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1.  Rats Prone to Obesity Under a High-Carbohydrate Diet have Increased Post-Meal CCK mRNA Expression and Characteristics of Rats Fed a High-Glycemic Index Diet 
We previously reported that rats prone to obesity exhibit an exaggerated increase in glucose oxidation and an exaggerated decline in lipid oxidation under a low-fat high-carbohydrate (LF/HC) diet. The aim of the present study was to investigate the mechanisms involved in these metabolic dysregulations. After a 1-week adaptation to laboratory conditions, 48 male Wistar rats were fed a LF/HC diet for 3 weeks. During weeks 2 and 3, glucose tolerance tests (GTT), insulin tolerance tests (ITT), and meal tolerance tests (MTT) were performed to evaluate blood glucose, plasma, and insulin. Glucose and lipid oxidation were also assayed during the GTT. At the end of the study, body composition was measured in all the rats, and they were classified as carbohydrate resistant (CR) or carbohydrate sensitive (CS) according to their adiposity. Before sacrifice, 24 of the 48 rats received a calibrated LF/HC meal. Liver, muscle, and intestine tissue samples were taken to measure mRNA expression of key genes involved in glucose, lipid, and protein metabolism. ITT, GTT, and MTT showed that CS rats were neither insulin resistant nor glucose intolerant, but mRNA expression of cholecystokinin (CCK) in the duodenum was higher and that of CPT1, PPARα, and PGC1α in liver were lower than in CR rats. From these results, we make the hypothesis that in CS rats, CCK increased pancreatic secretion, which may favor a quicker absorption of carbohydrates and consequently induces an enhanced inhibition of lipid oxidation in the liver, leading to a progressive accumulation of fat preferentially in visceral deposits. Such a mechanism may explain why CS rats share many characteristics observed in rats fed a high-glycemic index diet.
PMCID: PMC4497311  PMID: 26217667
rat model; obesity prone; glucose; insulin; CCK; dietary obesity; indirect calorimetry; glucose tolerance test
2.  The Carbohydrate Sensitive Rat as a Model of Obesity 
PLoS ONE  2013;8(7):e68436.
Sensitivity to obesity is highly variable in humans, and rats fed a high fat diet (HFD) are used as a model of this inhomogeneity. Energy expenditure components (basal metabolism, thermic effect of feeding, activity) and variations in substrate partitioning are possible factors underlying the variability. Unfortunately, in rats as in humans, results have often been inconclusive and measurements usually made after obesity onset, obscuring if metabolism was a cause or consequence. Additionally, the role of high carbohydrate diet (HCD) has seldom been studied.
Rats (n=24) were fed for 3 weeks on HCD and then 3 weeks on HFD. Body composition was tracked by MRI and compared to energy expenditure components measured prior to obesity. Results: 1) under HFD, as expected, by adiposity rats were variable enough to be separable into relatively fat resistant (FR) and sensitive (FS) groups, 2) under HCD, and again by adiposity, rats were also variable enough to be separable into carbohydrate resistant (CR) and sensitive (CS) groups, the normal body weight of CS rats hiding viscerally-biased fat accumulation, 3) HCD adiposity sensitivity was not related to that under HFD, and both HCD and HFD adiposity sensitivities were not related to energy expenditure components (BMR, TEF, activity cost), and 4) only carbohydrate to fat partitioning in response to an HCD test meal was related to HCD-induced adiposity.
The rat model of human obesity is based on substantial variance in adiposity gains under HFD (FR/FS model). Here, since we also found this phenomenon under HCD, where it was also linked to an identifiable metabolic difference, we should consider the existence of another model: the carbohydrate resistant (CR) or sensitive (CS) rat. This new model is potentially complementary to the FR/FS model due to relatively greater visceral fat accumulation on a low fat high carbohydrate diet.
PMCID: PMC3728328  PMID: 23935869
3.  The Calm Mouse: An Animal Model of Stress Reduction 
Molecular Medicine  2012;18(1):606-617.
