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Jeon BT Jeong EA Shin HJ Lee Y Lee DH Kim HJ Kang SS Cho GJ Choi WS Roh GS 《Diabetes》2012,61(6):1444-1454
Obesity-induced diabetes is associated with chronic inflammation and is considered a risk factor for neurodegeneration. We tested the hypothesis that an AMP-activated protein kinase activator, resveratrol (RES), which is known to exert potent anti-inflammatory effects, would attenuate peripheral and central inflammation and improve memory deficit in mice fed a high-fat diet (HFD). C57BL/6J mice were fed an HFD or an HFD supplemented with RES for 20 weeks. Metabolic parameters in serum were evaluated, and Western blot analysis and immunohistochemistry in peripheral organs and brain were completed. We used the Morris water maze test to study the role of RES on memory function in HFD-treated mice. RES treatment reduced hepatic steatosis, macrophage infiltration, and insulin resistance in HFD-fed mice. In the hippocampus of HFD-fed mice, the protein levels of tumor necrosis factor-α and Iba-1 expression were reduced by RES treatment. Choline acetyltransferase was increased, and the phosphorylation of tau was decreased in the hippocampus of HFD-fed mice upon RES treatment. In particular, we found that RES significantly improved memory deficit in HFD-fed mice. These findings indicate that RES reverses obesity-related peripheral and central inflammation and metabolic derangements and improves memory deficit in HFD-fed diabetic mice. 相似文献
3.
Mathur A Al-Azzawi HH Lu D Yancey KW Swartz-Basile DA Nakeeb A Pitt HA 《The Journal of surgical research》2008,147(2):290-297
INTRODUCTION: We have recently demonstrated that obese and lean mice fed a high fat diet have increased gallbladder wall fat and decreased gallbladder contractility, cholecystosteatosis. Animal and human data also suggest that diets high in refined carbohydrates lead to gallstone formation. However, no data are available on the role of dietary carbohydrates on gallbladder wall fat and inflammation. Therefore, we tested the hypothesis that both obesity and dietary carbohydrates would increase gallbladder fat and cytokines, steatocholecystitis. METHODS: At 8 wk of age, 47 lean and 22 obese female mice were fed a 45% carbohydrate (CHO) diet while an equal number of lean and obese mice were fed a 75% CHO diet for 4 wk. All mice underwent cholecystectomy, and the gallbladders were snap-frozen. Individual and total lipids were measured by gas chromatography. Interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha, and IL-6 were measured by enzyme-linked immunosorbent assay. Data were analyzed by analysis of variance and Tukey test. RESULTS: Gallbladder total fat, triglycerides, and cholesterol were maximum (P < 0.001) in obese mice on the 75% CHO diet. Gallbladder TNF-alpha and IL-1beta as well as serum cholesterol levels showed a similar pattern (P < 0.001). Gallbladder saturated free fatty acids and IL-6 levels were highest (P < 0.001) in obese mice on the 45% CHO diet. CONCLUSIONS: These data suggest that (1) both obesity and dietary carbohydrates increase gallbladder total fat, triglycerides, cholesterol, TNF-alpha, and IL-1beta and (2) obesity also increases gallbladder free fatty acids and IL-6. Therefore, we conclude that obesity is associated with steatocholecystitis and that a high carbohydrate diet exacerbates this phenomenon. 相似文献
4.
Abbas Norouzi Javidan Maryam Nazari Zahra Soltani Ramin Heshmat Bagher Larijani 《The journal of spinal cord medicine》2017,40(2):201-212
Objective: The probable effect of dietary amino acids intake pattern on serum lipid profile and blood pressure (BP) have not yet been described among individuals with spinal cord injury (SCI).Design: Cross-sectional.Setting: Tertiary rehabilitation center.Participants: People with SCI referred to Brain and Spinal Cord Injury Research Center between 2011 and 2014.Outcome measures: Dietary intakes were assessed by recording consumed foods by 24-hour dietary recall interviews using Nutritionist IV 3.5.3 modified for Iranian foods. Partial correlation test with adjustment for age, weight, body mass index, total energy intake, total fat, cholesterol and carbohydrate intake, and injury-related variables was used.Results: Dietary intake of lysine was positively related to levels of fasting plasma glucose (FPG), triglyceride (TG), systolic blood pressure (SBP) and diastolic blood pressure (DBP) (P?0.0001, 0.046, 0.002 and 0.009, respectively). There was a positive significant relationship between the intake of cysteine and levels of TG and SBP as well (P : 0.027 and 0.048, respectively). Higher intakes of threonine and leucine had a negative relationship with TG level (P : 0.001 and 0.026, respectively). Furthermore, tyrosine, threonine and leucine were inversely correlated to blood pressure. Total cholesterol level was only related to intake of threonine and leucine (P : 0.004 and 0.012, respectively). FPG was positively associated with intake of all amino acids except for cysteine, glutamic acid, threonine, leucine and histidine.Conclusion: In the present study, the pattern of relationships between dietary intake of amino acids and serum lipid profile and BP has been described among people with SCI. 相似文献
5.
