Comparison of the obesity phenotypes related to monosodium glutamate effect on arcuate nucleus and/or the high fat diet feeding in C57BL/6 and NMRI mice

In this study, susceptibility of inbred C57BL/6 and outbred NMRI mice to monosodium glutamate (MSG) obesity or diet-induced obesity (DIO) was compared in terms of food intake, body weight, adiposity as well as leptin, insulin and glucose levels. MSG obesity is an early-onset obesity resulting from MSG-induced lesions in arcuate nucleus to neonatal mice. Both male and female C57BL/6 and NMRI mice with MSG obesity did not differ in body weight from their lean controls, but had dramatically increased fat to body weight ratio. All MSG obese mice developed severe hyperleptinemia, more remarkable in females, but only NMRI male mice showed massive hyperinsulinemia and an extremely high HOMA index that pointed to development of insulin resistance. Diet-induced obesity is a late-onset obesity; it developed during 16-week-long feeding with high-fat diet containing 60 % calories as fat. Inbred C57BL/6 mice, which are frequently used in DIO studies, both male and female, had significantly increased fat to body weight ratio and leptin and glucose levels compared with their appropriate lean controls, but only female C57BL/6 mice had also significantly elevated body weight and insulin level. NMRI mice were less prone to DIO than C57BL/6 ones and did not show significant changes in metabolic parameters after feeding with high-fat diet.     

Characterization of single nucleotide polymorphisms for a forward genetics approach using genetic crosses in C57BL/6 and BALB/c substrains of mice

Forward genetics is a powerful approach based on chromosomal mapping of phenotypes and has successfully led to the discovery of many mouse mutations in genes responsible for various phenotypes. Although crossing between genetically remote strains can produce F₂ and backcross mice for chromosomal mapping, the phenotypes are often affected by background effects from the partner strains in genetic crosses. Genetic crosses between substrains might be useful in genetic mapping to avoid genetic background effects. In this study, we investigated single nucleotide polymorphisms (SNPs) available for genetic mapping using substrains of C57BL/6 and BALB/c mice. In C57BL/6 mice, 114 SNP markers were developed and assigned to locations on all chromosomes for full utilization for genetic mapping using genetic crosses between the C57BL/6J and C57BL/6N substrains. Moreover, genetic differences were identified in the 114 SNP markers among the seven C57BL/6 substrains from five production breeders. In addition, 106 SNPs were detected on all chromosomes of BALB/cAJcl and BALB/cByJJcl substrains. These SNPs could be used for genotyping in BALB/cJ, BALB/cAJcl, BALB/cAnNCrlCrlj, and BALB/cCrSlc mice, and they are particularly useful for genetic mapping using crosses between BALB/cByJJcl and other BALB/c substrains. The SNPs characterized in this study can be utilized for genetic mapping to identify the causative mutations of the phenotypes induced by N-ethyl-N-nitrosourea mutagenesis and the SNPs responsible for phenotypic differences between the substrains of C57BL/6 and BALB/c mice.     

Genetic and behavioral differences among five inbred mouse strains commonly used in the production of transgenic and knockout mice

Five strains of mice commonly used in transgenic and knockout production were compared with regard to genetic background and behavior. These strains were: C57BL/6J, C57BL/6NTac, 129P3/J (formerly 129/J), 129S6/SvEvTac (formerly 129/SvEvTac) and FVB/NTac. Genotypes for 342 microsatellite markers and performance in three behavioral tests (rotorod, open field activity and habituation, and contextual and cued fear conditioning) were determined. C57BL/6J and C57BL/6NTac were found to be true substrains; there were only 12 microsatellite differences between them. Given the data on the genetic background, one might predict that the two C57BL/6 substrains should be very similar behaviorally. Indeed, there were no significant behavioral differences between C57BL/6J and C57BL/6NTac. Contrary to literature reports on other 129 strains, 129S6/SvEvTac often performed similarly to C57BL/6 strains, except that it was less active. FVB/NTac showed impaired rotorod learning and cued fear conditioning. Therefore, both 129S6/SvEvTac and C57BL/6 are recommended as background strains for targeted mutations when researchers want to evaluate their mice in any of these three behavior tests. However, any transgene on the FVB/NTac background should be transferred to B6. Habituation to the open field was analyzed using the parameters: total distance, center distance, velocity and vertical activity. Contrary to earlier studies, we found that all strains habituated to the open field in at least two of these parameters (center distance and velocity).     

