Protective Effects of Diets Supplemented with Omega-3 Polyunsaturated Fatty Acids and Calcium Against Colorectal Tumor Formation

This study is to evaluate the effect of dietary omega-3 polyunsaturated fatty acid (omega-3 PUFA) and/or calcium supplementation on colon tissue of the carcinogenic N-methyl-N-nitrosurea (NMU)-injected rats and to investigate this effect by the assessment of the oxidative stress. The rats were divided into four groups: those fed with a standard diet, with a diet supplemented by omega-3 PUFA, those fed with a diet with calcium, and those fed with a standard diet with the combination of omega-3 PUFA and calcium. Rats were injected with an intrarectal NMU. After 32 weeks, colon tissue specimens and plasma were taken to histopathologically investigate and analyze tissue superoxide dismutase (SOD) and glutathione peroxidase (GSH-px) activities and erythrocyte MDA levels. The tumor incidences in supplemented-diet groups II and IV were found to be significantly lower when compared with those of the controls (P < 0.05). Superoxide dismutase and glutathione peroxidase antioxidative enzyme activities in colorectal tissue were increased in the study groups when compared with control rats (P < 0.001) and MDA levels were significantly lower than in the controls (P < 0.001) while the levels in group IV were rather decreased than those in group III (P = 0.011). These results suggest that the dietary supplementation of PUFA and/or calcium may be useful in the prevention of colorectal tumor formation.     

Effect of dietary polyunsaturated fatty acids on age-related changes in cardiac mitochondrial membranes

Remodeling of myocardial cell membranes is a major feature of advanced age. Mitochondrial function, crucial to sustaining energy production and management of myocardial metabolism, is impacted by age-dependent remodeling and ultimately exhibits a diminished threshold for excess Ca2+ buffering during events that stimulate increased myocardial Ca2+, such as augmented cardiac work, oxidative stress or post-ischemic reflow. Relative Ca2+, intolerance, augmented superoxide formation and reduced efficiency in the management of reactive oxygen species, are important mitochondrial factors (of many) that are apparent in senescence and predispose the myocardium to be more vulnerable to ischemic injury. In addition to cell death, surviving myocytes increase in size and exhibit altered gene expression of key effector proteins, including those that sustain Ca2+ homeostasis. Age-associated mitochondrial membrane changes include increases in membrane rigidity, cholesterol, phosphatidylcholine, omega-6 polyunsaturated fatty acids (PUFA), 4-hydroxy-2-nonenal, and decreases in omega-3 PUFA and cardiolipin. These effects have been shown in animal studies to be exaggerated by diet rich in long chain omega-6 PUFA (i.e. arachidonic acid), and have profound consequences on the efficacy of membrane proteins involved with ion homeostasis, signal transduction, redox reactions and oxidative phosphorylation. However, some of the age-related detrimental adaptations may be beneficially modified by dietary strategy. Diet rich in omega-3 PUFA reverses the age-associated membrane omega-3:omega-6 PUFA imbalance, and dysfunctional Ca2+ metabolism, facilitating increased efficiency of mitochondrial energy production and improved tolerance of ischemia and reperfusion.     

Protection against zinc toxicity by metallothionein and zinc transporter 1

Cells protect themselves from zinc toxicity by inducing proteins such as metallothionein (MT) that bind it tightly, by sequestering it in organelles, or by exporting it. In this study, the interplay between zinc binding by MT and its efflux by zinc transporter 1 (ZnT1) was examined genetically. Inactivation of the Znt1 gene in baby hamster kidney (BHK) cells that do not express their Mt genes results in a zinc-sensitive phenotype and a high level of "free" zinc. Restoration of Mt gene expression increases resistance to zinc toxicity approximately 4-fold, but only slightly reduces free zinc levels. Expression of ZnT1 provides greater protection (approximately 7-fold) and lowers free zinc substantially. Selection for zinc resistance in BHK cells that cannot synthesize either MT or ZnT1 is ineffective. However, parental BHK cells that grow in high concentrations (>500 microM) of zinc can be selected; these cells have amplified their endogenous Znt1 genes. The Znt1 gene is also amplified in zinc-resistant mouse cells that cannot induce their Mt genes. However, if Mt genes can be expressed, then they are preferentially amplified. Thus, both ZnT1 and MT genes contribute to zinc resistance in BHK cells, whereas ZnT1 plays a larger role in regulating free zinc levels.     