Pasha Apontes Zhongbo Liu Kai Su Outhiriaradjou Benard Dou Y. Youn Xisong Li Wei Li Raihan H. Mirza Claire C. Bastie Linda A. Jelicks Jeffrey E. Pessin Radhika H. Muzumdar Anthony A. Sauve Yuling Chi 《Diabetes》2014,63(11):3626-3636
Excessive dietary fat intake causes systemic metabolic toxicity, manifested in weight gain, hyperglycemia, and insulin resistance. In addition, carbohydrate utilization as a fuel is substantially inhibited. Correction or reversal of these effects during high-fat diet (HFD) intake is of exceptional interest in light of widespread occurrence of diet-associated metabolic disorders in global human populations. Here we report that mangiferin (MGF), a natural compound (the predominant constituent of Mangifera indica extract from the plant that produces mango), protected against HFD-induced weight gain, increased aerobic mitochondrial capacity and thermogenesis, and improved glucose and insulin profiles. To obtain mechanistic insight into the basis for these effects, we determined that mice exposed to an HFD combined with MGF exhibited a substantial shift in respiratory quotient from fatty acid toward carbohydrate utilization. MGF treatment significantly increased glucose oxidation in muscle of HFD-fed mice without changing fatty acid oxidation. These results indicate that MGF redirects fuel utilization toward carbohydrates. In cultured C2C12 myotubes, MGF increased glucose and pyruvate oxidation and ATP production without affecting fatty acid oxidation, confirming in vivo and ex vivo effects. Furthermore, MGF inhibited anaerobic metabolism of pyruvate to lactate but enhanced pyruvate oxidation. A key target of MGF appears to be pyruvate dehydrogenase, determined to be activated by MGF in a variety of assays. These findings underscore the therapeutic potential of activation of carbohydrate utilization in correction of metabolic syndrome and highlight the potential of MGF to serve as a model compound that can elicit fuel-switching effects. 相似文献
6.
Antonio J. Melendez-Martinez Andre F. Nascimento Yan Wang Chun Liu Yilei Mao Xiang-Dong Wang 《肝胆外科与营养》2013,2(4):198-208
Higher intake of tomatoes or tomato-based products has been associated with lower risk for liver cancer. In this study, we investigated the effects of supplementing tomato extract (TE), which contains mainly lycopene (LY) and less amounts of its precursors, phytoene (PT) and phytofluene (PTF) against high-fat-diet related hepatic inflammation and lipid profiles, and carcinogenesis. Four groups of rats were injected with a hepatic carcinogen, diethylnitrosamine (DEN) and then fed either Lieber-DeCarli control diet (35% fat, CD) or high fat diet (71% fat, HFD) with or without TE supplementation for 6 weeks. Results showed that the supplementation of TE significantly decreased the multiplicity of both inflammatory foci and altered hepatic foci (AHF) expressing placental form glutathione-S transferase (p-GST) in the liver of HFD-fed rats. High-performance liquid chromatography (HPLC) analysis showed that TE supplementation results in a significantly higher accumulation of both PT and PTF than LY in livers of rats. In addition, the TE supplementation led to a decrease of plasma cholesterol levels but an overall increase in hepatic lipids which is associated with changes in the genes on lipid metabolism, including the peroxisome proliferator-activated receptor gamma (PPARγ) and the sterol-regulatory element binding protein (SREBP-1). These data suggest that TE supplementation decreases hepatic inflammation and plasma total cholesterol associated with high dietary fat intake. Moreover, TE supplementation results in an accumulation of hepatic PT and PTF as well as increased lipogenesis suggesting further investigation into their biological function(s).Key Words: Hepatic carcinogenesis, inflammation, lycopene (LY), phytoene (PT), phytofluene (PTF) 相似文献
7.