Development of SNP markers for C57BL/6N-derived mouse inbred strains

C57BL/6N inbred mice are used as the genetic background for producing knockout mice in large-scale projects worldwide; however, the genetic divergence among C57BL/6N-derived substrains has not been verified. Here, we identified novel single nucleotide polymorphisms (SNPs) specific to the C57BL/6NJ strain and selected useful SNPs for the genetic monitoring of C57BL/6N-derived substrains. Informative SNPs were selected from the public SNP database at the Wellcome Trust Sanger Institute by comparing sequence data from C57BL/6NJ and C57BL/6J mice. A total of 1,361 candidate SNPs from the SNP database could distinguish the C57BL/6NJ strain from 12 other inbred strains. We confirmed 277 C57BL/6NJ-specific SNPs including 10 nonsynonymous SNPs by direct sequencing, and selected 100 useful SNPs that cover all of the chromosomes except Y. Genotyping of 11 C57BL/6N-derived substrains at these 100 SNP loci demonstrated genetic differences among the substrains. This information will be useful for accurate genetic monitoring of mouse strains with a C57BL/6N-derived background.     

Genetic polymorphisms among C57BL/6 mouse inbred strains

Mice from the inbred C57BL/6 strain have been commonly used for the generation and analysis of transgenic and knockout animal models. However, several C57BL/6 substrains exist, and these are genetically and phenotypically different. In addition, each of these substrains can be purchased from different animal providers and, in some cases, they have maintained their breeding stocks separated for a long time, allowing genetic differences to accumulate due to individual variability and genetic drift. With the aim of describing the differences in the genotype of several C57BL/6 substrains, we applied the Illumina^® Mouse Medium Density Linkage Mapping panel, with 1,449 single nucleotide polymorphisms (SNPs), to individuals from ten C57BL/6-related strains: C57BL/6JArc, C57BL/6J from The Jackson Lab, C57BL/6J from Crl, C57BL6/JRccHsd, C57BL/6JOlaHsd, C57BL/6JBomTac, B6(Cg)-Tyr ^c?2j /J, C57BL/6NCrl, C57BL/6NHsd and C57BL/6NTac. Twelve SNPs were found informative to discriminate among the mouse strains considered. Mice derived from the original C57BL/6J: C57BL/6JArc, C57BL/6J from The Jackson Lab and C57BL/6J from Crl, were indistinguishable. Similarly, all C57BL/6N substrains displayed the same genotype, whereas the additional substrains showed intermediate cases with substrain-specific polymorphisms. These results will be instrumental for the correct genetic monitoring and appropriate mouse colony handling of different transgenic and knockout mice produced in distinct C57BL/6 inbred substrains.     

Npvf: Hypothalamic Biomarker of Ambient Temperature Independent of Nutritional Status

The mechanism by which mice, exposed to the cold, mobilize endogenous or exogenous fuel sources for heat production is unknown. To address this issue we carried out experiments using 3 models of obesity in mice: C57BL/6J+/+ (wild-type B6) mice with variable susceptibility to obesity in response to being fed a high-fat diet (HFD), B6. Ucp1-/- mice with variable diet-induced obesity (DIO) and a deficiency in brown fat thermogenesis and B6. Lep-/- with defects in thermogenesis, fat mobilization and hyperphagia. Mice were exposed to the cold and monitored for changes in food intake and body composition to determine their energy balance phenotype. Upon cold exposure wild-type B6 and Ucp1-/- mice with diet-induced obesity burned endogenous fat in direct proportion to their fat reserves and changes in food intake were inversely related to fat mass, whereas leptin-deficient and lean wild-type B6 mice fed a chow diet depended on increased food intake to fuel thermogenesis. Analysis of gene expression in the hypothalamus to uncover a central regulatory mechanism revealed suppression of the Npvf gene in a manner that depends on the reduced ambient temperature and degree of exposure to the cold, but not on adiposity, leptin levels, food intake or functional brown fat.     

