Hypoferraemia (i.e. iron deficiency) was initially reported among obese individuals several decades ago; however, whether obesity and iron deficiency are correlated remains unclear. Here, we evaluated the putative association between obesity and iron deficiency by assessing the concentration of haematological iron markers and the risks associated with iron deficiency in both obese (including overweight) subjects and non-overweight participants. We performed a systematic search in the databases PubMed and Embase for relevant research articles published through December 2014. A total of 26 cross-sectional and case-control studies were analysed, comprising 13,393 overweight/obese individuals and 26,621 non-overweight participants. Weighted or standardized mean differences of blood iron markers and odds ratio (OR) of iron deficiency were compared between the overweight/obese participants and the non-overweight participants using a random-effects model. Compared with the non-overweight participants, the overweight/obese participants had lower serum iron concentrations (weighted mean difference [WMD]: -8.37 μg dL(-1) ; 95% confidence interval [CI]: -11.38 to -5.36 μg dL(-1) ) and lower transferrin saturation percentages (WMD: 2.34%, 95% CI: -3.29% to -1.40%). Consistent with this finding, the overweight/obese participants had a significantly increased risk of iron deficiency (OR: 1.31; 95% CI: 1.01-1.68). Moreover, subgroup analyses revealed that the method used to diagnose iron deficiency can have a critical effect on the results of the association test; specifically, we found a significant correlation between iron deficiency and obesity in studies without a ferritin-based diagnosis, but not in studies that used a ferritin-based diagnosis. Based upon these findings, we concluded that obesity is significantly associated with iron deficiency, and we recommend early monitoring and treatment of iron deficiency in overweight and obese individuals. Future longitudinal studies will help to test whether causal relationship exists between obesity and iron deficiency.
Diet-induced obesity is associated with proteinuria and glomerular disease in humans and rodents. We have shown that in mice fed a high-fat diet, increased renal expression of the transcriptional factor sterol-regulatory element binding protein-1 (SREBP-1) plays a critical role in renal lipid accumulation and increases the activity of proinflammatory cytokines and profibrotic growth factors. In the current study, we have determined a key role of the farnesoid X receptor (FXR) in modulating renal SREBP-1 activity, glomerular lesions, and proteinuria. We found that feeding a Western-style diet to DBA/2J mice results in proteinuria, podocyte loss, mesangial expansion, renal lipid accumulation, and increased expression of proinflammatory factors, oxidative stress, and profibrotic growth factors. Treatment of these mice with the highly selective and potent FXR-activating ligand 6-alpha-ethyl-chenodeoxycholic acid (INT-747) ameliorates triglyceride accumulation by modulating fatty acid synthesis and oxidation, improves proteinuria, prevents podocyte loss, mesangial expansion, accumulation of extracellular matrix proteins, and increased expression of profibrotic growth factors and fibrosis markers, and modulates inflammation and oxidative stress. Our results therefore indicate that FXR activation could represent an effective therapy for treatment of abnormal renal lipid metabolism with associated inflammation, oxidative stress, and kidney pathology in patients affected by obesity.
OBJECTIVEThe pathogenesis of diabetic nephropathy is complex and involves activation of multiple pathways leading to kidney damage. An important role for altered lipid metabolism via sterol regulatory element binding proteins (SREBPs) has been recently recognized in diabetic kidney disease. Our previous studies have shown that the farnesoid X receptor (FXR), a bile acid-activated nuclear hormone receptor, modulates renal SREBP-1 expression. The purpose of the present study was then to determine if FXR deficiency accelerates type 1 diabetic nephropathy in part by further stimulation of SREBPs and related pathways, and conversely, if a selective FXR agonist can prevent the development of type 1 diabetic nephropathy.RESEARCH DESIGN AND METHODSInsulin deficiency and hyperglycemia were induced with streptozotocin (STZ) in C57BL/6 FXR KO mice. Progress of renal injury was compared with nephropathy-resistant wild-type C57BL/6 mice given STZ. DBA/2J mice with STZ-induced hyperglycemia were treated with the selective FXR agonist INT-747 for 12 weeks. To accelerate disease progression, all mice were placed on the Western diet after hyperglycemia development.RESULTSThe present study demonstrates accelerated renal injury in diabetic FXR KO mice. In contrast, treatment with the FXR agonist INT-747 improves renal injury by decreasing proteinuria, glomerulosclerosis, and tubulointerstitial fibrosis, and modulating renal lipid metabolism, macrophage infiltration, and renal expression of SREBPs, profibrotic growth factors, and oxidative stress enzymes in the diabetic DBA/2J strain.CONCLUSIONSOur findings indicate a critical role for FXR in the development of diabetic nephropathy and show that FXR activation prevents nephropathy in type 1 diabetes.
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