Adaptive response to a low-protein diet in predialysis chronic renal failure patients 总被引:8,自引:0,他引:8
Bernhard J Beaufrère B Laville M Fouque D 《Journal of the American Society of Nephrology : JASN》2001,12(6):1249-1254
Arandomized, controlled study of 12 patients with mild chronic renal failure was designed to assess the metabolic effects of a low-protein diet supplemented (n = 6) or not (n = 6) with ketoanalogs of amino acids. The protein intake was prescribed so that both groups were isonitrogenous. The dietary survey each month included a 3-d food record and a 24-h urine collection for urea measurement. After a 4- to 6-wk equilibrium period (standard occidental diet, 1.11 g of protein and 32 kcal/kg per d), patients reduced their protein intake to reach 0.71 g of protein/kg per d during the third month. Energy intake was kept constant (31 kcal/kg per d) during the 3-mo period. Compliance to the diet was achieved after 2 mo of training. Leucine turnover measurement was performed before and at the end of the 3-mo low-protein period. There was no clinical change, whereas total body flux decreased by 8% (P < 0.05) and leucine oxidation by 18% (P < 0.05). No difference could be attributed to the ketoanalogs themselves. Thus, under sufficient energy intake, a low-protein diet is nutritionally and metabolically safe during chronic renal failure. The nitrogen-sparing effect of a low-protein diet is still present during mild chronic renal insufficiency. 相似文献
8.
Louise Lantier Ashley S. Williams Ian M. Williams Karen K. Yang Deanna P. Bracy Mickael Goelzer Freyja D. James David Gius David H. Wasserman 《Diabetes》2015,64(9):3081-3092
Protein hyperacetylation is associated with glucose intolerance and insulin resistance, suggesting that the enzymes regulating the acetylome play a role in this pathological process. Sirtuin 3 (SIRT3), the primary mitochondrial deacetylase, has been linked to energy homeostasis. Thus, it is hypothesized that the dysregulation of the mitochondrial acetylation state, via genetic deletion of SIRT3, will amplify the deleterious effects of a high-fat diet (HFD). Hyperinsulinemic-euglycemic clamp experiments show, for the first time, that mice lacking SIRT3 exhibit increased insulin resistance due to defects in skeletal muscle glucose uptake. Permeabilized muscle fibers from HFD-fed SIRT3 knockout (KO) mice showed that tricarboxylic acid cycle substrate–based respiration is decreased while fatty acid–based respiration is increased, reflecting a fuel switch from glucose to fatty acids. Consistent with reduced muscle glucose uptake, hexokinase II (HKII) binding to the mitochondria is decreased in muscle from HFD-fed SIRT3 KO mice, suggesting decreased HKII activity. These results show that the absence of SIRT3 in HFD-fed mice causes profound impairments in insulin-stimulated muscle glucose uptake, creating an increased reliance on fatty acids. Insulin action was not impaired in the lean SIRT3 KO mice. This suggests that SIRT3 protects against dietary insulin resistance by facilitating glucose disposal and mitochondrial function. 相似文献
9.
Insulin stimulates both glucose and K(+) uptake, and high-fat feeding is known to decrease insulin-stimulated glucose uptake. The purpose of this study was to examine whether insulin's actions on glucose and K(+) uptake are similarly decreased by a high-fat diet. Wistar rats were fed a standard control (12.2% fat; n = 6) or high-fat (66.5% fat; n = 13) diet for 15 days. Because K(+) content was 1% in the control and 0.5% in the high-fat diet and because the rats ate less of the high-fat diet, we also compared the high-fat diet with 0.5% K(+) (HFD; n = 7) to a high-fat diet supplemented with 1.5% K(+) (HFD+K; n = 6). K(+) intake was matched between the control and HFD+K groups (246 +/- 8 vs. 224 +/- 2 mg/day), but was lower in the HFD group (78 +/- 10 mg/day; P < 0.05). Insulin-stimulated glucose and K(+) uptake were determined by hyperinsulinemic (5 mU.kg(-1).min(-1)) glucose and K(+) clamps. The HFD depressed both insulin-stimulated glucose uptake compared to the control (133 +/- 5 vs. 166 +/- 7 micromol.kg(-1).min(-1); P < 0.05) and K(+) uptake (5.5 +/- 0.9 vs. 8.9 +/- 1.0 micromol.kg(-1).min(-1); P < 0.05) compared to the control. However, insulin-stimulated K(+) uptake was unchanged in the HFD+K versus in the control group (10.0 +/- 0.6 vs. 8.9 +/- 1.0 micromol.kg(-1).min(-1); P > 0.05), whereas insulin-stimulated glucose uptake in the HFD+K group was decreased to a rate (137 +/- 9 micromol.kg(-1).min(-1)), similar to that of the HFD group. We concluded that the decrease in insulin-stimulated K(+) uptake during high-fat feeding was a result of decreased K(+) intake, and that insulin's actions on glucose uptake and K(+) uptake are independently regulated by dietary fat and K(+) content, respectively. 相似文献
10.
