Genotype × diet interactions in mice predisposed to mammary cancer: II. Tumors and metastasis

High dietary fat intake and obesity may increase the risk of susceptibility to certain forms of cancer. To study the interactions of dietary fat, obesity, and metastatic mammary cancer, we created a population of F₂ mice cosegregating obesity QTL and the MMTV-PyMT transgene. We fed the F₂ mice either a very high-fat or a matched-control-fat diet, and we measured growth, body composition, age at mammary tumor onset, tumor number and severity, and formation of pulmonary metastases. SNP genotyping across the genome facilitated analyses of QTL and QTL × diet interaction effects. Here we describe effects of diet on mammary tumor and metastases phenotypes, mapping of tumor/metastasis modifier genes, and the interaction between dietary fat levels and effects of cancer modifiers. Results demonstrate that animals fed a high-fat diet are not only more likely to experience decreased mammary cancer latency but increased tumor growth and pulmonary metastases occurrence over an equivalent time. We identified 25 modifier loci for mammary cancer and pulmonary metastasis, likely representing 13 unique loci after accounting for pleiotropy, and novel QTL × diet interactions at a majority of these loci. These findings highlight the importance of accurately modeling not only the human cancer characteristics in mice but also the environmental exposures of human populations.     

Tumour incidence, growth, reproduction and longevity in female C3H mice fed polyunsaturated ruminant-derived foodstuffs

Earlier studies with the random-bred Quackenbush mouse strain showed that human-type diets based on linoleic acid-enriched foodstuffs derived from ruminants fed protected polyunsaturated oils have no detrimental effects on growth, reproduction or longevity. Tumour incidence and time of onset of tumour development have now been studied in the inbred, tumour-prone mouse strain C3H, in addition to growth, reproduction and longevity. Mice were fed a polyunsaturated human diet, a conventional human diet, or mouse cubes. The results with C3H mice tended to confirm those with Quackenbush strain mice-growth rates and reproductive productivities were very similar in the two groups eating human diets. Mice on the conventional human diet tended to survive better to about 60 weeks of age than mice on the polyunsaturated diet or the cube diet, after which the mortality rates of the mice on the three diets were similar. The degree of unsaturation of the dietary fat had no significant effect on the incidence of tumours. The tumour incidence was about 40% which, taken in conjunction with the average age of onset (about 80 weeks), suggested that the NIV virus rather than the MMTV virus was responsible. It would appear that the high-fat human diets had no effect on the incidence of mammary tumours caused by this virus.     

Effects of dietary fat on mammary development relative to age and hormones in BALB/c mice

Earlier studies reported that mammary ducts grew faster if the 10% fat in the diet was composed of oils containing polyunsaturated fatty acids (corn oil: CO) compared to hydrogenated cottonseed oil (HCTO), which is devoid of such fatty acids. These experiments were primarily carried out in immature mice and left unanswered questions regarding the effects of dietary fats on more differentiated stages of mammary development. The use of transplanted ducts permitted the study of mammary growth rates in adult mice. If the diet was started when the animals were adults, there was no difference in the growth rate of those fed HCTO diet compared to those fed CO diet. However, when the diets were fed to immature mice, the mammary gland grew slower in mice fed the HCTO diet, confirming our earlier observations. The HCTO and CO diets caused no difference in the growth rate or morphology of fine ducts and alveoli that developed during pregnancy. Furthermore, no differences were seen in female mice following 6 weeks of progesterone administration begun at 3 weeks of age. Experiments that used male mice to examine the initial stages of mammary duct growth also showed that the effect of dietary fat was not observed when estrogen (E) or E and progesterone (P) were injected. In addition, there was no effect of dietary fat in ovariectomized 3-week-old females when any dose of E was administered from 0.01 to 1 microgram/day. Examination of the ovaries from mice fed either HCTO or CO diets from 3 to 9 weeks or 3 to 13 weeks of age showed that mice fed HCTO diet did not develop corpora lutea, while those fed CO diet had normal appearing ovaries. The HCTO diet inhibits normal maturation of the follicle and corpus luteum formation. We conclude that the effect of the dietary fat on the developing mouse is on the maturation of the ovary and subsequently on mammary growth.     

