Effects Of Long-term High-fat Diet Research Articles

Effects of long term diabetogenic high fat diet on bone in ovariectomized female rats

ABSTRACT A diabetogenic high fat diet (HFD) can be used to induce insulin resistance and obesity in animal models; however, its effects on bone are unknown. We investigated the effects of long term HFD on bone in ovariectomized (OVX) female rats. We used 12-week-old female rats divided randomly into four groups: sham operation (sham), sham operation with HFD (SHFD), OVX and OVX with HFD (OVX + HFD). Ovaries were removed in the OVX and OVX + HFD groups and the SHFD and OVX + HFD groups were fed a HFD for 28 weeks. Serum estrogen, testosterone, lipid, adiponectin, leptin, tartrate-resistant acid phosphatase (TRAP) and N-mid fragment of osteocalcin (N-MID-OT) levels were measured. Structure, apoptosis and specific transcription factors in bone were evaluated using pathologic, densitometric and immunohistochemical analysis. Body weight, serum leptin, TRAP and testosterone levels were increased, while serum N-MID-OT, estrogen and adiponectin levels were decreased in the SHFD, OVX and OVX + HFD groups. Expression of BCL2-associated X protein, caspase-3, matrix metalloproteinase-9 and calcitonin was increased, while bone mineral density (BMD) and content (BMC) in femurs and lumbar spine, and expression of B cell lymphoma 2, type 1 collagen and osteocalcin were decreased in the bones of the SHFD, OVX and OVX + HFD groups. All indices were greatest in the OVX + HFD group and HFD produced a detrimental effect on bone in both normal and OVX rats, which may be due to increased apoptosis in bone and increased leptin and decreased adiponectin levels in serum. The effects of HFD and OVX may be synergistic.

Long term high fat diet induces metabolic disorders and aggravates behavioral disorders and cognitive deficits in MAPT P301L transgenic mice.

Most Alzheimer disease (AD) patients present as sporadic late onset AD, with metabolic factors playing an important role in the occurrence and development of AD. Given the link between peripheral insulin resistance and tau pathology in streptozotocin-injected and db/db mouse models of diabetes, we fed high fat diet (HFD) to pR5 mice expressing P301L mutant human tau, with the aim of developing a new model with characteristics of obesity, T2DM and AD to mimic AD patients exacerbated by obesity and T2DM, an increasing trend in modern society. In our study, pR5 and C57BL/6 (WT) mice were randomly allocated to a standard diet (STD) or HFD for 30 weeks starting at 8 weeks of age. Food intake was measured weekly, body weight and fasting glucose levels were measured fortnightly, and a comprehensive behavioral test battery was performed to assess anxiety, depression and cognitive dysfunction. Glucose and insulin tolerance tests were performed after 30 weeks of HFD. We also investigated the effect of long term HFD on tau pathology in the brains of WT and P301L mice by performing western blotting of whole brain homogenates for total tau, phosphorylated tau at Ser396 and Thr231. Our results show that pR5 mice fed with HFD are more vulnerable to diet induced obesity compared to WT, especially with increasing age. In addition, pR5 mice on HFD developed glucose intolerance and insulin resistance. It was identified that long term HFD significantly aggravates depression like behavior and impairs cognitive function in pR5 mice, and also induces anxiety like behavior in both pR5 and WT mice. Long term HFD was also shown to aggravate tau hyperphosphorylation in pR5 transgenic mice, and increase total and hyperphosphorylated tau in WT mice. These results indicate that diet induced obesity of pR5 transgenic mice expressing P301L mutant human tau generates T2DM, and aggravates tau phosphorylation, and is therefore a model useful for investigations that seek to understand the relationships between AD, T2DM and obesity, and the underlying biochemical changes and mechanisms associated with metabolic disorders and AD tauopathy.

Long-term diet-induced obesity does not lead to learning and memory impairment in adult mice.