Effects of voluntary running on oxygen consumption, RQ, and energy expenditure during primary prevention of diet-induced obesity in C57BL/6N mice

Diet-induced obesity (DIO) in C57BL/6 mice is the standard model for studying obesity in mice. The few reports of DIO utilizing voluntary running provide contradictory results with respect to prevention of obesity. However, total energy expenditures associated with voluntary running during DIO are unknown. We hypothesized that voluntary running would increase the amount of total energy expended during DIO. Female C57BL/6N mice were randomly assigned to one of three experimental groups [high-fat diet with voluntary running (HFRun); high-fat diet without running (HFSed); and low-fat diet without running (LFSed)] for a 10-wk period. We confirmed production of obesity in HFSed, and more importantly demonstrated primary prevention of obesity by voluntary running in a group of cohorts (HFRun). Indirect calorimetry was performed to determine oxygen consumption (Vo(2)) and respiratory quotient (RQ). The following novel mechanisms were identified in female C57BL/6N mice: 1) HFRun showed ～2 times greater total energy expenditures during a day compared with HFSed and LFSed; 2) HFRun had increased Vo(2) compared with HFSed and LFSed, lower RQ in the light period than HFSed, and lower RQ in both light and dark periods than LFSed; and 3) in the HFRun group, the magnitude of change in Vo(2) and RQ differed in dark and light periods during voluntary running. Our data combined with existing literature point to a potential threshold of physical activity that would prevent DIO in this mouse model. These data give a mechanistic explanation to resolve contradictory reports on whether voluntary running can prevent obesity in the DIO mouse model. In conclusion, voluntary running rescues high-fat fed, female C57BL/6N mice from obesity in DIO by doubling energy expenditure during the dark period and significantly increasing energy expenditure during the light cycle.     

Diet‐induced Obesity in Two C57BL/6 Substrains With Intact or Mutant Nicotinamide Nucleotide Transhydrogenase (Nnt) Gene

The C57BL/6J (B6/J) male mouse represents a standard for diet‐induced obesity (DIO) and is unique in expressing a loss‐of‐function nicotinamide nucleotide transhydrogenase (Nnt) gene. This mutation was associated with a marked reduction in glucose‐stimulated insulin secretion from B6/J islets in vitro and moderately impaired glucose clearance in vivo. To assess the contribution of this Nnt mutation, we compared DIO responsiveness of Nnt‐mutant B6/J males to Nnt wild‐type C57BL/6NJ (B6/NJ) males over a 14‐week period of feeding a high‐fat (60% of calories) diet. Initial mean body weights at 6 weeks did not distinguish the substrains and both substrains were DIO‐sensitive. However, B6/J males outgained the B6/NJ males, with a significant 3 g higher mean body weight at 20 weeks accompanied by significant increases in both lean and fat mass. Mean nonfasting serum glucose over time was also significantly higher in B6/J males, as was impairment of glucose tolerance assessed at 8 and 20 weeks of age. Serum leptin, but not insulin, was significantly higher in B6/J males over time. Potential contributions of the wild‐type Nnt gene were demonstrable on a lower fat diet (10% of calories) where a significantly greater weight gain over time by B6/NJ males was correlated with a significantly higher serum insulin. In conclusion, DIO developed in response to 60% fat feeding regardless of Nnt allele status. Contribution of the B6/J‐unique Nnt mutation was most evident in response to 10% fat feeding that resulted in reduced serum insulin and weight gain compared to B6/NJ males.     

