Abstract
Obesity is associated with a chronic low-grade inflammatory state that drives the development of obesity-related co-morbidities such as insulin resistance/type 2 diabetes, non-alcoholic fatty liver disease (NAFLD), and cardiovascular disease. This metabolic inflammation is thought to originate in the adipose tissue, which becomes inflamed and insulin resistant when it is no longer able to expand in response to excess caloric and nutrient intake. The production of inflammatory mediators by dysfunctional adipose tissue is thought to drive the development of more complex forms of disease such as type 2 diabetes and NAFLD. An important factor that may contribute to metabolic inflammation is the cytokine macrophage migration inhibitory factor (MIF). Increasing evidence suggests that MIF is released by adipose tissue in obesity and that it is also involved in metabolic and inflammatory processes that underlie the development of obesity-related pathologies. This review provides a comprehensive summary of our current knowledge on the role of MIF in obesity, its production by adipose tissue, and its involvement in the development of insulin resistance, type 2 diabetes, and NAFLD. We discuss the main findings from recent clinical studies in obese subjects and weight-loss intervention studies as well as results from clinical studies in patients with insulin resistance and type 2 diabetes. Furthermore, we summarize findings from experimental disease models studying the contribution of MIF in obesity and insulin resistance, type 2 diabetes, and hepatic lipid accumulation and fibrosis. Although many of the findings support a pro-inflammatory role of MIF in disease development, recent reports also provide indications that MIF may exert protective effects under certain conditions.
Highlights
The development of obesity-associated co-morbidities such as type 2 diabetes (T2D), non-alcoholic fatty liver disease (NAFLD), and cardiovascular disease (CVD) is considered to be driven by the chronic low-grade inflammatory state that characterizes obesity [1]
While these studies indicate that migration inhibitory factor (MIF) may contribute to insulin function in non-pathological glucose homeostasis, the associations observed in human studies indicate that it may have a detrimental role in obesity and the development of obesity-associated insulin resistance and T2D, i.e. conditions of metabolic stress and disturbed metabolic homeostasis
The development of insulin resistance and T2D in obesity is related to elevated MIF levels, which rise with increasing severity of disease
Summary
The development of obesity-associated co-morbidities such as type 2 diabetes (T2D), non-alcoholic fatty liver disease (NAFLD), and cardiovascular disease (CVD) is considered to be driven by the chronic low-grade inflammatory state that characterizes obesity [1]. Since epidemiological studies have shown both insulin resistance [18, 19] and NAFLD [20, 21] to be associated with future CVD risk, this may have relevance for the role of MIF in vascular disease, which has been described elsewhere for rodents [22, 23] and humans [24, 25], and will not be addressed here This survey aims to advance our understanding on the functions of Figure 1 | In obesity, adipose tissue can become a source of inflammation that drives disease development in distant organs. Adipocytes and infiltrated immune cells produce inflammatory mediators that spill over into the circulation (spillover phase) where they drive the progression of obesity-related co-morbidities in distant organs, such as type 2 diabetes, non-alcoholic fatty liver disease, and atherosclerosis. Where the original article stated mean ± SD, SEM was calculated from SD by dividing SD by the square root of n
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