Leptin Receptor-Deficient db/db Mice Show Significant Heterogeneity in Response to High Non-heme Iron Diet

Abstract

Recent studies have shown an association between iron homeostasis, obesity and diabetes. In this work, we investigated the differences in the metabolic status and inflammation in liver, pancreas and visceral adipose tissue of leptin receptor-deficient db/db mice dependent on high iron concentration diet. 3-month-old male BKS-Leprdb/db/JOrlRj (db/db) mice were divided into two groups, which were fed with different diets containing high iron (29 g/kg, n = 57) or standard iron (0.178 g/kg; n = 42) concentrations for 4 months. As anticipated, standard iron-fed db/db mice developed obesity and diabetes. However, high iron-fed mice exhibited a wide heterogeneity. By dividing into two subgroups at the diabetes level, non-diabetic subgroup 1 (<13.5 mmol/l, n = 30) significantly differed from diabetic subgroup two (>13.5 mmol/l, n = 27). Blood glucose concentration, HbA1c value, inflammation markers interleukin six and tumor necrosis factor α and heme oxygenase one in visceral adipose tissue were reduced in subgroup one compared to subgroup two. In contrast, body weight, C-peptide, serum insulin and serum iron concentrations, pancreatic islet and signal ratio as well as cholesterol, LDL and HDL levels were enhanced in subgroup one. While these significant differences require further studies and explanation, our results might also explain the often-contradictory results of the metabolic studies with db/db mice.

Aedes aegypti Shows Increased Susceptibility to Zika Virus via Both In Vitro and In Vivo Models of Type II Diabetes

“…Further studies utilizing transcriptomics to investigate this possibility are warranted. It is worth noting that the LEPR DB/DB mice demonstrate serum insulin levels of ≈ 1-5 ng/mL, corresponding to 2.25 to 11.23 PM [50,59]. These are levels 15.2-to 75.6-fold lower than the 17 PM utilized to produce the phenotype observed in Culex mosquitoes exposed to WNV [56].…”

Molecular Mechanisms and Mediators of Hepatotoxicity Resulting from an Excess of Lipids and Non-Alcoholic Fatty Liver Disease

“…Steatosis is associated with (at least to some extent) liver damage as a result of inflammation and the pro-apoptotic activity of free fatty acids (FFAs), regardless of its underlying etiology [92]. Observations from a few studies using obese mice with leptin deficiency (ob/ob) and leptin receptor deficiency (db/db), as well as many in vitro lipotoxicity models, suggest that the hepatotoxic effects of FFAs are not mediated by RIPK1-dependent signal pathways, but rather by mitochondrial apoptosis and death-receptor-transduced signals [93,94]. In particular, TRAIL receptor overexpression [95]; ROS production [96]; BAX binding with p-MLKL mediating lysosomal membrane permeabilization [97]; activation of the tumor suppressor protein p53 [98]; and direct mitochondriotoxic effects induced by the local accumulation of modified lipids, such as oxidized cardiolipin [99] and ceramides [100], appear to be involved in FFA-induced apoptosis.…”

Physicochemical properties of dietary fiber of bergamot and its effect on diabetic mice

“…Insulin resistance is a pathophysiological state in which cells or tissues are resistant to insulin activity and is the primary pathogenic cause leading to T2DM (21). Additionally, T2DM in db/db mice is characterized by insulin resistance, followed by pancreatic β-cell loss (37). The pancreatic structure of db/db mice was disrupted, according to histological analysis of degenerative alterations in the pancreas, and the islet cells had an irregular shape, blurred contour, uneven distribution, and decreased amount.…”