Glutathione reductase is essential for host defense against bacterial infection.

Glutathione reductase (Gsr) catalyzes the reduction of glutathione disulfide to glutathione, a major cellular antioxidant. We have recently shown that Gsr is essential for host defense against the gram-negative bacteria Escherichia coli in a mouse model of sepsis. Although we have demonstrated that Gsr is required for sustaining the oxidative burst and the development of neutrophil extracellular traps, the role of Gsr in other phagocytic functions remains unclear. It is also unclear whether Gsr-deficient mice exhibit host defense defects against gram-positive bacteria. In this study, we characterized the effects of Gsr deficiency on the innate immune responses to a gram-positive bacterium, group B Streptococcus, and to the gram-negative bacterial cell wall component lipopolysaccharide (LPS). We found that, like E. coli, group B Streptococcus resulted in a substantially more robust cytokine response and a markedly higher morbidity and mortality in Gsr-deficient mice than in wild-type mice. The increased morbidity and mortality were associated with greater bacterial burden in the Gsr-deficient mice. Interestingly, Gsr-deficient mice did not exhibit a greater sensitivity to LPS than did wild-type mice. Analysis of the neutrophils of Gsr-deficient mice revealed impaired phagocytosis. In response to thioglycollate stimulation, Gsr-deficient mice mobilized far fewer phagocytes, including neutrophils, macrophages, and eosinophils, into their peritoneal cavities than did wild-type mice. The defective phagocyte mobilization is associated with profound oxidation and aggregation of ascitic proteins, particularly albumin. Our results indicate that the oxidative defense mechanism mediated by Gsr is required for an effective innate immune response against bacteria, probably by preventing phagocyte dysfunction due to oxidative damage.

Studies of different female rat models of hypothalamic obesity.

Hypothalamic obesity (HO) is a major and unsolved problem in patients with medial hypothalamic lesions and is associated with hyperinsulinemia and hyperleptinemia. The purpose of this study was to create a rodent model that mimics metabolic changes in HO for use in therapeutic testing. Female Sprague-Dawley rats were used to test the individual and combined effects of two types of medial hypothalamic lesions: arcuate nucleus (ARC) lesions by injection of monosodium glutamate at neonatal age, and ventromedial nucleus (VMN) lesions by passing an anodal current through an electrode placed in the VMN at age 80 days. Adiposity in ARC-lesioned animals was associated with decreased food intake and stunted growth, while VMN lesions were associated with hyperphagia but not reduced growth. The greatest weight gain (weight at age 200 days 712 +/- 65 vs. 451 +/- 19 g in controls), hyperphagia (food intake 10 days following surgery 33 +/- 0.8 vs. 18.5 +/- 0.7 g/day in sham-treated rats), hyperinsulinemia and hyperleptinemia occurred in rats that received both ARC and VMN lesions. Thus, the combined medial hypothalamic lesions result in an obesity phenotype similar to that of patients that suffer from HO and are consequently more suitable for testing potential therapeutics for this disorder than lesions of single hypothalamic nuclei.

A novel rodent model that mimics the metabolic sequelae of obese craniopharyngioma patients.

Patients with craniopharyngioma (CP), a tumor located in the pituitary and/or hypothalamus, are susceptible to developing obesity and many metabolic complications. The study aim was to create a rodent model that mimics the complex neuroanatomical and metabolic disturbances commonly seen in obese CP patients. We compared the metabolic phenotype of animals with three distinct types of hypothalamic lesions: 1) destruction of the arcuate nucleus (ARC) induced by monosodium glutamate (MSG), 2) electrolytic lesion of the adjacent ventromedial nucleus (VMN) alone, 3) both the VMN and dorsomedial nucleus (DMN), or a 4) combined medial hypothalamic lesion (CMHL) affecting the VMN, DMN, and the ARC. Only the CMHL model exhibited all key features observed in patients with hypothalamic obesity induced by CP. These features included excessive weight gain due to increased adiposity, increased food intake, and pronounced hyperinsulinemia and hyperleptinemia. Similar to characteristics of patients with CP, CMHL animals exhibited reduced plasma levels of alpha-melanocyte stimulating hormone and reduced ambulatory activity compared with weight-matched controls. Therefore, the CMHL model best mimics the complex metabolic abnormalities observed in obese CP patients compared with lesions to other hypothalamic areas and provides a foundation for future pharmacological approaches to treat obesity in children with hypothalamic damage.

Changes in adipose-derived inflammatory cytokines and chemokines after successful lifestyle intervention in obese children.

Obesity has been associated with low-grade chronic systemic inflammation, potentially leading to insulin resistance. This study was designed to examine relationships between cardiovascular risk factors, insulin resistance, and simultaneously measured inflammatory parameters in obese children. We examined serum inflammatory parameters in 115 obese children and 30 normal-weight controls; 62 obese children were followed longitudinally in a 1-year obesity intervention study. Serum concentrations of adipose tissue hormones adiponectin and resistin as well as adipocytokines were assessed. Cross-sectional analysis showed significant correlations between standard deviation score body mass index and resistin (P = .0004) as well as monocyte chemoattractant protein-1 (MCP-1, P = .04). Increased homeostasis model assessment of insulin resistance index greater than 95th percentile was present in 32% of obese patients, correlating with adiponectin (r = -0.40, P = .0007). Significant correlations were found between adiponectin and several mediators of inflammation (interleukins [ILs] IL-1ß, IL-6, and IL-8 and tumor necrosis factor-α). In longitudinal analysis, substantial weight loss (change standard deviation score body mass index >0.5) observed after intervention in 29 children was associated with a significant decrease in blood pressure, homeostasis model assessment of insulin resistance index, and serum concentrations of insulin and IL-1ß, IL-8, and MCP-1, but increase of adiponectin (all Ps < .05). In 33 children without substantial weight loss, resistin and MCP-1 levels increased after 1 year. Changes in IL-1ß correlated positively with changes of weight status, interferon-γ, IL-6, IL-8, and tumor necrosis factor-α (all Ps < .01). Our study demonstrates significant correlations between different metabolic risk factors at baseline and after changes of weight status and that weight loss in obese children reduces low-grade inflammation, insulin resistance, and blood pressure.