Central leptin gene therapy blocks high-fat diet-induced weight gain,hyperleptinemia, and hyperinsulinemia: increase in serum ghrelin levels 总被引:4,自引:0,他引:4
Recombinant adeno-associated virus (rAAV), encoding either rat leptin (rAAV-lep) or green fluorescent protein (rAAV-GFP, control), was injected intracerebroventricularly in rats consuming a high-fat diet (HFD; 45 kcal%). Caloric consumption and body weight were monitored weekly until the rats were killed at 9 weeks. Untreated control rats consuming regular rat diet (RCD; 11 kcal%) were monitored in parallel. Body weight gain was accelerated in rAAV-GFP + HFD control rats relative to those consuming RCD, despite equivalent kcal consumption. At 9 weeks, serum leptin, free fatty acids, triglycerides, and insulin were elevated in HFD control rats. In contrast, rAAV-lep treatment reduced intake and blocked the HFD-induced increase in weight, adiposity, and metabolic variables. Blood glucose was slightly reduced but within the normal range, and serum ghrelin levels were significantly elevated in rAAV-lep + HFD rats. Uncoupling protein-1 (UCP1) mRNA in brown adipose tissue (BAT), an index of energy expenditure through nonshivering thermogenesis, was decreased in rats consuming HFD. Treatment with rAAV-lep significantly augmented BAT UCP1 mRNA expression, indicating increased thermogenic energy expenditure. These findings demonstrate that central leptin gene therapy efficiently prevents weight gain, increased adiposity, and hyperinsulinemia in rats consuming an HFD by decreasing energy intake and increasing thermogenic energy expenditure. 相似文献
11.
Adaptation to low-protein diets in renal failure: leucine turnover and nitrogen balance 总被引:4,自引:0,他引:4
T H Goodship W E Mitch R A Hoerr D A Wagner T I Steinman V R Young 《Journal of the American Society of Nephrology : JASN》1990,1(1):66-75
In normal subjects, short to intermediate responses to dietary protein restriction include decreased amino acid oxidation and protein degradation plus increased utilization of amino acids for protein synthesis; these responses are activated to improve amino acid utilization and nitrogen balance. To assess whether chronic renal failure (CRF) impairs the adaptive responses to a low-protein diet, we measured nitrogen balance and the kinetics of infused L-(15N,1-13C)leucine during fasting and feeding. In six adult CRF and four control (C) subjects, 0.6 (LP) and 1.0 (HP) g protein kg-1 day-1 diets were compared. LP reduced feeding stimulated oxidation of leucine by 26% in CRF and 33% in C (P = NS). During fasting, oxidation was unaffected by diet or CRF. For both groups, feeding suppressed protein degradation to the same extent; leucine incorporation into protein did not change. Nitrogen balance during the two diets was the same with C and CRF, as was protein balance estimated from results of measured leucine kinetics. Thus, patients with CRF can activate appropriate adaptive responses to LP inasmuch as reduced amino acid oxidation occurring with feeding and estimates of protein balance did not differ from control. 相似文献
12.
