
Because in mice higher resistin levels (produced by fat cells) are linked to diabetes, one possibility is that obesity in humans, by being similar to inflammation, causes immune cells to make lots of resistin and hence promotes diabetes that way.
More research is necessary to confirm these findings and to find out how important resistin is as a link between obesity and diabetes, and how resistin promotes diabetes.