leptin and Iron-Overload

Chronic kidney disease (CKD) patients have an extremely high risk of developing cardiovascular diseases (CVD) compared to the general population. Systemic inflammation associated with oxidative stress could be an important determinant of morbidity and mortality associated with CVD. We suspected that dysregulation of iron metabolism should be considered in these patients. Anemia is prevalent in CKD patients and is often treated with erythropoiesis-stimulating agents (ESAs) and iron. In addition, iron administration sometimes causes iron overdose. Excessive iron in the cytosol and mitochondria can accelerate the formation of a highly toxic reactive oxygen species, hydroxyl radicals, which damage lipids, proteins, and DNA. In this review, we propose the following four major reasons for oxidative stress in CKD patients: 1) iron is sequestered in cells by proinflammatory cytokines and hepcidin; 2) the reduction in frataxin increases "free" iron in mitochondria; 3) the accumulation of 5-aminolevulinic acid, a heme precursor, has toxic effects on iron and mitochondrial metabolism; and 4) the elevated levels of the metabolic hormone, leptin, promote hepatic hepcidin production. Although an efficient therapy for preventing oxidative stress in these patients has not yet been well defined, we propose that ESAs for renal anemia may ameliorate these causes of oxidative stress. Further clinical trials are necessary to clarify the effectiveness of ESAs on oxidative stress in CKD patients.

Topics: Aminolevulinic Acid; Anemia; Hematinics; Heme; Hepcidins; Humans; Inflammation; Iron; Iron Overload; Leptin; Mitochondria; Oxidative Stress; Renal Insufficiency, Chronic

Iron overload is tightly connected with metabolic disorders. Excess iron in the adipose and its roles in dyslipidemia are of interest to be identified. In acute iron overload mice receiving intraperitoneal injection of 100 mg/kg/day dextran-iron for 5 days, the epididymis adipose showed a remarkable increase in iron. Serum triglyceride and low-density lipoprotein cholesterol (LDL-C) levels were increased and high-density lipoprotein cholesterol (HDL-C) level was decreased, while serum alkaline phosphatase, aspartate aminotransferase, glucose, and insulin were not affected. The serum-cytokine-microarray showed that adipocytokines, including adiponectin, leptin, and resistin were significantly decreased. Other serum cytokines, including pro-insulin cytokines, inflammatory cytokines, chemokines, and growth factors were not changed, except that ghrelin and chemokine RANTES were increased. Iron overload decreased expressions of adiponectin and leptin both in vivo and in vitro. Intraperitoneal injection of recombinant leptin at 1 μg/g in acute iron overload mice had no significant effects on serum levels of TC, TG, HDL-C, and LDL-C, while intraperitoneal injection of recombinant adiponectin at 3 μg/g partially restored serum TG level through improving activities of lipoprotein lipase and hepatic lipase, but abnormal serum LDL-C and HDL-C were not redressed, suggesting other mechanisms also existed. In conclusion, the adipose responds to iron overload at an early stage to interfere with lipid metabolism by secreting adipocytokines, which may further affect glucose metabolism, inflammation, and other iron overload-induced effects on the body.

Topics: 3T3-L1 Cells; Adipocytes; Adiponectin; Animals; Disease Models, Animal; Dyslipidemias; Iron; Iron Overload; Iron-Dextran Complex; Leptin; Liver; Mice; Mice, Inbred C57BL; Triglycerides

Iron 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.. To 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.. High 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.. Our 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.

Topics: Adiponectin; Adipose Tissue; Adiposity; Animals; Blood Glucose; Disease Models, Animal; Epididymis; Insulin Resistance; Iron; Iron Overload; Leptin; Male; Mice; Mice, Mutant Strains; Obesity; Tissue Distribution