Chronic stress is associated with negative health outcomes and is linked with neuroendocrine changes, deleterious effects on innate and adaptive immunity, and central nervous system neuropathology. Although stress management is commonly advocated clinically, there is insufficient mechanistic understanding of how decreasing stress affects disease pathogenesis. Therefore, we have developed a “calm mouse model” with caging enhancements designed to reduce murine stress. Male BALB/c mice were divided into four groups: control (Cntl), standard caging; calm (Calm), large caging to reduce animal density, a cardboard nest box for shelter, paper nesting material to promote innate nesting behavior, and a polycarbonate tube to mimic tunneling; control exercise (Cntl Ex), standard caging with a running wheel, known to reduce stress; and calm exercise (Calm Ex), calm caging with a running wheel. Calm, Cntl Ex and Calm Ex animals exhibited significantly less corticosterone production than Cntl animals. We also observed changes in spleen mass, and in vitro splenocyte studies demonstrated that Calm Ex animals had innate and adaptive immune responses that were more sensitive to acute handling stress than those in Cntl. Calm animals gained greater body mass than Cntl, although they had similar food intake, and we also observed changes in body composition, using magnetic resonance imaging. Together, our results suggest that the Calm mouse model represents a promising approach to studying the biological effects of stress reduction in the context of health and in conjunction with existing disease models.
PMCID: PMC3388136  PMID: 22398685
4.  Identification of Behavioral and Metabolic Factors Predicting Adiposity Sensitivity to Both High Fat and High Carbohydrate Diets in Rats 
Individuals exhibit a great variation in their body weight (BW) gain response to a high fat diet. Identification of predictive factors would enable better directed intervention toward susceptible individuals to treat obesity, and uncover potential mechanisms for treatment targeting. We set out to identify predictive behavioral and metabolic factors in an outbred rat model. 12 rats were analyzed in metabolic cages for a period of 5 days during both high carbohydrate diet (HCD), and transition to a high fat diet (HFD). After a recovery period, rats were given a HFD for 6 days to identify those resistant or sensitive to it according to BW gain. Rats were dissected at the end of the study to analyze body composition. This showed that small differences in final BW hid large variations in adiposity, allowing separation of rats into a second classification (final adiposity). Since these rats had been fed a HCD during most of their life, under which most of the adiposity presumably evolved, we considered this carbohydrate-sensitivity or -resistance. Meal size and meal number were found to be good predictors of sensitivity to a HFD, intensity of motor activity and ingestion speed good predictors of sensitivity to a HCD. Rats that were sensitive to the HCD could be resistant to the HFD and vice versa. This points to four types of individuals (carbohydrate/fat resistant/sensitive) though our sample size inhibited deeper investigation of this. This contributes to the idea that to be “obesity prone” does not necessarily need a HFD, it can also happen under a HCD, and be a hidden adiposity change with stable BW.
PMCID: PMC3241340  PMID: 22203804
obesity prone; obesity resistant; rat; food intake; motor activity; energy metabolism; high fat diet/low fat diet; indirect calorimetry
6.  Role for Centromeric Heterochromatin and PML Nuclear Bodies in the Cellular Response to Foreign DNA 
Molecular and Cellular Biology  2006;26(7):2583-2594.
Nuclear spatial positioning plays an important role in the epigenetic regulation of eukaryotic gene expression. Here we show a role for nuclear spatial positioning in regulating episomal transgenes that are delivered by virus-like particles (VLPs). VLPs mediate the delivery of plasmid DNA (pDNA) to cell nuclei but lack viral factors involved in initiating and regulating transcription. By tracking single fluorescently labeled VLPs, coupled with luciferase reporter gene assays, we found that VLPs transported pDNA to cell nuclei efficiently but transgenes were immediately silenced by the cell. An investigation of the nuclear location of fluorescent VLPs revealed that the pDNAs were positioned next to centromeric heterochromatin. The activation of transcription by providing viral factors or inhibiting histone deacetylase activity resulted in the localization to euchromatin regions. Further, the activation of transcription induced the recruitment of PML nuclear bodies (PML-NBs) to the VLPs. This association did not play a role in regulating transgene expression, but PML protein was necessary for the inhibition of transgene expression with alpha interferon (IFN-α). These results support a model whereby cells can prevent foreign gene expression at two levels: by positioning transgenes next to centromeric heterochromatin or, if that is overcome, via the type I IFN response facilitated by PML-NB recruitment.
PMCID: PMC1430340  PMID: 16537904

Results 1-6 (6)