Obesity arising from excessive dietary fat intake is a risk factor for cognitive decline, dementia and neurodegenerative diseases, including Alzheimer’s disease. Here, we studied the effect of long-term high-fat diet (HFD) (24 weeks) and return to normal diet (ND) on behavioral features, microglia and neurons in adult male C57BL/6J mice. Consequences of HFD-induced obesity and dietary changes on general health (coat appearance, presence of vibrissae), sensory and motor reflexes, learning and memory were assessed by applying a phenotypic assessment protocol, the Y maze and Morris Water Maze test. Neurons and microglia were histologically analyzed within the mediobasal hypothalamus, hippocampus and frontal motor cortex after long-term HFD and change of diet. Long periods of HFD caused general health issues (coat alterations, loss of vibrissae), but did not affect sensory and motor reflexes, emotional state, memory and learning. Long-term HFD increased the microglial response (increased Iba1 fluorescence intensity, percentage of Iba1-stained area and Iba1 gene expression) within the hypothalamus, but not in the cortex and hippocampus. In neither of these regions, neurodegeneration or intracellular lipid droplet accumulation was observed. The former alterations were reversible in mice whose diet was changed from HFD to ND. Taken together, long periods of excessive dietary fat alone do not cause learning deficits or spatial memory impairment, though HFD-induced obesity may have detrimental consequences for cognitive flexibility. Our data confirm the selective responsiveness of hypothalamic microglia to HFD.

Long-term high-fat diet disrupts lipid metabolism and causes inflammation in adult male rats: possible intervention of endoplasmic reticulum stress

This study investigated the effect of long-term high-fat diet (HFD) on plasma lipid profile and probability of inflammation in adult rats. After weaning, male offspring were divided into six groups based on diet type and medication. After 20 weeks of dietary intake, 4-PBA (endoplasmic reticulum (ER) stress inhibitor) was injected for three days. Then, blood samples were taken to measure plasma concentrations of low-density lipoprotein (LDL), triglyceride (TG), high-density lipoprotein (HDL), cholesterol, leptin and interleukin 1-β (IL 1-β). The HFD increased body weight and food intake and intra-abdominal fat and thymus weights, which were associated with elevated plasma leptin level. Moreover, HFD increased plasma concentrations of TG, LDL, cholesterol and IL 1-β and decreased HDL level. Injection of 4-PBA reversed the plasma parameters changes caused by HFD. It seems that long-term HFD feeding through inducing the ER stress, disrupted the lipid metabolism and resulted in inflammation.

Long-term, high-fat feeding exacerbates short-term increases in adipose mitochondrial reactive oxygen species, without impairing mitochondrial respiration.

White adipose tissue (WAT) dysfunction in obesity is implicated in the onset of whole body insulin resistance. Alterations in mitochondrial bioenergetics, namely impaired mitochondrial respiration and increased mitochondrial reactive oxygen species (mtROS) production, have been suggested to contribute to this metabolic dysregulation. However, techniques investigating mitochondrial function are classically normalized to tissue weight, which may be confounding when considering obesity-related adipocyte hypertrophy. Furthermore, the effect of long-term high-fat diet (HFD) on mtROS in WAT has yet to be elucidated. Therefore, we sought to determine the HFD-mediated temporal changes in mitochondrial respiration and mtROS emission in WAT. C57BL/6N mice received low-fat diet or HFD for 1 or 8 wk and changes in inguinal WAT (iWAT) and epididymal WAT (eWAT) were assessed. While tissue weight-normalized mitochondrial respiration was reduced in iWAT following 8-wk HFD-feeding, this effect was mitigated when adipocyte cell size and/or number were considered. These data suggest HFD does not impair mitochondrial respiratory capacity per adipocyte within WAT. In support of this assertion, within eWAT compensatory increases in lipid-supported and maximal succinate-supported respiration occurred at 8 wk despite cell hypertrophy and increases in WAT inflammation. Although these data suggest impairments in mitochondrial respiration do not contribute to HFD-mediated WAT phenotype, lipid-supported mtROS emission increased following 1-wk HFD in eWAT, while both lipid and carbohydrate-supported mtROS were increased at 8 wk in both depots. Combined, these data establish that while HFD does not impair adipocyte mitochondrial respiratory capacity, increased mtROS is an enduring physiological occurrence within WAT in HFD-induced obesity.