Effect of dietary polyunsaturated fatty acids on age-related changes in cardiac mitochondrial membranes

Remodeling of myocardial cell membranes is a major feature of advanced age. Mitochondrial function, crucial to sustaining energy production and management of myocardial metabolism, is impacted by age-dependent remodeling and ultimately exhibits a diminished threshold for excess Ca(2+) buffering during events that stimulate increased myocardial Ca(2+), such as augmented cardiac work, oxidative stress or post-ischemic reflow. Relative Ca(2+) intolerance, augmented superoxide formation and reduced efficiency in the management of reactive oxygen species, are important mitochondrial factors (of many) that are apparent in senescence and predispose the myocardium to be more vulnerable to ischemic injury. In addition to cell death, surviving myocytes increase in size and exhibit altered gene expression of key effector proteins, including those that sustain Ca(2+) homeostasis. Age-associated mitochondrial membrane changes include increases in membrane rigidity, cholesterol, phosphatidylcholine, omega-6 polyunsaturated fatty acids (PUFA), 4-hydroxy-2-nonenal, and decreases in omega-3 PUFA and cardiolipin. These effects have been shown in animal studies to be exaggerated by diet rich in long chain omega-6 PUFA (i.e., arachidonic acid), and have profound consequences on the efficacy of membrane proteins involved with ion homeostasis, signal transduction, redox reactions and oxidative phosphorylation. However, some of the age-related detrimental adaptations may be beneficially modified by dietary strategy. Diet rich in omega-3 PUFA reverses the age-associated membrane omega-3:omega-6 PUFA imbalance, and dysfunctional Ca(2+) metabolism, facilitating increased efficiency of mitochondrial energy production and improved tolerance of ischemia and reperfusion.     

Omega-6 and omega-3 polyunsaturated fatty acid levels are reduced in whole blood of Italian patients with a recent myocardial infarction: the AGE-IM study

Objective

The relationship between whole blood fatty acids and myocardial infarction (MI) risk has not been analyzed in detail, especially in Mediterranean countries. The AGE-IM (Acidi Grassi Essenziali e Infarto Miocardico) study was planned to examine the relationships between MI, whole blood fatty acids and the diet in an Italian cohort.

Methods

119 Patients with a recent MI and 103 control subjects were enrolled in the study. The whole blood fatty acid composition was determined; information on anthropometrics, biochemical parameters and blood pressure values were also obtained. Diet composition was assessed using a validated food frequency questionnaire from 86 cases and 72 controls.

Results

Total PUFA, omega-6 and omega-3 PUFA (as percentage of whole blood fatty acids) were significantly lower in MI patients than in matched controls, whereas saturated and monounsaturated fatty acids were higher in cases. MI infarction risk significantly and steadily decreased with increasing levels of total PUFA (OR: 0.14) and of total omega-6 and omega-3 (OR: 0.15 and 0.37, respectively). No correlation was identified between dietary fats and MI risk or between whole blood fatty acid levels and dietary nutrients and fats.

Conclusion

Percentage levels of total PUFA, total omega-3 PUFA and total omega-6 PUFA are lower in MI patients than in matched control subjects in the AGE-IM cohort. These data support a favorable association not only of whole blood percentage levels of total omega-3, but also of total omega-6, with cardiovascular risk.     