Adamasco Cupisti Claudia D'Alessandro Lorenzo Ghiadoni Ester Morelli Vincenzo Panichi Giuliano Barsotti 《Journal of renal nutrition》2004,14(1):31-35
OBJECTIVE: The aim of the present study was to evaluate the effect of a soy-protein diet on plasma lipid levels of renal transplant recipients with moderate hypercholesterolemia. DESIGN: Dietary intervention case-control observational study. SETTING: Renal transplantation outpatient clinic. PATIENTS: Fifteen stable patients who had renal transplantation (serum creatinine < 2 mg/dL) with moderate hypercholesterolemia (low-density lipoprotein [LDL] cholesterol > 140 mg/dL). INTERVENTION: After a baseline dietary interview, dietary counseling was given individually with the goal of substituting 25 g of animal protein with 25 g of soy protein for a 5-week period, using commercially available soy foods, according to each patient's own preference.Main outcome measures Before and after the soy-diet period, plasma lipid profiles including total, LDL, and high-density lipoprotein (HDL) cholesterol, triglycerides, apolipoprotein A1 and B were determined. Protein catabolic rate was assumed as a measure of dietary protein intake. RESULTS: Two patients dropped out. After the soy diet, total cholesterol (254 +/- 22 to 231 +/- 31 mg/dL, P <.05) and LDL cholesterol (165 +/- 20 versus 143 +/- 20 mg/dL, P <.01) decreased significantly. No significant changes were observed regarding HDL cholesterol and triglycerides. Dietary protein intake did not differ at baseline (73.2 +/- 22.9 g/day) and during the soy diet (72.6 +/- 15.6 g/day), when the reported actual soy protein intake resulted 26 +/- 8 g/day. CONCLUSIONS: This study shows that soy proteins given as part of the daily protein intake have beneficial effects on serum LDL cholesterol levels of renal transplant recipients with moderate hypercholesterolemia. Soy proteins could be of use in the nutritional management of renal transplant recipients. 相似文献
13.
Graewin SJ Lee KH Tran KQ Goldblatt MI Svatek CL Nakeeb A Pitt HA 《The Journal of surgical research》2004,122(2):145-149
INTRODUCTION: Human obesity is associated with leptin resistance and cholesterol gallstone formation. Previously, we demonstrated that leptin-resistant (Lep(db)) obese mice fed a low cholesterol diet have enlarged gallbladders, but a decreased cholesterol saturation index, despite elevated serum cholesterol. Obese humans, however, consume a high cholesterol diet. Therefore, we hypothesized that on a high cholesterol diet, leptin-resistant mice would have cholesterol saturated bile and would form biliary crystals. METHODS: Eight-week old female lean control (n = 70) and leptin-resistant (n = 72) mice were fed a 1% cholesterol diet for 4 weeks. All animals then had cholecystectomies. Bile was collected, grouped into pools to determine cholesterol saturation index (CSI), and examined for cholesterol crystals. Serum cholesterol and leptin were also measured. RESULTS: Gallbladder volumes for Lep(db) mice were enlarged compared with the lean mice (35.8 microl versus 19.1 microl, P < 0.001), but the CSI for the Lep(db) mice was lower than for the lean animals (0.91 versus 1.15, P < 0.03). The obese animals did not form cholesterol crystals, whereas the lean animals averaged 2.2 crystals per high-powered field (hpf) (P < 0.001). Serum cholesterol and leptin were also elevated (P < 0.001) in the obese animals. CONCLUSIONS: These data suggest that Lep(db) obese mice fed a high cholesterol diet have increased gallbladder volume and decreased biliary cholesterol saturation and crystal formation despite elevated serum cholesterol compared with lean control mice. We conclude that the link among obesity, diet, and gallstone formation may not require hypersecretion of biliary cholesterol and may be related to the effects of diabetes, hyperlipidemia, or both on gallbladder motility. 相似文献
14.