High-fat diet selectively decreases bone marrow lin- /CD117+ cell population in aging mice through increased ROS production.

Bone marrow (BM) stem cells (BMSCs) are an important source for cell therapy. The outcome of cell therapy could be ultimately associated with the number and function of donor BMSCs. The present study was to evaluate the effect of long-term high-fat diet (HFD) on the population of BMSCs and the role of reactive oxygen species (ROS) in aging mice. Forty-week-old male C57BL/6 mice were fed with HFD for 3 months with regular diet as control. Experiments were repeated when ROS production was reduced in mice treated with N-acetylcysteine (NAC) or using mice overexpressing antioxidant enzyme network (AON) of superoxide dismutase (SOD)1, SOD3, and glutathione peroxidase. BM and blood cells were analyzed with flowcytometry for lineage negative (lin- ) and Sca-1+ , or lin- /CD117+ , or lin- /CD133+ cells. Lin- /CD117+ cell population was significantly decreased with increased intracellular ROS and apoptosis and decreased proliferation in BM, not in blood, in HFD-treated mice without change for Sca-1+ or CD133+ cell populations in BM or blood. NAC treatment or AON overexpression effectively prevented HFD-induced intracellular ROS production and reduction of BM lin- /CD117+ population. These data suggested that long-term HFD selectively decreased BM lin- /CD117+ cell population in aging mice through increased ROS production.

Effects of Long-Term High-Fat Diet and Its Reversal on Lipids and Lipoproteins Composition in Thoracic Duct Lymph in Pigs.

BackgroundThis study was carried out to evaluate the effects of a long-term high-fat diet on lipids and lipoproteins composition in thoracic duct lymph in pigs.Material/MethodsWe examined lymph taken from the thoracic duct from 24 female white sharp-ear pigs, divided into 3 experimental groups fed different diets for 12 months: (a) the control group, fed the standard balanced diet; (b) the HFD group, fed an unbalanced, high-fat diet, and (c) the reversal diet group (RD), fed an unbalanced, high-fat diet for 9 months and then a standard balanced diet for 3 months.ResultsLymph analysis after 12 months of fixed diets revealed significantly higher concentration of proteins in the HFD group in comparison to the control and RD groups. Examination of lymph lipoproteins fractions showed that the high-fat diet in the HFD group in comparison to control group caused an increase in cholesterol, phospholipids, and proteins content within HDL and chylomicrons. There were also more proteins within HDL in the HFD group in comparison to the RD group and more triglycerides within chylomicrons in the HFD group in comparison to the control group.ConclusionA long-term high-fat diet resulted in changed structure of HDL and chylomicrons in the thoracic duct lymph. Alterations in HDL composition suggest that a high-fat diet enhances reverses cholesterol transport. Changes in chylomicrons structure show the adaptation to more intense transport of dietary fat from the intestine to the liver under the influence of a high-fat diet. Reversal to a standard balanced diet had the opposite effects.

The effect of long-term high-fat diet in ovariectomized Wistar rat ( Rattus norvegicus )study on lipid profile, endothelial nitric oxide synthase (eNOS) dan endhotelin -1 (ET-1) serum