Contribution by synaptic zinc to the gender-disparate plaque formation in human Swedish mutant APP transgenic mice

Endogenous metals may contribute to the accumulation of amyloid plaques in Alzheimer's disease. To specifically examine the role of synaptic zinc in the plaque accumulation, Tg2576 (also called APP2576) transgenic mice (hAPP(+)) expressing cerebral amyloid plaque pathology were crossed with mice lacking zinc transporter 3 (ZnT3(-/-)), which is required for zinc transport into synaptic vesicles. With aging, female hAPP(+):ZnT3(+/+) mice manifested higher levels of synaptic zinc, insoluble amyloid beta, and plaques than males; these sex differences disappeared in hAPP(+):ZnT3(-/-) mice. Both sexes of hAPP(+):ZnT3(-/-) mice had markedly reduced plaque load and less insoluble amyloid beta compared with hAPP(+):ZnT3(+/+) mice. Hence, of endogenous metals, synaptic zinc contributes predominantly to amyloid deposition in hAPP(+) mice.     

Fatty acid and cholesterol in eggs: a review

Elevated serum cholesterol, a major cause of vascular disease, has been strongly correlated with eating greater than normal amounts of cholesterol and saturated fatty acids. The role at omega-3 polyunsaturated fatty acids (PUFA), especially eicosa pentanoic acid (EPA) and decosahexaconic (DHA), has been associated with the prevention of degenerative disease. Breast milk and eggs fulfill the human requirement for DHA, however the DHA level is influenced by lactation levels and the maternal diet. Omega-3 PUFA are derived mainly from fish, eggs, and certain plants. Epidemiological observations, population studies, and basic research indicate the importance of these fatty acids for the membranes of the brain, for the retina in developing infants, and for the possibility of controlling coronary heart disease and other diseases by the ingestion of these fatty acids. Linolenic acid (LNA) enriched eggs may be an excellent source of dietary omega-3 PUFA and an ideal food ingredient for developing infants.     

Effect of diet or very long chain omega-3 fatty acids on progression of atherosclerosis, evaluated by carotid plaques, intima-media thickness and by pulse wave propagation in elderly men with hypercholesterolaemia.

BACKGROUND: This randomized study targeted a comparison of the effect of 3-year diet counselling or omega-3 polyunsaturated fatty acid (PUFA) supplementation (2.4 g/day) on the progression of atherosclerosis in carotid arteries and on finger pulse wave propagation. METHODS: Measurements were assessed by high-resolution B-mode ultrasound and a photopletysmographic finger pulse-sensor, respectively. Altogether, 563 elderly men with long-standing hyperlipidaemia were randomized into four groups: controls (no dietary counselling and placebo); dietary counselling (and placebo); omega-3 PUFA supplementation (no dietary counselling); dietary counselling and omega-3 PUFA supplementation. RESULTS: In the diet only group, the carotid intima-media thickness increase (0.929 to 0.967 mm) was significantly less than in the control group (0.909 to 0.977 mm), (P = 0.018). Significant increase in carotid plaques score and plaques area were observed in all four groups, but without between group differences. Changes in carotid intima-media thickness and in high-density lipoprotein-cholesterol were negatively correlated (adjusted P < 0.001). Pulse wave propagation time decreased significantly in the control group (206 to 198 ms; P = 0.002), reflecting reduced arterial elasticity. In the group receiving omega-3 PUFA only, pulse wave propagation time increased significantly when compared with the control group (P = 0.013). CONCLUSION: Reduced progression in carotid intima-media thickness was observed after dietary counselling, whereas omega-3 PUFA supplementation imposed a favourable effect on arterial elasticity.     

Responsive transporter genes within the murine intestinal-pancreatic axis form a basis of zinc homeostasis

