Activation of brown adipose tissue in diet-induced thermogenesis is GC-C dependent.

Uroguanylin (UGN) is released from the intestine after a meal. When applied in brain ventricles, UGN increases expression of markers of thermogenesis in brown adipose tissue (BAT). Therefore, we determine the effects of its receptor, guanylate cyclase C (GC-C), on mouse interscapular BAT (iBAT) activity during diet-induced thermogenesis (DIT). The activation of iBAT after a meal is diminished in GC-C KO mice, decreased in female wild type (WT) mice, and abolished in old WT animals. The activation of iBAT after a meal is the highest in male WT animals which leads to an increase in GC-C expression in the hypothalamus, an increase in iBAT volume by aging, and induction of iBAT markers of thermogenesis. In contrast to iBAT activation after a meal, iBAT activation after a cold exposure could still exist in GC-C KO mice and it is significantly higher in female WT mice. The expression of GC-C in the proopiomelanocortin neurons of the arcuate nucleus of the hypothalamus but not in iBAT suggests central regulation of iBAT function. The iBAT activity during DIT has significantly reduced in old mice but an intranasal application of UGN leads to an increase in iBAT activity in a dose-dependent manner which is in strong negative correlation to glucose concentration in blood. This activation was not present in GC-C KO mice. Our results suggest the physiological role of GC-C on the BAT regulation and its importance in the regulation of glucose homeostasis and the development of new therapy for obesity and insulin resistance.

Cognitive, behavioral and metabolic effects of oral galactose treatment in the transgenic Tg2576 mice.

Alzheimer's disease (AD) is the most common neurodegenerative disorder associated with insulin resistance and glucose hypometabolism in the brain. Oral administration of galactose, a nutrient that provides an alternative source of energy, prevents and ameliorates early cognitive impairment in a streptozotocin-induced model (STZ-icv) of the sporadic AD (sAD). Here we explored the influence of 2-month oral galactose treatment (200 mg/kg/day) in the familial AD (fAD) by using 5- (5M) and 10- (10M) month-old transgenic Tg2576 mice mimicking the presymptomatic and the mild stage of fAD, and compared it to that observed in 7-month old STZ-icv rats mimicking mild-to-moderate sAD. Cognitive and behavioral performance was tested by Morris Water Maze, Open Field and Elevated Plus Maze tests, and metabolic status by intraperitoneal glucose tolerance test and fluorodeoxyglucose Positron-Emission Tomography scan. The level of insulin, glucagon-like peptide-1 (GLP-1) and soluble amyloid ß1-42 (sAß1-42) was measured by ELISA and the protein expression of insulin receptor (IR), glycogen synthase kinase-3ß (GSK-3ß), and pre-/post-synaptic markers by Western blot analysis. Although galactose normalized alterations in cerebral glucose metabolism in all Tg2576 mice (5M+2M; 10M+2M) and STZ-icv rats, it did not improve cognitive impairment in either model. Improvement of reduced grooming behavior and normalization in reduced plasma insulin levels were seen only in 5M+2M Tg2576 mice while in 10M+2M Tg2576 mice oral galactose induced metabolic exacerbation at the level of plasma insulin, GLP-1 homeostasis and glucose intolerance, and additionally increased hippocampal sAß1-42 level, decreased IR expression and increased GSK-3ß activity. The results indicate that therapeutic potential of oral galactose seems to depend on the stage and the type/model of AD and to differ in the absence and the presence of AD-like pathology.

Diminished Resistance to Hyperoxia in Brains of Reproductively Senescent Female CBA/H Mice.

BACKGROUND We have explored sex differences in ability to maintain redox balance during acute oxidative stress in brains of mice. We aimed to determine if there were differences in oxidative/antioxidative status upon hyperoxia in brains of reproductively senescent CBA/H mice in order to elucidate some of the possible mechanisms of lifespan regulation. MATERIAL AND METHODS The brains of 12-month-old male and female CBA/H mice (n=9 per sex and treatment) subjected to 18-h hyperoxia were evaluated for lipid peroxidation (LPO), antioxidative enzyme expression and activity - superoxide dismutase 1 and 2 (Sod-1, Sod-2), catalase (Cat), glutathione peroxidase 1 (Gpx-1), heme-oxygenase 1 (Ho-1), nad NF-E2-related factor 2 (Nrf2), and for 2-deoxy-2-[18F] fluoro-D-glucose (18FDG) uptake. RESULTS No increase in LPO was observed after hyperoxia, regardless of sex. Expression of Nrf-2 showed significant downregulation in hyperoxia-treated males (p=0.001), and upregulation in hyperoxia-treated females (p=0.023). Also, in females hyperoxia upregulated Sod-1 (p=0.046), and Ho-1 (p=0.014) genes. SOD1 protein was upregulated in both sexes after hyperoxia (p=0.009 for males and p=0.011 for females). SOD2 protein was upregulated only in females (p=0.008) while CAT (p=0.026) and HO-1 (p=0.042) proteins were increased after hyperoxia only in males. Uptake of 18FDG was decreased after hyperoxia in the back brain of females. CONCLUSIONS We found that females at their reproductive senescence are more susceptible to hyperoxia, compared to males. We propose this model of hyperoxia as a useful tool to assess sex differences in adaptive response to acute stress conditions, which may be partially responsible for observed sex differences in longevity of CBA/H mice.