Accumulation of cholesterol in the blood will cause stiffness in arteries and trigger the formation of atherosclerotic lesions. Estrogen has a role as an antioxidant that can prevent the low density lipoprotein(LDL) oxidation. In menopause with high-fat diet, the decrease of estrogen levels will trigger cholesterol accumulation in the blood lead to endothelial dysfunction mediated by endotelin-1 (ET-1) and nitric oxide synthase (eNOS). This study aimed to investigate the effect of long-term high-fat diet on the lipid profile, serum eNOS and ET-1levels on ovariectomized rat. It was experimental using 28 female Wistar rat divided into 4 groups. Group 1 was ovariectomized mice and given a standard diet (OVX-SD), Group 2 was ovariectomized mice and given a high-fat diet (OVX-HFD), Group 3 was not ovariectomized mice and given a standard diet(SHAM-SD) group, and Group 4 was not ovariectomized mice and given a high-fat diet (SHAM-HFD).Lipid profile of blood samples was measured pre- and post-treatment, whereas serum eNOS and ET-1 levels were measured post-treatment using ELISA method. No significantly difference of lipid profileon OVX-HFD group compared to that OVX-SD was observed. The serum eNOSlevel on OVX-HFD(702.11±68.73 pg/mL) was significantly lower than that OVX-SD (857.18±118.08 pg/mL) (p 0.05). In conclusion, the serum eNOS levelon ovariectomized rat with long-term high-fat diet is lower than that on ovariectomized rat with standard diet.

Long-term high-fat diet inhibits hippocampal expression of insulin receptor substrates and accelerates cognitive deterioration in obese rats

To assess the effect of long-term high-fat diet on the expressions of insulin receptor substrates in the hippocampus and spatial learning and memory ability of obese rats. A total of 100 4-week-old male SD rats were randomly divided into two groups and fed with common diet (CD group, n=40) or high-fat diet (HFD group, n=60) for 16 weeks. At 4, 8, 12, 16 and 20 weeks, 8 rats were randomly selected from each group for testing their spatial learning and memory function using Morris water maze. After the tests, the rats were sacrificed for measurement of the metabolic parameters and detection of the expressions of insulin receptor substrate-1 (IRS-1) and IRS-2 mRNAs in the CA1 region of the hippocampus. Compared with those in CD group, the rats in HFD group showed a prolonged escape latency, longer swimming distance, faster average swimming speed, and shorter stay in the platformat 12 weeks. In HFD group, the serum levels of total cholesterol, triglyceride, low-density lipoprotein cholesterol, and fasting insulin were all significantly increased (P<0.05) and the level of high-density lipoprotein cholesterol decreased (P<0.01) in comparison with those in CD group at each of the time points. No significant difference was found in fast glucose levels between the two groups (P>0.05), but the expressions of IRS-1 and IRS-2 mRNAs were significantly decreased in HFD group at 12 weeks (P<0.05). In obese rats, long-term feeding with high-fat diet leads to insulin resistance, which interferes with hippocampal expression of insulin receptor substrates and insulin metabolism to cause impairment of the cognitive function and accelerate cognitive deterioration.

The effect of long-term high-fat diet on hippocampal neurons ultrastructural and cognitive function in obese rats

Objective To investigate the effect of long-term high-fat diet on cognitive function and hippocampus neurons ultrastructure in obese rats. Methods Forty SD rats were randomly assigned to a high-fat diet (HFD) group and a common diet (CD) group.Meanwhile, HFD-induced obese rat model were established.The spatial learning and memory were measured by the Morris water maze, and the neurons ultrastructural changes in rat hippocampus CA1 region at the corresponding period were observed by transmission electron microscopy. Results The average weight of rats was 25%, 28%, and 22% higher in the HFD group than in the CD group at the 12, 16, and 20 weeks, respectively; the Lee's indexes were 6%, 4%, and 8% higher; the average swimming latency were 52%, 44%, and 40% longer; the average swimming distance were 85%, 45%, and 51% longer; the average swimming speed were 57%, 34%, and 18% higher; the duration of staying in the target quadrant were 32%, 54%, and 63% shorter; and the average times of crossing the plate-form were 30%, 34%, and 34% shorter, respectively (all P<0.001). In comparison of ultrastructure in hippocampus CA1 region of rats at corresponding time points, the amounts of degenerated and necrosis neurons, of the deformed and vacuolar mitochondria, and of the less rough endoplasmic reticulum were significantly more at 12, 16, and 20 weeks in the HFD group than in the CD group. Conclusions Long-term HFD-induced obesity damages the structure of neurons in the hippocampus, impairs spatial learning and memory function, and accelerates cognitive aging in rats. Key words: Cognition; Hippocampus; Dietary fats, unsaturated