Changes in gene expression foreshadow diet-induced obesity in genetically identical mice

High phenotypic variation in diet-induced obesity in male C57BL/6J inbred mice suggests a molecular model to investigate non-genetic mechanisms of obesity. Feeding mice a high-fat diet beginning at 8 wk of age resulted in a 4-fold difference in adiposity. The phenotypes of mice characteristic of high or low gainers were evident by 6 wk of age, when mice were still on a low-fat diet; they were amplified after being switched to the high-fat diet and persisted even after the obesogenic protocol was interrupted with a calorically restricted, low-fat chow diet. Accordingly, susceptibility to diet-induced obesity in genetically identical mice is a stable phenotype that can be detected in mice shortly after weaning. Chronologically, differences in adiposity preceded those of feeding efficiency and food intake, suggesting that observed difference in leptin secretion is a factor in determining phenotypes related to food intake. Gene expression analyses of adipose tissue and hypothalamus from mice with low and high weight gain, by microarray and qRT-PCR, showed major changes in the expression of genes of Wnt signaling and tissue re-modeling in adipose tissue. In particular, elevated expression of SFRP5, an inhibitor of Wnt signaling, the imprinted gene MEST and BMP3 may be causally linked to fat mass expansion, since differences in gene expression observed in biopsies of epididymal fat at 7 wk of age (before the high-fat diet) correlated with adiposity after 8 wk on a high-fat diet. We propose that C57BL/6J mice have the phenotypic characteristics suitable for a model to investigate epigenetic mechanisms within adipose tissue that underlie diet-induced obesity.     

Method of leptin dosing,strain, and group housing influence leptin sensitivity in high-fat-fed weanling mice

High-fat diets are reported to induce resistance to peripherally administered leptin. In an attempt to develop a model of juvenile diet-induced obesity, mice were weaned onto high-fat diet. Male and female, 35-day-old, C57BL/6J high-fat (45% kcal fat) diet-fed mice housed individually on grid floors did not decrease food intake or body weight in response to intraperitoneal (30 microg), lateral ventricle (5 microg), or third ventricle (0.5 microg) injections of leptin. Body weight and fat were significantly reduced by 13-day intraperitoneal infusions of 10 microg leptin/day, which doubled circulating leptin. Leptin infusion also reduced body fat in weanling, high-fat diet-fed NIH Swiss mice. Group housing mice on bedding prevented loss of fat in high-fat diet-fed male and female NIH Swiss and female C57BL/6J mice. These results indicate that peripherally infused leptin reduces fat in part by increasing thermogenesis and that inhibition of food intake in high-fat diet-fed mice requires either chronic activation of central leptin receptors or is independent of receptors that inhibit feeding in response to an acute central injection of leptin.     

Adropin deficiency is associated with increased adiposity and insulin resistance

Adropin is a secreted peptide that improves hepatic steatosis and glucose homeostasis when administered to diet-induced obese mice. It is not clear if adropin is a peptide hormone regulated by signals of metabolic state. Moreover, the significance of a decline in adropin expression with obesity with respect to metabolic disease is also not clear. We investigated the regulation of serum adropin by metabolic status and diet. Serum adropin levels were high in chow-fed conditions and were suppressed by fasting and diet-induced obesity (DIO). High adropin levels were observed in mice fed a high-fat low carbohydrate diet, whereas lower levels were observed in mice fed a low-fat high carbohydrate diet. To investigate the role of adropin deficiency in metabolic homeostasis, we generated adropin knockout mice (AdrKO) on the C57BL/6J background. AdrKO displayed a 50%-increase in increase in adiposity, although food intake and energy expenditure were normal. AdrKO also exhibited dyslipidemia and impaired suppression of endogenous glucose production (EndoR(a)) in hyperinsulinemic-euglycemic clamp conditions, suggesting insulin resistance. While homo- and heterozygous carriers of the null adropin allele exhibited normal DIO relative to controls, impaired glucose tolerance associated with weight gain was more severe in both groups. In summary, adropin is a peptide hormone regulated by fasting and feeding. In fed conditions, adropin levels are regulated dietary macronutrients, and increase with dietary fat content. Adropin is not required for regulating food intake, however, its functions impact on adiposity and are involved in preventing insulin resistance, dyslipidemia, and impaired glucose tolerance.     