Influence of fatty acid‐free diet on mammary tumor development and growth rate in HER‐2/neu transgenic mice

Numerous investigations have found a relationship between higher risk of cancer and increased intake of fats, while results of clinical studies of fat reduction and breast cancer recurrence have been mixed. A diet completely free of fats cannot be easily administered to humans, but experimental studies in mice can be done to determine whether this extreme condition influences tumor development. Here, we examined the effects of a FA‐free diet on mammary tumor development and growth rate in female FVB‐neu proto‐oncogene transgenic mice that develop spontaneous multifocal mammary tumors after a long latency period. Mice were fed a fatty acid‐free diet beginning at 112, 35, and 30 days of age. In all these experiments, tumor appearance was delayed, tumor incidence was reduced and the mean number of palpable mammary tumors per mouse was lower, as compared to standard diet‐fed mice. By contrast, tumor growth rate was unaffected in mice fed the fatty acid‐free diet. Plasma of mice fed the fatty acid‐free diet revealed significantly higher contents of oleic, palmitoleic and 20:3ω9 acids and lower contents of linoleic and palmitic acids. In conclusion, these findings indicate that a FA‐free diet reduces tumor incidence and latency but not tumor growth rate, suggesting that a reduction in dietary FAs in humans may have a protective effect on tumorigenesis but not on tumors once they appear. J. Cell. Physiol. 228: 242–249, 2013. © 2012 Wiley Periodicals, Inc.     

The HIV protease inhibitor ritonavir increases lipoprotein production and has no effect on lipoprotein clearance in mice

This study examined the effect of human immunodeficiency virus (HIV) protease inhibitor therapy on lipoprotein production and catabolism in vivo. The HIV protease inhibitor ritonavir was given to C57BL/6 mice fed either a basal low-fat diet or a Western type high-fat diet. Fasted mice were injected with Triton WR1339 followed by hourly blood collection to monitor lipoprotein production. Results showed that ritonavir increased VLDL triglyceride production by 30% over a 4 h period when mice were fed the low-fat basal diet. The ritonavir effect was more pronounced under high-fat feeding conditions, with a 2-fold increase in VLDL triglyceride production rate. Ritonavir did not alter hepatic expression levels of diacylglycerol acyltransferase or microsomal triglyceride transfer protein, but increased hepatic apolipoprotein B (apoB) secretion rates under both low- and high-fat dietary conditions. In contrast to its effect on lipoprotein production, ritonavir did not alter triglyceride-rich lipoprotein clearance from circulation under either dietary condition. Taken together, these results indicate that the hyperlipidemic effect of HIV protease inhibitors is a direct result of increased hepatic lipoprotein production. The mechanism appears to be related to their role in preventing proteasome-mediated degradation of apoB and activated sterol regulatory element binding proteins in the liver.     

Addition of dietary fat to cholesterol in the diets of LDL receptor knockout mice: effects on plasma insulin, lipoproteins, and atherosclerosis

The factors underlying cardiovascular risk in patients with diabetes have not been clearly elucidated. Efforts to study this in mice have been hindered because the usual atherogenic diets that contain fat and cholesterol also lead to obesity and insulin resistance. We compared plasma glucose, insulin, and atherosclerotic lesion formation in LDL receptor knockout (Ldlr(-/-)) mice fed diets with varying fat and cholesterol content that induced similar lipoprotein profiles. Ldlr(-/-) mice fed a high-fat diet developed obesity, mild hyperglycemia, hyperinsulinemia, and hypertriglyceridemia. Quantitative and qualitative assessments of atherosclerosis were unchanged in diabetic Ldlr(-/-) mice fed a high-fat diet compared with lean nondiabetic control mice after 20 weeks of diet. Although one group of mice fed diets for 40 weeks had larger lesions at the aortic root, this was associated with a more atherogenic lipoprotein profile. The presence of a human aldose reductase transgene had no effect on atherosclerosis in fat-fed Ldlr(-/-) mice with mild diabetes. Our data suggest that when lipoprotein profiles are similar, addition of fat to a cholesterol-rich diet does not increase atherosclerotic lesion formation in Ldlr(-/-) mice.     