The effect of long-term high-fat diet in ovariectomized Wistar rat on leptin serum levels

ABSTRACT Leptin and estrogen have an important role in energy homeostasis through anorexic effects on the central nervous system. These hormones can decrease food intake, increases energy expenditure and thermogenesis. Long-term high-fat diet can lead to impaired leptin function. Moreover, estrogen, deficiency is a risk factor of obesity in menopause. The aim of this study is to investigate the effect of long-term high-fat diet on leptin serum levels in ovariectomized rats. Twenty-eight female Wistar rats (Rattus norvegicus) aged 6-8 weeks with body weight 120-150 g were used in this study. Rats were divided into 4 groups i.e. OVXSC groups: rat were ovariectomized and given a standard diet; OVXH groups: rat were ovariectomized and given a high-fat diet; SHAMSC groups: rat were not ovariectomized and given a standard diet; SHAMHF groups : rat were not ovariectomized and given a high-fat diet. Pre-post test with control group design for measurement of serum leptin levels, food intake, and Lee index. While post-test only control group design for measurement of abdominal fat mass. Pearson test was used to analyze the correlation between leptin serum levels, food intake, Lee index and abdominal fat mass. Paired t-test was used to analyze the differences between values before and after being treated. The daily food intake dropped in rat fed a high-fat diet although it was not statistically significant (p>0.05). Ovariectomy significantly increase Lee index (p<0.05). Obesity occurs in ovariectomized group, both of high-fat diet and standard diet. Abdominal fat mass was significantly higher in high-fat compared to standard diet group (p<0.05). Increase in levels of serum leptin highest in OVX-HF group (16.45 ± 8.75 ng/mL), and the lowest in the SHAM-SC (2.98 ± 1.61 ng/mL). In conclusion, serum leptin levels positively correlated with Lee index and abdominal fat mass, but negatively correlated with daily food intake.

Diet composition, not calorie intake, rapidly alters intrinsic excitability of hypothalamic AgRP/NPY neurons in mice

Obesity is a chronic condition resulting from a long-term pattern of poor diet and lifestyle. Long-term consumption of high-fat diet (HFD) leads to persistent activation and leptin resistance in AgRP neurons in the arcuate nucleus of the hypothalamus (ARH). Here, for the first time, we demonstrate acute effects of HFD on AgRP neuronal excitability and highlight a critical role for diet composition. In parallel with our earlier finding in obese, long-term HFD mice, we found that even brief HFD feeding results in persistent activation of ARH AgRP neurons. However, unlike long-term HFD-fed mice, AgRP neurons from short-term HFD-fed mice were still leptin-sensitive, indicating that the development of leptin-insensitivity is not a prerequisite for the increased firing rate of AgRP neurons. To distinguish between diet composition, caloric intake, and body weight, we compared acute and long-term effects of HFD and CD in pair-fed mice on AgRP neuronal spiking. HFD consumption in pair-fed mice resulted in a significant increase in AgRP neuronal spiking despite controls for weight gain and caloric intake. Taken together, our results suggest that diet composition may be more important than either calorie intake or body weight for electrically remodeling arcuate AgRP/NPY neurons.