Protein kinase Cδ contributes to phenylephrine-mediated contraction in the aortae of high fat diet-induced obese mice

The down-regulation of α-adrenoceptor-mediated signaling casacade has been implicated in obesity but the underlying mechanism remains largely unknown. The present study investigated whether inositol 1,4,5-trisphosphate (IP3) receptor and protein kinase C (PKC) were involved in the reduction of α₁-adrenoceptor agonist phenylephrine-evoked contraction in aortae of high fat diet-induced obese (DIO) mice. C57BL/6 mice were fed with a rodent diet containing 45 kcal% fat for 16 weeks to induce obesity. Isolated mouse aortae were suspended in myograph for isometric force measurement. Protein phosphorylations and expressions were determined by Western blotting. In C57BL/6 mouse aortae, phenylephrine-induced contraction was partially inhibited by either IP3 receptor antagonist heparin or PKC inhibitor GFX, and the combined treatment with heparin and GFX abolished the contraction. Phenylephrine-induced contraction was significantly less in the aortae of DIO mice than those of control mice; only GFX but not heparin attenuated the contraction, indicating a diminishing role of IP3 receptor in DIO mice. Western blotting showed the reduced expression and phosphorylation of IP3 receptor and the down-regulated expression of PKC, PKCβ, PKCδ, and PKCζ in DIO mouse aortae. Importantly, PKCδ was more likely to maintain phenylephrine-mediated contraction in DIO mouse aortae because that (1) PKCδ inhibitor rottlerin but not PKCα and PKCβ inhibitor Gö6976, PKCβ inhibitor hispidin, or PKCζ pseudosubstrate inhibitor attenuated the contraction; and (2) PKCδ phosphorylation was increased but phosphorylations of PKCα, PKCβ, and PKCζ were reduced in DIO mouse aortae. The present study thus provides additional insights into the cellular mechanisms responsible for vascular dysfunction in obesity.     

Regulation of adiponectin and its receptors in response to development of diet-induced obesity in mice

Adiponectin and its receptors play an important role in energy homeostasis and insulin resistance, but their regulation remains to be fully elucidated. We hypothesized that high-fat diet would decrease adiponectin but increase adiponectin receptor (AdipoR1 and AdipoR2) expression in diet-induced obesity (DIO)-prone C57BL/6J and DIO-resistant A/J mice. We found that circulating adiponectin and adiponectin expression in white adipose tissue are higher at baseline in C57BL/6J mice compared with A/J mice. Circulating adiponectin increases at 10 wk but decreases at 18 wk in response to advancing age and high-fat feeding. However, adiponectin levels corrected for visceral fat mass and adiponectin mRNA expression in WAT are affected by high-fat feeding only, with both being decreased after 10 wk in C57BL/6J mice. Muscle AdipoR1 expression in both C57BL/6J and A/J mice and liver adipoR1 expression in C57BL/6J mice increase at 18 wk of age. High-fat feeding increases both AdipoR1 and AdipoR2 expression in liver in both strains of mice and increases muscle AdipoR1 expression in C57BL/6J mice after 18 wk. Thus advanced age and high-fat feeding, both of which are factors that predispose humans to obesity and insulin resistance, are associated with decreasing adiponectin and increasing AdipoR1 and/or AdipoR2 levels.     

Genetic control of ATGL-mediated lipolysis modulates adipose triglyceride stores in leptin-deficient mice