The effect of dietary fat on lipogenesis in mammary gland and liver from lactating and virgin mice

1. Virgin and lactating C(3)H mice maintained on laboratory chow were transferred to a high-fat (15% corn oil) or a fat-free diet 3 days before being killed. 2. The linoleate content of liver, mammary gland and milk was decreased in lactating mice given the fat-free diet but was increased in those fed on the high-fat diet. Changes in linoleate content and mammary gland followed a similar but much less marked trend in virgin animals. 3. Hepatic fatty acid synthesis in lactating and virgin mice fed on the fat-free diet was higher than in corresponding animals fed on either the chow or the high-fat diet. The lipogenic capacity of livers from mice fed on either the chow or the high-fat diet was greater in lactating than in virgin animals. These changes in hepatic lipogenic capacity were accompanied by alterations in the specific activities of certain enzymes involved in fat synthesis. 4. Mammary gland from virgin and lactating animals showed no such adaptation to dietary fat. Results indicate that fatty acid synthesis in neither mammary-gland parenchymal cells nor mammary-gland adipose cells can be influenced by dietary fat in the same way as in the hepatocyte.     

Phytosterols and lecithin do not have an additive effect in lowering plasma and hepatic cholesterol levels in diet-induced hypercholesterolemic rats

Both plant sterols and lecithin are used as dietary supplements for lowering blood cholesterol in Western countries. This study evaluated the possibility of an additive effect of these ingredients on the regulation of lipid concentrations and cholesterol metabolism. Male Sprague-Dawley rats were randomly divided into three groups, and fed one of the following diets for 5 weeks; high cholesterol diet (HCD), phytosterol mixture-supplemented diet (PD, HCD+0.25% phytosterols), or phytosterol mixture and lecithin-supplemented diet (PLD, PD+0.15% lecithin). Feeding the PD for 5 weeks resulted in a 34% and 41% decrease in plasma total- and VLDL+LDL-cholesterol levels, respectively, and a 23% decrease in hepatic cholesterol content compared to those for the HCD rats (p < 0.05). These cholesterol-lowering properties of the phytosterol mixture were also associated with the down-regulation of hepatic acyl CoA:cholesterol acytransferase (ACAT) activity (p < 0.05). Addition of lecithin plus phytosterol mixture to the hypercholesterolemic diet did not significantly affect blood and hepatic lipid concentrations (with the exception of 36% decrease in hepatic triglyceride level, p < 0.05) as well as hepatic ACAT activity compared to feeding the hypercholesterolemic diet supplemented with phytosterol alone. These results indicate that combining lecithin, at a 0.15% level, with a phytosterol mixture-supplemented diet does not exhibit an additive effect in regulating hepatic ACAT activity or lowering blood cholesterol in hypercholesterolemic rats.     

SMXA-5 mouse as a diabetic model susceptible to feeding a high-fat diet

The SMXA-5 strain, a new mouse model for type 2 diabetes, is a recombinant inbred strain derived from non-diabetic SM/J and A/J strains. As dietary fat is a key component in the development of diabetes, we compared the glucose tolerance and diabetes-related traits among the SMXA-5, SM/J, and A/J strains while feeding a high-fat diet for 10 weeks. SMXA-5 fed on a high-fat diet showed an increased serum insulin concentration. Judging from the hyperinsulinemia in SMXA-5, this strain showed insulin resistance, an inability of peripheral tissues to respond to insulin, which was strengthened by feeding with a high-fat diet. When fed on a high-fat diet for 5 weeks, the SMXA-5 mice showed severely impaired glucose tolerance. On the other hand, SM/J showed mildly impaired glucose tolerance, even when fed on a high-fat diet for 10 weeks. These results indicate that SMXA-5 would be available for use as a diabetic model susceptible to a high-fat diet.     