A high-fat diet coordinately downregulates genes required for mitochondrial oxidative phosphorylation in skeletal muscle 总被引:12,自引:0,他引:12
Obesity and type 2 diabetes have been associated with a high-fat diet (HFD) and reduced mitochondrial mass and function. We hypothesized a HFD may affect expression of genes involved in mitochondrial function and biogenesis. To test this hypothesis, we fed 10 insulin-sensitive males an isoenergetic HFD for 3 days with muscle biopsies before and after intervention. Oligonucleotide microarray analysis revealed 297 genes were differentially regulated by the HFD (Bonferonni adjusted P < 0.001). Six genes involved in oxidative phosphorylation (OXPHOS) decreased. Four were members of mitochondrial complex I: NDUFB3, NDUFB5, NDUFS1, and NDUFV1; one was SDHB in complex II and a mitochondrial carrier protein SLC25A12. Peroxisome proliferator-activated receptor gamma coactivator-1 (PGC1) alpha and PGC1beta mRNA were decreased by -20%, P < 0.01, and -25%, P < 0.01, respectively. In a separate experiment, we fed C57Bl/6J mice a HFD for 3 weeks and found that the same OXPHOS and PGC1 mRNAs were downregulated by approximately 90%, cytochrome C and PGC1alpha protein by approximately 40%. Combined, these results suggest a mechanism whereby HFD downregulates genes necessary for OXPHOS and mitochondrial biogenesis. These changes mimic those observed in diabetes and insulin resistance and, if sustained, may result in mitochondrial dysfunction in the prediabetic/insulin-resistant state. 相似文献
15.
Bin Feng Ping Jiao Ynes Helou Yujie Li Qin He Matthew S. Walters Arthur Salomon Haiyan Xu 《Diabetes》2014,63(9):2924-2934
Mitogen-activated protein kinase phosphatase 3 (MKP-3) is a negative regulator of extracellular signal–related kinase signaling. Our laboratory recently demonstrated that MKP-3 plays an important role in obesity-related hyperglycemia by promoting hepatic glucose output. This study shows that MKP-3 deficiency attenuates body weight gain induced by a high-fat diet (HFD) and protects mice from developing obesity-related hepatosteatosis. Triglyceride (TG) contents are dramatically decreased in the liver of MKP-3−/− mice fed an HFD compared with wild-type (WT) controls. The absence of MKP-3 also reduces adiposity, possibly by repressing adipocyte differentiation. In addition, MKP-3−/− mice display increased energy expenditure, enhanced peripheral glucose disposal, and improved systemic insulin sensitivity. We performed global phosphoproteomic studies to search for downstream mediators of MKP-3 action in liver lipid metabolism. Our results revealed that MKP-3 deficiency increases the phosphorylation of histone deacetylase (HDAC) 1 on serine 393 by 3.3-fold and HDAC2 on serine 394 by 2.33-fold. Activities of HDAC1 and 2 are increased in the livers of MKP-3−/− mice fed an HFD. Reduction of HDAC1/2 activities is sufficient to restore TG content of MKP-3−/− primary hepatocytes to a level similar to that in WT cells. 相似文献
16.
Uncoupling protein 2 knockout mice have enhanced insulin secretory capacity after a high-fat diet 总被引:24,自引:0,他引:24
Uncoupling protein 2 (UCP2) may act as an important regulator of insulin secretion. In this study, beta-cell function in UCP2-deficient mice was examined after a 45% high-fat diet (HFD) to assess its role during the development of diet-induced type 2 diabetes. HFD-fed UCP2 (-/-) mice have lower fasting blood glucose and elevated insulin levels when compared with wild-type (WT) mice. UCP2 (-/-) mice also have enhanced beta-cell glucose sensitivity compared with WT mice after HFD, a result that is due in part to the deterioration of glucose responsiveness in WT mice. HFD-fed UCP2 (-/-) mice have increased insulin secretory capacity as a result of increased pancreatic beta-cell mass and insulin content per islet. Islets from WT mice exposed to 0.5 mmol/l palmitate for 48 h have significantly reduced mitochondrial membrane potential, ATP concentrations, and glucose responsiveness compared with UCP2 (-/-) islets, suggesting that elevated UCP2 in WT mice increases proton leak and decreases mitochondrial ATP production. Highly increased carnitine palmitoyl transferase-1 gene expression in UCP2 (-/-) mice is suggestive of enhanced fatty acid oxidizing capacity, particularly after HFD stress. These results further establish UCP2 as a component in glucose sensing and suggest a possible new aspect of UCP2 function during the progression of type 2 diabetes. 相似文献
17.
