Abstract
BackgroundIron dysregulation is a potential contributor to the pathology of obesity-related metabolic complications. KK/HIJ (KK) mice, a polygenic obese mouse model, have elevated serum iron levels. A subset of KK male mice display a bronzing of epididymal adipose tissue (eAT) associated with >100-fold (p<0.001) higher iron concentration.MethodsTo further phenotype and characterize the adipose tissue iron overload, 27 male KK mice were evaluated. 14 had bronzing eAT and 13 had normal appearing eAT. Fasting serum and tissues were collected for iron content, qPCR, histology and western blot.ResultsHigh iron levels were confirmed in bronzing eAT (High Iron group, HI) versus normal iron level (NI) in normal appearing eAT. Surprisingly, iron levels in subcutaneous and brown adipose depots were not different between the groups (p>0.05). The eAT histology revealed iron retention, macrophage clustering, tissue fibrosis, cell death as well as accumulation of HIF-2α in the high iron eAT. qPCR showed significantly decreased Lep (leptin) and AdipoQ (adiponectin), whereas Tnfα (tumor necrosis factor α), and Slc40a1 (ferroportin) were up-regulated in HI (p<0.05). Elevated HIF-2α, oxidative stress and local insulin signaling loss was also observed.SignificanceOur data suggest that deposition of iron in adipose tissue is limited to the epididymal depot in male KK mice. A robust adipose tissue remodeling is concomitant with the high iron concentration, which causes local adipose tissue insulin resistance.
Highlights
Iron dysregulation is a potential contributor to the pathology of obesity-related metabolic complications, such as type 2 diabetes mellitus (T2DM)
Our data suggest that deposition of iron in adipose tissue is limited to the epididymal depot in male KK mice
We found that the adipose tissue deposition of iron in a subset of male KK/HIJ mice was specific to the epididymal adipose tissue (eAT) depot and not evident in the subcutaneous or brown adipose tissue depots
Summary
Iron dysregulation is a potential contributor to the pathology of obesity-related metabolic complications, such as type 2 diabetes mellitus (T2DM). Human studies have demonstrated elevated iron stores to precede insulin resistance [1, 2], while lowering serum iron can increase insulin sensitivity [3] This association between iron and diabetes is hypothesized to induce inflammation and promote oxidative stress [4, 5]. Strategies to reduce iron concentration (e.g. low iron diet, chelation therapy, and phlebotomy) have led to improvements in insulin sensitivity in obese animal models [6, 12, 13] and humans [3, 7, 14] To this end, iron has been demonstrated to play an important role in metabolic syndrome, including detrimental effects on the modulation of metabolism through inflammation and oxidative stress. A subset of KK male mice display a bronzing of epididymal adipose tissue (eAT) associated with >100-fold (p
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