Activity of AMP-Regulated Protein Kinase and AMP-Deaminase in the Heart of Mice Fed High-Fat Diet

AMP-regulated protein kinase (AMPK) is involved in numerous regulatory processes and its role in control of cardiac energy metabolism is particularly important. This activity could be affected by AMP-deaminase (AMPD) since substrate of AMPD is AMPK activator. Hearts of male mouse, fed for six weeks with normal or high-fat diet, were fractionated to enrich AMPK activity. Purified fraction was incubated with AMARA peptide for up to 5 minutes and then conversion of AMARA to pAMARA was determined by liquid chromatography—mass spectrometry (LC/MS) using mass detector. Activity of AMPK in heart was 0.038 ± 0.012 pmol/min/mg protein for mice fed high-fat diet and that was not different to control (0.032 ± 0.01 pmol/min/mg protein). We observed change in AMPD activity. It was 5.39 ± 1.5 nmol/mg tissue/min in heart of mice fed high-fat diet while in heart of mice fed low-fat diet it was 2.29 ± 0.32 nmol/mg tissue/min. Data we present indicate that while total AMPK activity is not changed decrease in AMPD activity may affect AMPK signaling in diabetic heart.     

Dietary creatine supplementation lowers hepatic triacylglycerol by increasing lipoprotein secretion in rats fed high-fat diet

Recent studies have shown that dietary creatine supplementation can prevent lipid accumulation in the liver. Creatine is a small molecule that plays a large role in energy metabolism, but since the enzyme creatine kinase is not present in the liver, the classical role in energy metabolism does not hold in this tissue. Fat accumulation in the liver can lead to the development of nonalcoholic fatty liver disease (NAFLD), a progressive disease that is prevalent in humans. We have previously reported that creatine can directly influence lipid metabolism in cell culture to promote lipid secretion and oxidation. Our goal in the current study was to determine whether similar mechanisms that occur in cell culture were present in vivo. We also sought to determine whether dietary creatine supplementation could be effective in reversing steatosis. Sprague–Dawley rats were fed a high-fat diet or a high-fat diet supplemented with creatine for 5 weeks. We found that rats supplemented with creatine had significantly improved rates of lipoprotein secretion and alterations in mitochondrial function that were consistent with greater oxidative capacity. We also find that introducing creatine into a high-fat diet halted hepatic lipid accumulation in rats with fatty liver. Our results support our previous report that liver cells in culture with creatine secrete and oxidize more oleic acid, demonstrating that dietary creatine can effectively change hepatic lipid metabolism by increasing lipoprotein secretion and oxidation in vivo. Our data suggest that creatine might be an effective therapy for NAFLD.     

Cyanidin 3-glucoside attenuates obesity-associated insulin resistance and hepatic steatosis in high-fat diet-fed and db/db mice via the transcription factor FoxO1