Zn homeostasis in animals is a consequence of avid uptake and retention, except during conditions of limited dietary availability, and/or factors such as parasites, which compete for this micronutrient or compromise retention by the host. Membrane proteins that facilitate Zn transport constitute the SLC30A (ZnT) and SLC39A (Zip) gene families. Because dietary recommendations are based on the balance between intestinal absorption and endogenous losses, we have studied Zn transporter expression of the murine intestinal-pancreatic axis to identify transporters that are likely to be involved in homeostatic control of Zn metabolism. Marked tissue specificity of expression was observed in Zn-depleted vs. Zn-adequate mice. As shown by quantitative PCR, Western blot analysis, and immunohistochemistry, intestinal Zip4 was markedly up-regulated in response to Zn-depletion conditions. The increased abundance of Zip4 is concentrated at the apical membrane of enterocytes. There are 16 ZnT and Zip transporters expressed in pancreas. Only two, ZnT1 and ZnT2 (both cellular Zn exporters), show a progressive down-regulation under Zn-depleted conditions. In Zn-adequate mice, ZnT1 is diffusely distributed in acinar cell cytoplasm and colocalizes with alpha-amylase but is not detected in pancreatic islets. In acinar cells during Zn depletion, ZnT1 is localized to the plasma membrane. Intestinal Zip4 up-regulation by Zn-depletion conditions is dampened in metallothionein knockout mice, suggesting that intracellular Zn pools influence these responses. The results show that Zn transporter expression in the intestinal-pancreatic axis is a component of the homeostatic regulation of this micronutrient.     

Comparative effect of fish oil feeding and other dietary fatty acids on plasma lipoproteins, biliary lipids, and hepatic expression of proteins involved in reverse cholesterol transport in the rat

BACKGROUND: While elevated plasma high-density lipoprotein (HDL) levels has been associated to a reduction in cardiovascular risk, dietary fish oils rich in omega-3 polyunsaturated fatty acids (PUFAs) may protect against this disease. The protective effect of HDL is associated to its participation in the reverse cholesterol transport pathway. On the other hand, omega-3 PUFAs decrease plasma HDL levels compared to other fatty acids, which may suggest an effect on reverse cholesterol transport. AIM: In this work, the effect of dietary fish oil on the fatty acid composition of hepatic membranes, plasma lipoprotein cholesterol profile, biliary lipids, and the expression of proteins involved in reverse cholesterol transport, was compared to other dietary oils having a different degree of fatty acid unsaturation. METHODS: Male rats were fed a semi synthetic diet containing fish oil (omega-3), sunflower oil (omega-6), olive oil (omega-9) or coconut oil (saturated). Hepatic membrane fatty acid composition, plasma cholesterol levels, lipoprotein cholesterol profile, biliary lipids, hepatic mRNA levels for lecithin cholesterol acyltransferase, hepatic lipase, apo E, and apo A-I, and hepatic protein levels of the scavenger receptor class B type I, caveolin-1, and the ATP binding cassette transporter A1 were analyzed. Plasma apo A-I and apo E protein levels were also evaluated. RESULTS: Compared to the other diets, omega-3 PUFAs significantly changed omega-3/omega-6 fatty acid ratio of hepatic membranes, caused a reduction of plasma total and HDL cholesterol, and selectively increased biliary cholesterol secretion. No modification in the expression levels of lecithin cholesterol acyltransferase, hepatic lipase, apo A-I and apo E mRNA was observed. Hepatic scavenger receptor class B type I, caveolin-1, and the ATP binding cassette transporter A1 protein levels were also not affected. Plasma apo A-I, but not apo E, was reduced. CONCLUSIONS: These results show that dietary omega-3 PUFAs reduce plasma HDL cholesterol and increase biliary cholesterol without concomitant modifications in the expression of key genes and proteins involved in reverse cholesterol transport. These findings suggest that functional changes in the activity of these proteins as consequence of the incorporation of omega-3 PUFAs into hepatic membranes and plasma lipoproteins may underlie the effect of fish oil feeding on plasma and hepatic cholesterol metabolism in the rat.     

A high cholesterol diet given to apolipoprotein E-knockout mice has a differential effect on the various neurotrophin systems in the hippocampus