Dissecting the genetics of complex traits such as obesity allows the identification of causal genes for disease. Here, we show that the BALB/c mouse strain carries genetic variants that confer resistance to obesity induced by leptin-deficiency or a high-fat diet (HFD). We set out to identify the physiological and genetic bases underlying this phenotype. When compared with C57BL6/J ob/ob mice (B6), BALB/c ob/ob mice exhibited decreased food intake, increased thermogenic capacity, and improved fat catabolism, each of which can potentially modify obesity. Interestingly, analysis of F1 ob/ob (progeny of B6 ob/+ × BALB/c ob+) mice revealed that obesity resistance in BALB/c ob/ob mice principally relied upon improved fat mobilization. This was mechanistically explained by increased adipose triglyceride lipase (ATGL) content in adipocytes, along with increased lipolysis and fatty acid oxidation. We conducted a genome-wide scan and defined a quantitative trait locus (QTL) on chromosome 2. BALB/c alleles on chromosome 2 not only associated with the obesity resistance phenotype but also supported increased ATGL content in adipose tissue. In summary, our study provides evidence that leptin-independent control of adipocyte lipolysis rates directly modifies the balance of macronutrient handling and is sufficient to regulate fat mass in the absence of alterations in food intake and energy expenditure.-Marcelin, G., S-M. Liu, X. Li, G. J. Schwartz, and S. Chua.     

Diet‐Induced Changes in Stearoyl‐CoA Desaturase 1 Expression in Obesity‐Prone and ‐Resistant Mice

Objective: To investigate stearoyl‐coenzyme A desaturase (SCD) 1 expression in obesity‐prone C57BL/6 mice and in obesity‐resistant FVB mice to explore the relationship of SCD1 expression and susceptibility to diet‐induced obesity. Research Methods and Procedures: Nine‐week‐old C57BL/6 and FVB mice were fed either a high‐ or low‐fat diet for 8 weeks. Body weight and body composition were measured before and at weeks 4 and 8 of the study. Energy expenditure was measured at weeks 1 and 5 of the study. Hepatic SCD1 mRNA was measured at 72 hours and at the end of study. Plasma leptin and insulin concentrations were measured at the end of study. Results: When C57BL/6 mice were switched to a calorie‐dense high‐fat diet, animals gained significantly more body weight than those maintained on a low‐calorie density diet primarily due to increased fat mass accretion. Fat mass continued to accrue throughout 8 weeks of study. Increased calorie intake did not account for all weight gain. On the high‐fat diet, C57BL/6 mice decreased their energy expenditure when compared with mice fed a low‐fat diet. In response to 8 weeks of a high‐fat diet, SCD1 gene expression in liver increased >2‐fold. In contrast, feeding a high‐fat diet did not change body weight, energy expenditure, or SCD1 expression in FVB mice. Discussion: Our study showed that a high‐fat hypercaloric diet increased body adiposity first by producing hyperphagia and then by decreasing energy expenditure of mice susceptible to diet‐induced obesity. Consumption of a high‐fat diet in species predisposed to obesity selectively increased SCD1 gene expression in liver.     

Diet-induced obesity causes innate airway hyperresponsiveness to methacholine and enhances ozone-induced pulmonary inflammation.

We previously reported that genetically obese mice exhibit innate airway hyperresponsiveness (AHR) and enhanced ozone (O(3))-induced pulmonary inflammation. Such genetic deficiencies in mice are rare in humans, and they may not be representative of human obesity. Thus the purpose of this study was to determine the pulmonary phenotype of mice with diet-induced obesity (DIO), which more closely mimics the cause of human obesity. Therefore, wild-type C57BL/6 mice were reared from the time of weaning until at least 30 wk of age on diets in which either 10 or 60% of the calories are derived from fat in the form of lard. Body mass was approximately 40% greater in mice fed 60 vs. 10% fat diets. Baseline airway responsiveness to intravenous methacholine, measured by forced oscillation, was greater in mice fed 60 vs. 10% fat diets. We also examined lung permeability and inflammation after exposure to room air or O(3) (2 parts/million for 3 h), an asthma trigger. Four hours after the exposure ended, O(3)-induced increases in bronchoalveolar lavage fluid protein, interleukin-6, KC, macrophage inflammatory protein-2, interferon-gamma-inducible protein-10, and eotaxin were greater in mice fed 60 vs. 10% fat diets. Innate AHR and augmented responses to O(3) were not observed in mice raised from weaning until 20-22 wk of age on a 60% fat diet. These results indicate that mice with DIO exhibit innate AHR and enhanced O(3)-induced pulmonary inflammation, similar to genetically obese mice. However, mice with DIO must remain obese for an extended period of time before this pulmonary phenotype is observed.     