Obesity is a major risk factor for the development of type 2 diabetes, and both conditions are now recognized to possess significant inflammatory components underlying their pathophysiologies. Here, we hypothesized that cyanidin 3-glucoside (C3G), a typical anthocyanin reported to possess potent anti-inflammatory properties, would ameliorate obesity-associated inflammation and metabolic disorders, such as insulin resistance and hepatic steatosis in mouse models of diabesity. Male C57BL/6J obese mice fed a high-fat diet for 12 weeks and genetically diabetic db/db mice at an age of 6 weeks received dietary C3G supplementation (0.2%) for 5 weeks. We found that dietary C3G lowered fasting glucose levels and markedly improved the insulin sensitivity in both high-fat diet fed and db/db mice as compared with unsupplemented controls. White adipose tissue messenger RNA levels and serum concentrations of inflammatory cytokines (tumor necrosis factor-α, interleukin-6, and monocyte chemoattractant protein-1) were reduced by C3G, as did macrophage infiltration in adipose tissue. Concomitantly, hepatic triglyceride content and steatosis were alleviated by C3G. Moreover, C3G treatment decreased c-Jun N-terminal kinase activation and promoted phosphorylation and nuclear exclusion of forkhead box O1 after refeeding. These findings clearly indicate that C3G has significant potency in antidiabetic effects by modulating the c-Jun N-terminal kinase/forkhead box O1 signaling pathway and the related inflammatory adipocytokines.     

Calorie consumption level influences development of C3H/Ou breast adenocarcinoma with indifference to calorie source

To analyze simultaneously the influence attributable to calorie consumption level and percentage of dietary fat on the spontaneous development of mammary adenocarcinoma, virgin female C3H/Ou mice were separated into five dietary groups. Four groups of mice were fed purified diets either ad libitum (16-18 kcal/mouse/day) or restricted 40% in calorie consumption (10-11 kcal/mouse/day), and diets contained either 4.5%, 7.5%, 67%, or 68% calories from fat. Mice that consumed isocaloric diets developed breast malignancy at a comparable pace. Consuming a diet in which fats were present only at levels sufficient to satisfy the threshold requirement of essential fatty acids, 4.5-7.5% of the total calories, or alternatively where dietary fat represented greater than 67% of the total calories consumed, did not significantly alter the tendency for breast tumor development. The pace and frequency with which tumors occurred reflected the host's level of calorie consumption. Mice consuming a high caloric diet, low or high in fat, tended to have a shortened latency to breast tumor formation, an increased incidence of breast tumors, elevated serum prolactin levels, elevated levels of antibodies to mouse mammary tumor virus, and elevated circulating immune complex levels.     

Impact of dietary sterols on life-history traits of a caterpillar

Although lepidopteran larvae have been shown to metabolise a number of different phytosterols, their life-history traits in response to these different phytosterols may vary with the species. Using the specialist moth, Plutella xylostella (Linaeus) (Lepidoptera), growth, development and fecundity on artificial diets containing host and non-host phytosterols were measured over two generations. Because of the nature of the experimental design, maternal effects linked to dietary sterol could be assessed. In both generations, survival was highest on diets containing sitosterol as the primary phytosterol. A significant decrease in survival on stigmasterol, a non-host phytosterol, was observed between generations. As expected, survival on a control diet with only trace-sterols decreased between generations. Larval duration and pupal duration in both generations was longest on the diets containing the non-host phytosterols, stigmasterol and spinasterol, and on the trace-sterol diet. Finally, fecundity was affected by dietary sterol. In the first generation, fewer viable eggs were produced on the stigmasterol and trace-sterol diets than on wheatgerm control diet. In both generations, dietary sterol significantly influenced percentage egg viability. Overall, these results indicate that differences in phytosterol structure can have pronounced effects on life-history traits, especially when they are projected to the population level. The implications of these results are discussed with respect to phytosterol use by phytophagous insects and their host plant affiliations.     

Aldehyde stress and up-regulation of Nrf2-mediated antioxidant systems accompany functional adaptations in cardiac mitochondria from mice fed n-3 polyunsaturated fatty acids