Abstract B23: A high-fat diet, but not obesity, promotes tumorigenesis in two mouse models of k-ras-driven lung cancer

Abstract Lung cancer is the leading cause of cancer-related mortality worldwide, and 85% of lung cancers are associated with tobacco use. Activating mutations in K-ras have been identified in ~25% of lung adenocarcinomas and are found predominantly in smokers. We previously demonstrated that reducing systemic IGF-1 levels, by treatment with the anti-diabetic drug metformin or by liver-specific ablation of the IGF-1 gene, decreases tumorigenesis in mouse models of k-ras-driven lung cancer. Since preclinical and clinical studies suggest that diet composition is the best predictor of systemic IGF-1 levels, we hypothesized that diets high in fat or carbohydrates might increase systemic IGF-1 levels and promote lung tumorigenesis. To assess the effect of diet, C57Bl/6J and A/J mice were fed standard cereal diet, high-carbohydrate diet, or high-fat diet (HFD) for 12 weeks starting at nine weeks of age, after which plasma and tissue samples were collected. The HFD increased levels of IGF-1 and insulin in both strains of mice, and increased the weights of C57BL/6J, but not A/J mice. In contrast, the high-carbohydrate diet did not increase the weights or circulating levels of IGF-1/insulin in either strain of mice. Since insulin and IGF-I were induced more with HFD, we investigated the impact of HFD on lung tumorigenesis using two mouse models of Kras-mutant lung cancer. In the first, genetically engineered C57BL/6LA2 mice were fed a cereal diet or HFD for 10 weeks starting at weaning. Lung tumor multiplicity and tumor burden increased 2.7-fold compared to littermates fed a cereal diet. In the second model, lung tumorigenesis was initiated in 6 week old A/J mice by three weekly IP injections of the tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) that invariably causes Kras mutations. . One week after the last NNK injection, mice were randomized to cereal or HFD for 10 weeks. Mice on HFD had a 40% increase in lung tumor multiplicity and a 60% increase in lung tumor burden. These studies show that a HFD promotes lung tumor growth caused by a mutation commonly observed in smokers. Conversely, the results imply that dietary modification could slow the progression of tumorigensis due to smoking related genetic changes in lung epithelium. Further, chemopreventative drugs, such as metformin, may have enhanced efficacy in a HFD model due to the associated increases in levels of insulin and/or IGF-I. Finally, understanding the long term effects of HFD could identify new targets for cancer prevention. Citation Format: Jeffrey W. Norris, Regan M. Memmott, Kristin Lastwika, Phillip Dennis. A high-fat diet, but not obesity, promotes tumorigenesis in two mouse models of k-ras-driven lung cancer. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr B23.

Effects of high-fat diet on skin wound repair in mice: an experimental study

Objective To evaluate the effects of long-term high-fat diet on skin wound repair in mice, and to explore its related mechanism. Methods A total of 16 ten-week-old C57BL/6J wild-type mice were randomly and equally divided into two groups to be fed a high-fat diet (HFD group) and a standard diet (SD group) respectively for 8 weeks. Then, an 8-mm full-thickness skin wound was created on the back of each mouse by using a biopsy punch. The degree of wound healing was observed, wound healing rate and epithelialization level were evaluated every day. The weight of mice was measured before feeding, after 8-week feeding and on day 14 after the operation. Peripheral blood samples were obtained from these mice for the determination of total cholesterol (TC) and triglyceride (TG) levels after a 12-hour fast on day 14 after the operation. Then, all the mice were sacrificed, and wound tissues were resected from the dorsal skin of mice for a histological study. The two-sample t test was used to compare the thickness of new epidermis in the wound surface, collagen deposition rate in the wound bed, count of new vessels, levels of cell proliferation and degree of inflammatory cell infiltration between the two groups. Results The average weight of mice was significantly higher in the HFD group than in the SD group after 8-week feeding (27.3±0.7 g vs. 21.2±0.6 g, t=21.98, P 0.05). Conclusion Long-term high-fat diet can affect wound healing and delay skin wound repair in mice. Key words: Diet, high-fat; Wound healing; Disease models, animal; Collagen; Mast cells; Macrophages; Blood vessels

Impact of a high-fat diet containing canola or soybean oil on body development and bone; parameters in adult male rats.

