Obesity is associated with insulin resistance, disturbed glucose homeostasis, low grade inflammation, and comorbidities such as type 2 diabetes and cardiovascular disease. The cytokine macrophage migration inhibitory factor (MIF) is an ubiquitously expressed protein that plays a crucial role in many inflammatory and autoimmune disorders. Increasing evidence suggests that MIF also controls metabolic and inflammatory processes underlying the development of metabolic pathologies associated with obesity. This is a comprehensive summary of our current knowledge on the role of MIF in obesity and obesity-associated comorbidities, based on human clinical data as well as animal models of disease.
The incidence of obesity is increasing in many populations in the world and in some regions now affects more than 30% of adults [
Macrophage migration inhibitory factor (MIF) is an innate cytokine involved in many inflammatory and autoimmune disorders; many of these pathologies are associated with obesity including cardiovascular [
Obesity and specifically the enlargement of the abdominal adipose depots are considered major risk factors for the development of insulin resistance, T2D, and diabetic complications. Several lines of clinical evidence support a relationship between MIF and obesity (Table
Relationship between plasma MIF concentrations and body mass index in human studies. Studies are listed on basis of increasing body mass index (BMI). The plasma MIF concentration is provided together with the number of male (m) and female (f) participants and the major effects observed. NS: not specified.
Average BMI | Gender (m; f) | MIF conc (ng/mL) | Effect observed | Reference |
---|---|---|---|---|
22.6 versus 37.5 | 19; 21 | 1.2 versus 2.8 | Positive correlation of BMI with plasma MIF conc. and MIF mRNA of MNC | [ |
22.6 versus 40.0 | 16; 16 | 1.3 versus 3.3 | No correlation of plasma MIF with BMI and FFA; pos. correlation with HOMA | [ |
18–25 versus 30–48 | 0; 46 | 0.5 versus 1.9 | Positive correlation with BMI | [ |
43.0 | 23; 48 | 8.4 | MIF decreased with weight loss MIF conc. elevated in women with HRT | [ |
32.5 to 30.6 | 0; 31 | 16.0 to 5.4 | MIF conc. decreased with weight loss | [ |
46.7 | 5; 22 | 0.2 | MIF conc. increased with weight loss | [ |
27 versus 37 | females | NS | MIF production of adipose tissue is positively correlated with BMI | [ |
36 | 34 | NS | mRNA conc positively associated with adipocyte diameter | [ |
The results of the above studies evaluating the relationship between obesity and MIF are not uniform and any causal relationship between obesity and MIF levels remains to be established. Factors that may contribute to the large variability between the studies include differences in gender (plasma MIF levels are higher in males [
Recent epidemiological data provide support for a role for MIF in the development of IR and T2D in humans (Table
Relationship between plasma MIF concentrations, glucose intolerance, and T2D. The table provides the type of subjects (study groups), the number of subjects per study group, and the plasma/serum MIF concentration together with the major effects. IGT: impaired glucose tolerance; PDR: proliferative diabetic retinopathy; ND: not determined.
Study groups | MIF conc (ng/mL) | Effect observed | Reference | |
---|---|---|---|---|
Control | 79 | 5.2 | MIF is elevated in T2D subjects | [ |
T2D | 79 | 20.7 | ||
Caucasians | 24 | Fasting MIF conc. are higher in Pima Indians | [ | |
Pima Indians | 28 | |||
Normoglycemic | 244 | 4.97 | Positive association of MIF with IGT and T2D independent of CRP and IL-6 | [ |
IGT | 242 | 7.95 | ||
T2D | 236 | 10.96 | ||
Noncases controls | 1632 | 17.7 | Females with | [ |
Future T2D | 502 | 18.5 | ||
Control | 257 | 5.8 | Identification of MIF as a novel immune marker to predict progression from IGT to T2D | [ |
Lifestyle intervention | 265 | 6.2 | ||
Control | 6 | ND | Increased kidney CD74 expression | [ |
Diabetic nephropathy | 20 | |||
Control | 39 | 1.8 | Increased MIF levels in vitreous of patients with PDR | [ |
PDR | 32 | 11.9 | ||
Nondiabetics | 24 | 1.1 | Increased MIF levels in patients with retinopathy | [ |
PDR | 40 | 6.3 | ||
Control diabetics | 140 | 4.3 | Higher MIF levels in diabetics with ulcer | [ |
Diabetics with ulcer | 170 | 7.7 |
Additional support for a causal role of MIF in the etiology of T2D comes from a population-based study comparing the effect of four SNPs of MIF (rs755622, rs2070766, rs2070767, and rs1007888) on serum concentrations and the risk of T2D (MONICA/KORA Augsburg Study) [
Different results were obtained in the Finnish Diabetes Prevention Study (
Elevated levels of MIF or its cell surface receptor (CD74) were found in patients with diabetic complications including diabetic nephropathy [
The above epidemiological and clinical studies suggest an important link between MIF, obesity, the dysregulation of glucose metabolism, and the development of insulin resistance and T2D, but it remains unclear whether such abnormalities in MIF and MIF receptor expression are epiphenomena or casual factors. In the past few years, studies in experimental models of disease have provided some confirmatory data indicating a mechanistic role for MIF in the comorbidities of obesity.
While a role for MIF could be demonstrated in various settings of experimental type I diabetes [
First evidence for a role for MIF in glucose metabolism was suggested by the immunohistochemical identification of MIF within the insulin-containing granules of the islets of Langerhans [
The development of a systemic inflammatory response during microbial infection or tissue invasion frequently leads to a catabolic state. Transient hyperglycemia and insulin resistance typically occur first, but this may be followed by a persistent state of lactate production and metabolic acidosis, glycogen depletion, and hypoglycemia. Circulating cytokines such as tumor necrosis factor (TNF) have long been considered to provoke these metabolic abnormalities, which unresolved, lead to protein wasting and cachexia. In murine studies the catabolic effect of TNF on muscle was found to be mediated by MIF [
These findings were further extended once MIF-KO mice became available. Hyperinsulinmeiceuglycemic clamp studies in endotoxemic or TNF injected MIF-KO mice showed these mice to exhibit normal blood glucose and lactate responses [
Finally, a recent study has identified a potentially critical role for MIF in the cardiomyocyte response to ischemia [
We recently showed that genetic deletion of MIF reduces systemic inflammation (SAA and fibrinogen) and protects mice against the development of glucose intolerance and insulin resistance [
An important event in the pathogenesis of insulin resistance of WAT is the infiltration of macrophages causing low-grade adipose inflammation [
Besides controlling local tissue-specific inflammation, MIF is implicated in controlling systemic inflammation, including the expression of risk factors of T2D. MIF affects the constitutive and interleukin-1 (IL-1)-induced expression of SAA as well as the expression of IL-6 and human CRP as demonstrated in human CRP transgenic mice [
The specific role of MIF in the regulation of T2D risk factors (e.g., the acute phase reactants CRP, SAA, fibrinogen) has yet to be systemically analyzed. Burger-Kentischer and coworkers showed that immunoneutralization of MIF lowers plasma fibrinogen and IL-6 levels and reduces the expression level of CCAAT-enhancer-binding protein beta (C/EBP
Finally, the identification of prevalent, functional polymorphisms in MIF, which show significant population stratification [
Grant support has been received from the NIH and the Brookdale Foundation (to the second author) as well as from the TNO research program “Humanized models of inflammatory metabolic diseases” (to the first author).