Partial gene deletion of heart-type fatty acid-binding protein limits the severity of dietary-induced insulin resistance 总被引:1,自引:0,他引:1
The aim of this study was to determine the contribution of heart-type fatty acid-binding protein (H-FABP) to glucose and long-chain fatty acid (LCFA) utilization in dietary-induced insulin resistance. We tested the hypothesis that H-FABP facilitates increases in LCFA flux present in glucose-intolerant states and that a partial reduction in the amount of this protein would compensate for all or part of the impairment. Transgenic H-FABP heterozygotes (HET) and wild-type (WT) littermates were studied following chow diet (CHD) or high-fat diet (HFD) for 12 weeks. Catheters were surgically implanted in the carotid artery and jugular vein for sampling and infusions, respectively. Following 5 days of recovery, mice received either a saline infusion or underwent a euglycemic insulin clamp (4 mU x kg(-1) x min(-1)) for 120 min. At 90 min, a bolus of 2-deoxyglucose and [125I]-15-(rho-iodophenyl)-3-R,S-methylpentadecanoic acid were administered to obtain indexes of glucose and LCFA utilization. At 120 min, skeletal muscles were excised for tracer determination. All HFD mice were obese and hyperinsulinemic; however, only HFD-WT mice were hyperglycemic. Glucose infusion rates during insulin clamps were 49 +/- 4, 59 +/- 4, 16 +/- 4, and 33 +/- 4 mg x kg(-1) x min(-1) for CHD-WT, CHD-HET, HFD-WT, and HFD-HET mice, respectively, showing that HET limited the severity of whole-body insulin resistance with HFD. Insulin-stimulated muscle glucose utilization was attenuated in HFD-WT but unaffected in HFD-HET mice. Conversely, rates of LCFA clearance were increased with HFD feeding in HFD-WT but not in HFD-HET mice. In conclusion, a partial reduction in H-FABP protein normalizes fasting glucose levels and improves whole-body insulin sensitivity in HFD-fed mice despite obesity. 相似文献
18.
《BONE》2014
Adequate protein intake during development is critical to ensure optimal bone gain and to attain a higher peak bone mass later on. We hypothesized that the quality of the dietary protein is of prime importance for bone physiology during moderate protein restriction. The target population was growing Balb/C mice. We compared two protein restricted diets (6% of total energy as protein), one based on soy (LP-SOY) and one based on casein (LP-CAS). For comparison, a normal protein soy-based control group (NP-SOY) and a low protein group receiving an anabolic daily parathyroid hormone (PTH) 1-34 injection (LP-SOY + PTH) were included in the protocol. After 8 weeks, LP-SOY mice had reduced body weights related to a lower lean mass whereas LP-CAS mice were not different from the NP-SOY group. LP-SOY mice were characterized by lower femoral cortical thickness, bone volume, trabecular number and thickness and increased medullar adiposity when compared to both the LP-CAS and NP-SOY groups. However, the dietary intervention had no effect on the vertebral parameters. The negative effect of the LP-SOY diet was correlated to an impaired bone formation as shown by the reduced P1NP serum level as well as the reduced osteoid surfaces and bone formation rate in the femur. PTH injection in LP-SOY mice had no effect on total weight or lean mass, but improved all bone parameters at both femoral and vertebral sites, suggesting that amino acid deficiency was not the primary reason for degraded bone status in mice consuming soy protein. In conclusion, our study showed that under the same protein restriction (6% of energy), a soy diet leads to impaired bone health whereas a casein diet has little effect when compared to a normal protein control. 相似文献
19.