Apolipoprotein E (apoE) is one of the major transporters of cholesterol in the body and is essential for maintaining various neural functions in the brain. Given that hypercholesterolemia is a risk factor in Alzheimer's disease (AD), it has been suggested that altered cholesterol metabolism may be involved in the development of the pathogenesis, including neural degeneration, commonly observed in AD patients. Neurotrophic factors and their receptors, which are known to regulate various neural functions, are also known to be altered in various neurodegenerative diseases. We therefore hypothesized that cholesterol metabolism may itself influence the neurotrophin system within the brain. We decided to investigate this possibility by modulating the amount of dietary cholesterol given to apoE-knockout (apoE-KO) and wild-type (WT) mice, and examining the mRNA expression of various neurotrophin ligands and receptors in their hippocampal formations. Groups of eight-week-old apoE-KO and WT mice were fed a diet containing either "high" (HCD) or "normal" (ND) levels of cholesterol for a period of 12?weeks. We found that high dietary cholesterol intake elevated BDNF mRNA expression in both apoE-KO and WT mice and TrkB mRNA expression in apoE-KO animals. On the other hand, NGF and TrkA mRNA levels remained unchanged irrespective of both diet and mouse type. These findings indicate that altered cholesterol metabolism induced by HCD ingestion combined with apoE deficiency can elicit a differential response in the various neurotrophin ligand/receptor systems in the mouse hippocampus. Whether such changes can lead to neural degeneration, and the mechanisms that may be involved in this, awaits further research.     

Adipose tissue triglyceride fatty acids and atherosclerosis in Alaska Natives and non-Natives

Essential polyunsaturated fatty acids (PUFA) of the omega-3 family are believed to protect against cardiovascular disease. A rich source of omega-3 PUFA is found in fish and marine mammals (seal, walrus, whale), which are a large part of the traditional diet of Alaska Natives (Eskimo, American Indians, Aleuts), a group that has been reported to have a lower mortality rate from cardiovascular disease than non-Natives. An autopsy study using standardized methods to evaluate the extent of atherosclerosis and its risk factors, and analyses of stored triglyceride fatty acids was conducted in a sample of Alaska Native subjects and non-Native subjects living in Alaska. Findings indicate that Alaska Natives had less advanced atherosclerosis in coronary arteries, along with higher proportions of omega-3 and lower proportions of omega-6 PUFA in adipose tissue, than did non-Natives. We conclude that high dietary intake of omega-3 PUFA may account for the lower extent of coronary artery atherosclerosis, contributing to the reported lower heart disease mortality among Alaska Natives.     

Improvement of the omega 3 index of healthy subjects does not alter the effects of dietary saturated fats or n-6PUFA on LDL profiles

Background and AimsDietary fat composition is known to modulate circulating lipid and lipoprotein levels. Although supplementation with long chain omega-3 polyunsaturated fatty acids (LCn-3PUFA) has been shown to reduce plasma triglyceride levels, the effect of the interactions between LCn-3PUFA and the major dietary fats consumed has not been previously investigated.MethodsIn a randomized controlled parallel design clinical intervention, we examined the effect of diets rich in either saturated fatty acids (SFA) or omega-6 polyunsaturated fatty acids (n-6PUFA) on plasma lipid levels and lipoprotein profiles (lipoprotein size, concentration and distribution in subclasses) in subjects with an adequate omega 3 index. Twenty six healthy subjects went through a four-week pre-supplementation period with LCn-3PUFA and were then randomized to diets rich in either n-6PUFA or SFA both supplemented with LCn-3PUFA.ResultsThe diet rich in n-6PUFA decreased low density lipoprotein (LDL) particle concentration (− 8%, p = 0.013) and LDL cholesterol (LDL-C) level (− 8%, p = 0.021), while the saturated fat rich diet did not affect LDL particle concentration or LDL-C levels significantly. Nevertheless, dietary saturated fatty acids increased LCn-3PUFA in plasma and tissue lipids compared with n-6PUFA, potentially reducing other cardiovascular risk factors such as inflammation and clotting tendency.ConclusionImprovement on the omega 3 index of healthy subjects did not alter the known effects of dietary saturated fats and n-6PUFA on LDL profiles.     

