Project description:Caloric Restriction in Leptin Deficiency Worsens Myocardial Steatosis: Failure to Upregulate PPAR gamma and Thermogenic Glyecrolipid/Fatty Acid Cycling Growing evidence supports an anti-lipotoxic role for leptin in preventing inappropriate peripheral tissue lipid deposition. Obese, leptin deficient ob/ob mice develop left ventricular (LV) hypertrophy and myocardial steatosis with increased apoptosis and decreased longevity. Here we investigated the cardiac effects of caloric restriction in leptin deficiency. Echocardiography was performed on C57Bl/6 wild-type mice (WT) and 7-month-old ob/ob mice fed ad lib, leptin-repleted (LR-ob/ob), or calorie-restricted (CR-ob/ob) for four weeks. Ventricular tissue was examined by electron microscopy (EM), mitochondrial coupling assay, and microarray expression profiling. LR and CR-ob/ob mice showed decreased body weight, heart weight, and LV wall thickness compared to ad lib ob/ob mice. LV fractional shortening was decreased in ad lib ob/ob mice, but restored to WT levels in LR and CR groups. However, EM revealed severe cardiac steatosis in the CR-ob/ob group compared to only moderate steatosis in ad lib ob/ob . Despite marked cardiac steatosis, CR (like LR) restored mitochondrial coupling to WT levels. CR up-regulated genes associated with oxidative stress and cell death, changes suggestive of cardiac lipotoxicity. LR, but not CR was shown to induce core genes involved in glycerolipid/free fatty acid cycling, a highly thermogenic pathway that can reduce intracellular lipid stores. LR, but not CR up-regulated and restored PGC1 and PPARto wild type levels; CR paradoxically further suppressed cardiac PPAR. Thus, leptin is essential in protecting the heart from lipotoxicity, and the inability to up-regulate the thermogenic glycerolipid/free fatty acid cycling pathway may impair the response of leptin deficient animals to the lipotoxic stress of calorie restriction. 6 month aged ob/ob mice were either leptin repleted with osmotic mini-pumps, calorie restricted to match the caloric intake of the leptin repleted mice, or fed ad lib for one month. 6-8 month C57Bl/6J mice were aged to serve as controls.

Project description:Astrocytes are key cells in brain aging, helping neurons to undertake healthy aging or otherwise letting them enter into a spiral of neurodegeneration. We aimed to characterize astrocytes cultured from senescence-accelerated prone 8 (SAMP8) mice, a mouse model of brain pathological aging, along with the effects of caloric restriction, the most effective rejuvenating treatment known so far. Analysis of the transcriptomic profiles of SAMP8 astrocytes cultured in control conditions and treated with caloric restriction serum was performed using mRNA microarrays. A decrease in mitochondrial and ribosome mRNA, which was restored by caloric restriction, confirmed the age-related profile of SAMP8 astrocytes and the benefits of caloric restriction. An amelioration of antioxidant and neurodegeneration-related path- ways confirmed the brain benefits of caloric restriction. Studies of oxidative stress and mitochondrial function demonstrated a reduction of oxidative damage and partial improvement of mito- chondria after caloric restriction. In summary, caloric restriction showed a significant tendency to normalize pathologically aged astrocytes through the activation of pathways that are protective against the age-related deterioration of brain physiology. Key words: astrocytes; caloric restriction; mitochondria; oxidative stress; RNA microarrays; SAMP8. Primary cultures enriched in astrocytes were obtained from cerebral cortical tissue from 2-day-old SAMP8 and SAMR1 mice. Astrocyte cultures were established and experiments were routinely carried out after 21 days in culture. Established astrocyte cultures of both SAMR1 and SAMP8 consisted of 85-90% astrocytes, 10-15% microglia and 0.1-1% oligodendroglia. Sera from rats subjected to ad libitum (AL) diet and to CR were obtained as described for the establishment of the CR in vitro model (de Cabo et al., 2003). Serum was heat inactivated at 56°C prior to use in astrocyte culture experiments. Treatment in vitro was performed by adding 10% volume CR or AL serum onto the astrocyte culture medium for 48 h, the cells were harvested and RNA was extracted for the microarray studies. Three biological replicates for each condition were done and RNA was extracted for the microarray studies. Please note that SAM models were developed from AKR/J by Kyoto University. Five litters with severe senescence were selected to further propagate and examine these characteristics. Litters that showed normal aging were selected as a senescence-resistant series (R-series). The genetic background of the SAM mice became suspect after the pathological findings were different from the AKR/J mouse. Each SAM model is genetically different. Each SAM colony was acquired by Harlan by Takeda Chemical Ltd. in 2002. And here is the link to the company site. http://www.harlan.com/products_and_services/research_models_and_services/research_models/sam_inbred_mice/samp8tahsd.hl

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Mus musculus

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