The role of the fatty acid in the prevention or progression of chronic diseases has generated significant interest on the part of researchers. Thus, our objective was to evaluate the long-term effects of high-fat diet containing soybean or canola oil on body development and bone parameters of male rats. After weaning, rats were grouped and fed either a control diet (7S) or a high-fat diet containing soybean (19S) or canola oil (19C). Femur and lumbar vertebra (LV4) structure were determined at 180 days by dual-energy X-ray absorptiometry and computed tomography. The groups showed similar food intake, body mass and length development. The bone parameters of the 19C were similar to the control group, while the 19S showed lower bone parameters when compared to the other groups. The high-fat diet containing soybean oil was unfavorable to bone structure, while the canola oil contributed bone health during the adult stage of life.

Long-term high-fat consumption leads to downregulation of Akt phosphorylation of eNOS at Ser1177 and upregulation of Sirtuin-1 expression in rat cavernous tissue

Long-term consumption of high-fat diets negatively interferes with metabolic status and promotes endothelial dysfunction and inflammation. In the cavernous tissue, these outcomes become conspicuous in the elderly and strongly affect penile erection, a vascular process highly dependent on local nitric oxide bioavailability. Although epidemiological data links erectile dysfunction to nutritional patterns, the underlying molecular mechanisms remain unclear. Therefore, we investigated the effects of long-term high-fat diet on endothelial nitric oxide synthase (eNOS)-Sirtuin-1 axis and Akt/eNOS phosphorylation in the cavernous tissue of Sprague-Dawley rats, and compared with energy-restricted animals. We demonstrated that high-fat diet intake led to a noteworthy decrease in eNOS phosphorylation at Ser1177 residue through the Akt pathway, which seems to be compensated by upregulation of phosphorylation at Ser615, but without an increment in nitric oxide production. These results are accompanied by an increase of systemic inflammatory markers and upregulation of the inducible NOS and of the deacetylase Sirtuin-1 in the cavernous tissue to levels apparently detrimental to cells and to metabolic homeostasis. Conversely, in long-term energy-restricted animals, the rate of phosphorylation of eNOS at Ser1177 diminished, but the activation of the enzyme increased through phosphorylation of eNOS at Ser615, resulting in an enhancement in nitric oxide bioavailability. Taken together, our results demonstrate that long-term nutritional conditions override the influence of age on the eNOS expression and activation in rat cavernous tissue.

Effects of high-fat diet and physical activity on pyruvate dehydrogenase kinase-4 in mouse skeletal muscle

BackgroundThe expression of PDK4 is elevated by diabetes, fasting and other conditions associated with the switch from the utilization of glucose to fatty acids as an energy source. It is previously shown that peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), a master regulator of energy metabolism, coactivates in cell lines pyruvate dehydrogenase kinase-4 (PDK4) gene expression via the estrogen-related receptor α (ERRα). We investigated the effects of long-term high-fat diet and physical activity on the expression of PDK4, PGC-1α and ERRα and the amount and function of mitochondria in skeletal muscle.MethodsInsulin resistance was induced by a high-fat (HF) diet for 19 weeks in C57BL/6 J mice, which were either sedentary or with access to running wheels. The skeletal muscle expression levels of PDK4, PGC-1α and ERRα were measured and the quality and quantity of mitochondrial function was assessed.ResultsThe HF mice were more insulin-resistant than the low-fat (LF) -fed mice. Upregulation of PDK4 and ERRα mRNA and protein levels were seen after the HF diet, and when combined with running even more profound effects on the mRNA expression levels were observed. Chronic HF feeding and voluntary running did not have significant effects on PGC-1α mRNA or protein levels. No remarkable difference was found in the amount or function of mitochondria.ConclusionsOur results support the view that insulin resistance is not mediated by the decreased qualitative or quantitative properties of mitochondria. Instead, the role of PDK4 should be contemplated as a possible contributor to high-fat diet-induced insulin resistance.