Development of insulin resistance preceded major changes in iron homeostasis in mice fed a high-fat diet

Abstract

Type 2 diabetes mellitus (T2DM) and insulin resistance (IR) have been associated with dysregulation of iron metabolism. The basis for this association is not completely understood. To attempt to investigate this, we studied temporal associations between onset of insulin resistance (IR) and dysregulated iron homeostasis, in a mouse model of T2DM. Male C57Bl/6 mice (aged 8 weeks) were fed a high-fat diet (HFD; 60% energy from fat) or a control diet (CD; 10% energy from fat) for 4, 8, 12, 16, 20 and 24 weeks. Development of IR was documented, and various metabolic, inflammatory and iron-related parameters were studied in these mice. HFD-feeding induced weight gain, hepato-steatosis and IR in the mice. Onset of IR occurred from 12 weeks onwards. Hepatic iron stores progressively declined from 16 weeks onwards. Accompanying changes included a decrease in hepatic hepcidin ( Hamp1 ) mRNA expression and serum hepcidin levels and an increase in iron content in the epididymal white adipose tissue (eWAT). Iron content in the liver negatively correlated with that in the eWAT. Factors known to regulate hepatic Hamp1 expression (such as serum iron levels, systemic inflammation, and bone marrow-derived erythroid regulators) were not affected by HFD-feeding. In conclusion, the results show that the onset of IR in HFD-fed mice preceded dysregulation of iron homeostasis, evidence of which were found both in the liver and visceral adipose tissue.

Insulin Resistance and Chronic Hepatitis C: Relationship With Serum Iron and Hepcidin

“…In the current study, CHC patients with diabetes exhibited a negative non-significant correlation between serum hepcidin with serum iron and serum hepcidin and insulin resistance. A positive association between the dysregulation of iron metabolism and deranged glucose parameters was reported in previous studies, which is quite different from the current study [ 21 , 22 ].…”

Fat specific adipose triglyceride lipase is necessary for iron-mediated lipolysis and lipid mobilization in response to negative energy balance

“…We found that an acute course of excess dietary iron caused an increase in energy expenditure relative to total body and lean mass, resulting in a negative energy balance. Thus our work is in agreement with clinical studies showing an association with the iron status of an individual and their energy balance as well as previous animal studies (Brownlie et al, 2004;Gao et al, 2015;Ikeda et al, 2013;Lawless et al, 1994;Stoltzfus et al, 2004;Varghese et al, 2020;Yook et al, 2019;Zhang et al, 2021). An outstanding question from our study is how the acute course of dietary iron causes an increase in energy expenditure.…”

Fat and Iron Don't Mix

“…This net loss in AT iron buffering is accompanied by a 4-fold increase in adipocyte iron stores and a depletion of liver iron stores [ 6 ]. This reapportioning of iron in the liver and visceral AT with obesity and insulin resistance has also been observed by another group [ 42 ]. These results suggest that MFe hi ATMs are crucial for the maintenance of optimal AT iron concentrations and when that function is impeded, AT health is jeopardized.…”

“…This is entirely in line with the observations noted above in the KK/HIJ and obese anemic mice [ 32 , 37 ]. Adipocyte iron overload is also a recurring theme in studies investigating the effects of iron excess on metabolic homeostasis [ 40 - 42 ]. In fact, the above-mentioned effects of iron in decreasing adiponectin and leptin have been replicated in mouse models of adipocyte-specific iron overload [ 38 , 39 , 43 ].…”