Prevention of reperfusion injury and microcirculatory failure in macrosteatotic mouse liver by omega-3 fatty acids

Macrovesicular hepatic steatosis has a lower tolerance to reperfusion injury than microvesicular steatosis with an abnormally high ratio of omega-6 (n-6): omega-3 (n-3) polyunsaturated fatty acids (PUFAs). We investigated the influence of PUFAs on microcirculation in steatotic livers and the potential to minimize reperfusion injury in the macrosteatotic liver by normalization of PUFAs. Ob/ob mice were used as a model of macrovesicular hepatic steatosis and C57/Bl6 mice fed a choline-deficient diet for microvesicular steatosis. Steatotic and lean livers were subjected to 45 minutes of ischemia and 3 hours of reperfusion. Hepatic content of omega-3 and omega-6 PUFAs was determined. Microcirculation was investigated using intravital fluorescence microscopy. A second group of ob/ob mice was supplemented with dietary omega-3 PUFAs and compared with the control diet-fed group. Microcirculation, AST, and Kupffer cell activity were assessed. Macrosteatotic livers had significant microcirculatory dysfunction correlating with high omega-6: omega-3 PUFA ratio. Dietary omega-3 PUFA resulted in normalization of this ratio, reduction of intrahepatic lipids, and decrease in the extent of macrosteatosis. Defective microcirculation was dramatically ameliorated with significant reduction in Kupffer cell activity and protection against hepatocellular injury both before ischemia and after reperfusion. CONCLUSION: Macrosteatotic livers disclosed an abnormal omega-6: omega-3 PUFA ratio that correlates with a microcirculatory defect that enhanced reperfusion injury. Thus, protective strategies applied during or after ischemia are unlikely to be useful. Preoperative dietary omega-3 PUFAs protect macrosteatotic livers against reperfusion injury and might represent a valuable method to expand the live liver donor pool.     

锌转运体8及其自身抗体

锌是胰岛素储存和分泌机制中的一个重要组分,β细胞需要有效且特异的转运体来累积足够量的锌.锌转运体8(ZnT8)是新近发现的一种1型糖尿病自身抗原,具有高度β细胞特异性,通过影响锌离子浓度而在胰岛素合成和分泌中发挥重要作用.ZnT8自身抗体对自身免疫性糖尿病(尤其对其他自身抗体阴性者)有着重要的诊断与预测价值.ZnT8基因(SLC30A8基因)多态性影响ZnT8自身抗体的特异性.     

A novel role for zinc transporter 8 in the facilitation of zinc accumulation and regulation of testosterone synthesis in Leydig cells of human and mouse testicles

ObjectiveZinc is intimately involved in testosterone production. Zinc transporter 8 (ZnT8) is found to be localized in insulin secretory granules as a β-cell specific Zn transporter. The effect of ZnT8 and related zinc accumulation in steroidogenesis, however, is still unknown. The present study aimed to explore whether ZnT8 plays a role in the facilitation of zinc accumulation and regulation of testosterone synthesis in testicles.MethodsLeydig cells were isolated from the testicles of human, CD-1 suckling and ZnT8-KO mice. Zn accumulation in mitochondria was induced by hCG stimulation. Transfection of hZnT8-EGFP and RNA interfere of mZnT8 were done in MLTC-1 cells. ZnT8 expression and its co-localization with steroidogenic acute regulatory (StAR) protein were analyzed with RT-PCR, Western blot and dual-fluorescent staining protocols. Serum testosterone levels in mice were determined with chemiluminescent enzyme immunoassay.ResultsZnT8 was found to be presented in Leydig cells and up-regulated in suckling mouse Leydig cells and MLTC-1 cells after hCG administration, by which zinc accumulation occurred in mitochondria. ZnT8 gene silencing or knockout inhibited stimulated progesterone and testosterone production, reduced stimulated zinc accumulation and down-regulated phosphorylated steroidogenic acute regulatory (StAR) expression in Leydig cells. Furthermore, an inhibitor (H89) of PKA blocked hCG-stimulated progesterone caused by ZnT8 over-expression and zinc treatment.ConclusionThe present study provided the first evidence that ZnT8 transports Zn into Leydig cell mitochondria with gonadotropin stimulation and suggests that ZnT8 may play a role in testosterone production via the PKA signaling pathway.     