Xiao F Huang Z Li H Yu J Wang C Chen S Meng Q Cheng Y Gao X Li J Liu Y Guo F 《Diabetes》2011,60(3):746-756
OBJECTIVE
We have previously shown that serum insulin levels decrease threefold and blood glucose levels remain normal in mice fed a leucine-deficient diet, suggesting increased insulin sensitivity. The goal of the current study is to investigate this possibility and elucidate the underlying cellular mechanisms.RESEARCH DESIGN AND METHODS
Changes in metabolic parameters and expression of genes and proteins involved in regulation of insulin sensitivity were analyzed in mice, human HepG2 cells, and mouse primary hepatocytes under leucine deprivation.RESULTS
We show that leucine deprivation improves hepatic insulin sensitivity by sequentially activating general control nonderepressible (GCN)2 and decreasing mammalian target of rapamycin/S6K1 signaling. In addition, we show that activation of AMP-activated protein kinase also contributes to leucine deprivation–increased hepatic insulin sensitivity. Finally, we show that leucine deprivation improves insulin sensitivity under insulin-resistant conditions.CONCLUSIONS
This study describes mechanisms underlying increased hepatic insulin sensitivity under leucine deprivation. Furthermore, we demonstrate a novel function for GCN2 in the regulation of insulin sensitivity. These observations provide a rationale for short-term dietary restriction of leucine for the treatment of insulin resistance and associated metabolic diseases.Insulin resistance is a common feature of many metabolic diseases, including type 2 diabetes and nonalcoholic fatty liver diseases. The hallmark of insulin resistance is reduced glucose uptake in muscle and adipose tissue, and increased glucose production in liver (1,2). Various strategies have been proposed to treat insulin resistance, including lifestyle modifications and pharmacologic interventions (3,4).Recently, there has been a growing interest in treating insulin resistance with dietary manipulation of micronutrients, including branched-chain amino acids (BCAAs). The BCAAs comprise the three essential amino acids having nonlinear aliphatic side chains: leucine, isoleucine, and valine. These amino acids not only serve as precursors in protein synthesis but also play regulatory roles in intracellular signaling (5).Several studies have shown that dietary supplementation of leucine influences insulin sensitivity. For example, Zhang and colleagues (6) recently demonstrated that increased oral intake of leucine improves whole-body glucose metabolism in mice maintained on a high-fat diet (HFD). The effect of increasing dietary leucine, however, is controversial. For example, other studies reported that increased serum levels of leucine have no effect (7) or increase insulin resistance in humans and in animal models of obesity (8,9).By contrast, our research has focused on the effect of eliminating leucine from the diet. As shown in our previous study (10), serum insulin levels decrease threefold in mice fed a leucine-deficient [(−) leu] diet. Blood glucose levels remain normal in these mice, however, suggesting increased insulin sensitivity. The goal of our current study is to investigate this possibility and elucidate the underlying molecular and cellular mechanisms.In our current study, we observed that leucine deprivation increases whole-body insulin sensitivity and insulin signaling in liver. Furthermore, we show that leucine deprivation improves hepatic insulin sensitivity by sequentially activating general control nonderepressible (GCN)2 and decreasing mammalian target of rapamycin (mTOR) signaling. In addition, we show that activation of AMP-activated protein kinase (AMPK) also contributes to increased hepatic insulin sensitivity under leucine deprivation. Finally, we show that leucine deprivation improves insulin sensitivity under insulin-resistant conditions. 相似文献20.
Hughes MS Kazmier P Burd TA Anglen J Stoker AM Kuroki K Carson WL Cook JL 《The Journal of bone and joint surgery. American volume》2006,88(11):2386-2394
BACKGROUND: Malnutrition is common in hospitalized injured patients. It contributes to delayed fracture-healing and increased morbidity. However, relatively little attention has been directed toward nutritional strategies for augmenting musculoskeletal recovery after a fracture. This animal study was designed to examine the effects of dietary protein intake and the role of conditionally essential amino acids in muscle and bone-healing after a fracture. METHODS: One hundred adult male rats were used. Ten rats served as controls and received a 15% protein diet throughout the study. The remaining ninety rats received a 6% protein diet for five weeks to induce protein malnutrition. The rats underwent intramedullary nailing and closed midshaft fracture of one femur. After the fracture, they were separated into three isocaloric dietary groups. Group P6 received a diet with 6% protein; Group P15, a diet with 15% protein; and group P30, a diet with 30% protein with conditionally essential amino acids. At two, four, and six weeks after surgery, ten animals from each group were killed and the femora were evaluated with dual x-ray absorptiometry, histomorphometric assessment of callus, and torsional testing. The quadriceps muscles were analyzed for total mass, total protein content, and for mRNA expression of insulin-like growth factor-1 (IGF-1), IGF-2, IGF receptors, actin, myosin, and vascular endothelial growth factor (VEGF). RESULTS: The P30 group demonstrated elevations in albumin, body mass, muscle mass, total protein content of muscle, and bone mineral density in the fracture callus compared with the P6 diet group at six weeks (p < 0.05). Molecular analysis of muscle revealed that IGF-1, IGF-2, IGF receptors, myosin, actin, and VEGF gene expression were significantly (p < 0.001) higher in the P6 group compared with the P30 group. Biomechanical testing of the femora, however, showed no significant differences. CONCLUSIONS: Dietary supplementation with conditionally essential amino acids in malnourished animals had anabolic effects on bone mineralization, body mass, and muscle mass. 相似文献