Diets replete with n-3 PUFAs (polyunsaturated fatty acids) are known to have therapeutic potential for the heart, although a specifically defined duration of the n-3 PUFA diet required to achieve these effects remains unknown, as does their mechanism of action. The present study was undertaken to establish whether adaptations in mitochondrial function and stress tolerance in the heart is evident following short- (3?weeks) and long- (14?weeks) term dietary intervention of n-3 PUFAs, and to identify novel mechanisms by which these adaptations occur. Mitochondrial respiration [mO2 (mitochondrial O2)], H2O2 emission [mH2O2 (mitochondrial H2O2)] and Ca2+-retention capacity [mCa2+ (mitochondrial Ca2+)] were assessed in mouse hearts following dietary intervention. Mice fed n-3 PUFAs for 14?weeks showed significantly lower mH2O2 and greater mCa2+ compared with all other groups. However, no significant differences were observed after 3?weeks of the n-3 PUFA diet, or in mice fed on an HFC (high-fat control) diet enriched with vegetable shortening, containing almost no n-3 PUFAs, for 14?weeks. Interestingly, expression and activity of key enzymes involved in antioxidant and phase II detoxification pathways, all mediated by Nrf2 (nuclear factor E2-related factor 2), were elevated in hearts from mice fed the n-3 PUFA diet, but not hearts from mice fed the HFC diet, even at 3?weeks. This increase in antioxidant systems in hearts from mice fed the n-3 PUFA diet was paralleled by increased levels of 4-hydroxyhexenal protein adducts, an aldehyde formed from peroxidation of n-3 PUFAs. The findings of the present study demonstrate distinct time-dependent effects of n-3 PUFAs on mitochondrial function and antioxidant response systems in the heart. In addition, they are the first to provide direct evidence that non-enzymatic oxidation products of n-3 PUFAs may be driving mitochondrial and redox-mediated adaptations, thereby revealing a novel mechanism for n-3 PUFA action in the heart.     

Insulin secretion after dietary supplementation with conjugated linoleic acids and n-3 polyunsaturated fatty acids in normal and insulin-resistant mice

Conjugated linoleic acids (CLAs) and n-3 polyunsaturated fatty acids (PUFAs) improve insulin sensitivity in insulin-resistant rodents. However, the effects of these fatty acids on insulin secretion are not known but are of importance to completely understand their influence on glucose homeostasis. We therefore examined islet function after dietary supplementation consisting of 1% CLAs in combination with 1% n-3 enriched PUFAs for 12 wk to mice on a normal diet and to insulin-resistant mice fed a high-fat diet (58% fat). In the mice fed a normal diet, CLA/PUFA supplementation resulted in insulin resistance associated with low plasma adiponectin levels and low body fat content. Intravenous and oral glucose tolerance tests revealed a marked increase in insulin secretion, which nevertheless was insufficient to counteract the insulin resistance, resulting in glucose intolerance. In freshly isolated islets from mice fed the normal diet, both basal and glucose-stimulated insulin secretion were adaptively augmented by CLA/PUFA, and at a high glucose concentration this was accompanied by elevated glucose oxidation. In contrast, in high-fat-fed mice, CLA/PUFA did not significantly affect insulin secretion, insulin resistance, or glucose tolerance. It is concluded that dietary supplementation of CLA/PUFA in mice fed the normal diet augments insulin secretion, partly because of increased islet glucose oxidation, but that this augmentation is insufficient to counterbalance the induction of insulin resistance, resulting in glucose intolerance. Furthermore, the high-fat diet partly prevents the deleterious effects of CLA/PUFA, but this dietary supplementation was not able to counteract high-fat-diet-induced insulin resistance.     

Rose hip exerts antidiabetic effects via a mechanism involving downregulation of the hepatic lipogenic program