Prevention of programmed hyperleptinemia and hypertension by postnatal dietary omega-3 fatty acids

Fetal programming is now recognized as a key determinant of the adult phenotype, with major implications for adult-onset diseases including hypertension. Two mediators of fetal programming are maternal nutrition and fetal glucocorticoid exposure. Recent studies show that postnatal dietary manipulations can exacerbate programming effects, but whether programming effects can be attenuated by postnatal dietary manipulations, and thus provide a possible therapeutic strategy, is unknown. In this study, we tested the hypothesis that a postnatal diet enriched with long-chain omega-3 fatty acids attenuates programmed hyperleptinemia and hypertension. Pregnant rats were treated with dexamethasone (Dex) from d 13 to term, and offspring were cross-fostered to mothers on either a standard diet or a diet high in omega-3 fatty acids and remained on these diets postweaning. Maternal Dex reduced birthweight and delayed the onset of puberty in offspring. Hyperleptinemia (associated with elevated leptin mRNA expression in adipose tissue) and hypertension were evident in offspring by 6 months of age in Dex-exposed animals consuming a standard diet, but these effects were completely blocked by a high omega-3 diet. These results demonstrate for the first time that manipulation of postnatal diet can limit adverse outcomes of fetal programming, with programmed hyperleptinemia and hypertension prevented by a postnatal diet enriched with omega-3 fatty acids. This raises the possibility that dietary supplementation with omega-3 fatty acids may provide a viable therapeutic option for preventing and/or reducing adverse programming outcomes in humans.     

Role of fat amount and type in ameliorating diet-induced obesity: insights at the level of hypothalamic arcuate nucleus leptin receptor, neuropeptide Y and pro-opiomelanocortin mRNA expression

Aims: Dietary fatty acid profile, independent of caloric percent of fat, is a major regulator of body adiposity. This study examined the effects of dietary fat amount and types on fat storage and hypothalamic gene expression in the mouse model of chronic diet‐induced obesity. Methods: The dietary interventions were in twofold: (1) the obesity was induced by a 13‐week obesogenic fat diet compared with a low‐fat (LF) diet, and (2) the reversibility was tested by using high n‐3 polyunsaturated fat (PUFA) and LF diets. Fifty‐four C57Bl/6 mice were fed a high‐fat (59% in kcal) diet for 13 weeks and then classified as diet‐induced obese (DIO) or diet‐resistant (DR) mice according to upper and lower tertiles of body weight gain. The DIO mice were then subdivided into three groups for a 6‐week secondary dietary intervention. Two of the groups were switched to either a high n‐3 PUFA (DIO‐n3) or a low‐fat (10% in kcal, DIO‐LF) diet, whereas the third (controls) and DR mice continued on the initial high‐fat diet. Food efficiency was calculated as weekly body weight gain per gram of food intake. Results: After switching the DIO mice to the n‐3 PUFA or LF diet, their body weights were reduced to the level of the DR and LF mice. The food efficiencies were, from the highest to lowest, in the order: DIO > LF > DR > DIO‐LF > DIO‐n3. Using quantitative in situ hybridization, we found that the DIO mice had higher levels of leptin receptor (LR, +290%, p < 0.005) and neuropeptide Y (NPY, +25%, p < 0.05) mRNA expression in the hypothalamic arcuate nucleus (Arc) than the DR mice, whereas the level of pro‐opiomelanocortin (POMC) mRNA expression was significantly reduced (?45%, p < 0.01). All effects that were essentially returned to DR levels by the change to the n‐3 PUFA diet and, with the exception of a failure to normalize Arc NPY mRNA levels, by the change to LF diet. Conclusions: Taken together, the present results show that both change in level and quality of dietary fat can potently alter hypothalamic neuropeptide expression and result in effective amelioration of diet‐induced obesity. Interestingly, the n‐3 PUFA diet when fed to already obese mice produced a pattern of hypothalamic gene expression similar to that in obesity resistant (DR) mice. It remains to be determined if the effects of n‐3 fatty acids on brain neuropeptide gene expression are direct or indirect.