Macrophage migration inhibitory factor deficiency leads to age-dependent impairment of glucose homeostasis in mice

Abstract

Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine produced by many cells and tissues including pancreatic b-cells, liver, skeletal muscle, and adipocytes. This study investigates the potential role of MIF in carbohydrate homeostasis in a physiological setting outside of severe inflammation, utilizing Mif knockout (MIFK/K) mice. Compared with wild-type (WT) mice, MIFK/K mice had a lower body weight, from birth until 4 months of age, but subsequently gained weight faster, resulting in a higher body weight at 12 months of age. The lower weight in young mice was related to a higher energy expenditure, and the higher weight in older mice was related to an increased food intake and a higher fat mass. Fasting blood insulin level was higher in MIFK/K mice compared with WT mice at any age. After i.p. glucose injection, the elevation of blood insulin level was higher in MIFK/K mice compared with WT mice, at 2 months of age, but was lower in 12-month-old MIFK/K mice. As a result, the glucose clearance during intraperitoneal glucose tolerance tests was higher in MIFK/K mice compared with WT mice until 4 months of age, and was lower in 12-month-old MIFK/K mice. Insulin resistance was estimated (euglycemic-hyperinsulinemic clamp tests), and the phosphorylation activity of AKT was similar in MIFK/K mice and WT mice. In conclusion, this mouse model provides evidence for the role of MIF in the control of glucose homeostasis.

Macrophage migration inhibitory factor is overexpressed in pancreatic cancer tissues and impairs insulin secretion function of β-cell

“…For example, the expression of MIF is increased in both pancreatic beta cells and peripheral lymphocytes of mice with autoimmune diabetes, in addition, in NOD mice treated with rMIF the incidence of diabetes is increased from 55% to 86% [30,31]. MIF-KO mice demonstrated an age-dependent weight gain, together with impaired both blood glucose and insulin secretion function, which seems like a T2DM pattern [32]. Serum concentrations of MIF are elevated in patients with T2DM in comparison with patients with impaired glucose tolerance and healthy individuals [33-36].…”

Mechanisms of Obesity-Induced Inflammation and Insulin Resistance: Insights into the Emerging Role of Nutritional Strategies

“…Unpublished work within our group implicates MIF as a critical inflammatory regulator in the pathogenesis of HFD-induced IR with an essential role in HFD-associated ATM recruitment. It has since emerged that lack of MIF signaling results in an age-dependent impairment of glucose homeostasis in mice fed a chow diet (Serre-Beinier et al, 2010), highlighting the intricacy of this molecule and lack of true clarity in terms of its functional role in obesity-induced IR.…”

Role of Macrophage Migration Inhibitory Factor in Obesity, Insulin Resistance, Type 2 Diabetes, and Associated Hepatic Co-Morbidities: A Comprehensive Review of Human and Rodent Studies

“…Serre-Beinier and colleagues (59) investigated the role of MIF in carbohydrate homeostasis over time with aging. For this they used Mif −/− C57BL/6 mice from a 129/Sv background (diet and sex not specified) and examined glucose and insulin tolerance over time.…”