The aim of this study was to investigate the metabolic effects of a dietary supplement of powdered rose hip to C57BL/6J mice fed a high-fat diet (HFD). Two different study protocols were used; rose hip was fed together with HFD to lean mice for 20 wk (prevention study) and to obese mice for 10 wk (intervention study). Parameters related to obesity and glucose tolerance were monitored, and livers were examined for lipids and expression of genes and proteins related to lipid metabolism and gluconeogenesis. A supplement of rose hip was capable of both preventing and reversing the increase in body weight and body fat mass imposed by a HFD in the C57BL/6J mouse. Oral and intravenous glucose tolerance tests together with lower basal levels of insulin and glucose showed improved glucose tolerance in mice fed a supplement of rose hip compared with control mice. Hepatic lipid accumulation was reduced in mice fed rose hip compared with control, and the expression of lipogenic proteins was downregulated, whereas AMP-activated protein kinase and other proteins involved in fatty acid oxidation were unaltered. Rose hip intake lowered total plasma cholesterol as well as the low-density lipoprotein-to-high-density lipoprotein ratio via a mechanism not involving altered gene expression of sterol regulatory element-binding protein 2 or 3-hydroxymethylglutaryl-CoA reductase. Taken together, these data show that a dietary supplement of rose hip prevents the development of a diabetic state in the C57BL/6J mouse and that downregulation of the hepatic lipogenic program appears to be at least one mechanism underlying the antidiabetic effect of rose hip.     

Effect of myostatin depletion on weight gain, hyperglycemia, and hepatic steatosis during five months of high-fat feeding in mice

The marked hypermuscularity in mice with constitutive myostatin deficiency reduces fat accumulation and hyperglycemia induced by high-fat feeding, but it is unclear whether the smaller increase in muscle mass caused by postdevelopmental loss of myostatin activity has beneficial metabolic effects during high-fat feeding. We therefore examined how postdevelopmental myostatin knockout influenced effects of high-fat feeding. Male mice with ubiquitous expression of tamoxifen-inducible Cre recombinase were fed tamoxifen for 2 weeks at 4 months of age. This depleted myostatin in mice with floxed myostatin genes, but not in control mice with normal myostatin genes. Some mice were fed a high-fat diet (60% of energy) for 22 weeks, starting 2 weeks after cessation of tamoxifen feeding. Myostatin depletion increased skeletal muscle mass ～30%. Hypermuscular mice had ～50% less weight gain than control mice over the first 8 weeks of high-fat feeding. During the subsequent 3 months of high-fat feeding, additional weight gain was similar in control and myostatin-deficient mice. After 5 months of high-fat feeding, the mass of epididymal and retroperitoneal fat pads was similar in control and myostatin-deficient mice even though myostatin depletion reduced the weight gain attributable to the high-fat diet (mean weight with high-fat diet minus mean weight with low-fat diet: 19.9 g in control mice, 14.1 g in myostatin-deficient mice). Myostatin depletion did not alter fasting blood glucose levels after 3 or 5 months of high-fat feeding, but reduced glucose levels measured 90 min after intraperitoneal glucose injection. Myostatin depletion also attenuated hepatic steatosis and accumulation of fat in muscle tissue. We conclude that blocking myostatin signaling after maturity can attenuate some of the adverse effects of a high-fat diet.     

Chronic high-fat diet affects intestinal fat absorption and postprandial triglyceride levels in the mouse

The effects of chronic fat overconsumption on intestinal physiology and lipid metabolism remain elusive. It is unknown whether a fat-mediated adaptation to lipid absorption takes place. To address this issue, mice fed a high-fat diet (40%, w/w) were refed or not a control diet (3%, w/w) for 3 additive weeks. Despite daily lipid intake 7.7-fold higher than in controls, fecal lipid output remained unchanged in mice fed the triglyceride (TG)-rich diet. In situ isolated jejunal loops revealed greater [1-(14)C]linoleic acid uptake without TG accumulation in mucosa, suggesting an increase in lipid absorption capacity. Induction both in intestinal mitotic index and in the expression of genes involved in fatty acid uptake, trafficking, and lipoprotein synthesis was found in high-fat diet mice. These changes were lipid-mediated, in that they were fully abolished in mice refed the control diet. A lipid load test performed in the presence or absence of the LPL inhibitor tyloxapol showed a sustained blood TG clearance in fat-fed mice likely attributable to intestinal modulation of LPL regulators (apolipoproteins C-II and C-III). These data demonstrate that a chronic high-fat diet greatly affects intestinal physiology and body lipid use in the mouse.