Macronutrient diet selection in thirteen mouse strains

The strain distribution for macronutrient diet selection was described in 13 mouse strains (AKR/J, NZB/B1NJ, C57BL/6J, C57BL/6ByJ, DBA/2J, SPRET/Ei, CD-1, SJL/J, SWR/J, 129/J, BALB/cByJ, CAST/Ei, and A/J) with the use of a self-selection protocol in which separate carbohydrate, fat, and protein diets were simultaneously available for 26-30 days. Relative to carbohydrate, nine strains consumed significantly more calories from the fat diet; two strains consumed more calories from carbohydrate than from fat (BALB/cByJ, CAST/Ei). Diet selection by SWR/J mice was variable over time, resulting in a lack of preference. One strain (A/J) failed to adapt to the diet paradigm due to inadequate protein intake. Comparisons of proportional fat intake across strains revealed that fat selection/consumption ranged from 26 to 83% of total energy. AKR/J, NZB/B1NJ, and C67BL/6J mice self-selected the highest proportion of dietary fat, whereas the CAST/Ei and BALB/cByJ strains chose the lowest. Finally, epididymal fat depot weight was correlated with fat consumption. There were significant positive correlations in AKR/J and C57BL/6J mice, which are highly sensitive to dietary obesity. However, absolute fat intake was inversely correlated with epididymal fat in two of the lean strains: SWR/J and CAST/Ei. We hypothesize that the SWR/J and CAST/Ei strains are highly sensitive to a negative feedback signal generated by increasing body fat, but the AKR/J and C67BL/6J mice are not. The variation in dietary fat selection across inbred strains provides a tool for dissecting the complex genetics of this trait.     

Hypoglycemic and hypolipidemic effects of processed Aloe vera gel in a mouse model of non-insulin-dependent diabetes mellitus

The effects of processed Aloe vera gel (PAG) on the course of established diet-induced non-insulin-dependent diabetes mellitus (NIDDM) were studied in C57BL/6J mice. NIDDM was induced in C57BL/6J mice by feeding them a high-fat diet. Mice exhibiting diet-induced obesity (DIO) with blood glucose levels above 180 mg/dl were selected to examine the antidiabetic effects of PAG. Oral administration of PAG for 8 weeks reduced circulating blood glucose concentrations to a normal level in these DIO mice. In addition, the administration of PAG significantly decreased plasma insulin. The antidiabetic effects of PAG were also confirmed by intraperitoneal glucose tolerance testing. PAG appeared to lower blood glucose levels by decreasing insulin resistance. The administration of PAG also lowered triacylglyceride levels in liver and plasma. Histological examinations of periepididymal fat pad showed that PAG reduced the average size of adipocytes. These results demonstrate that the oral administration of PAG prevents the progression of NIDDM-related symptoms in high-fat diet-fed mice, and suggest that PAG could be useful for treating NIDDM.     

Inactivation of PKCtheta leads to increased susceptibility to obesity and dietary insulin resistance in mice

In this study, we investigated the metabolic phenotype of PKCtheta knockout mice (C57BL/6J) on chow diet and high-fat diet (HFD). The knockout (KO) mice are normal in growth and reproduction. On the chow diet, body weight and food intake were not changed in the KO mice; however, body fat content was increased with a corresponding decrease in body lean mass. Energy expenditure and spontaneous physical activity were decreased in the KO mice. On HFD, energy expenditure and physical activity remained low in the KO mice. The body weight and fat content were increased rapidly in the KO mice. At 8 wk on HFD, severe insulin resistance was detected in the KO mice with hyperinsulinemic euglycemic clamp and insulin tolerance test. Insulin action in both hepatic and peripheral tissues was reduced in the KO mice. Plamsa free fatty acid was increased, and expression of adiponectin in the adipose tissue was decreased, in the KO mice on HFD. This study suggests that loss of PKCtheta reduces energy expenditure and increases the risk of dietary obesity and insulin resistance in mice.