Hypercaloric High-fat Diet Research Articles

Activation of hepatic acetyl-CoA carboxylase by S-nitrosylation in response to diet

Nitric oxide (NO), produced primarily by nitric oxide synthase enzymes, is known to influence energy metabolism by stimulating fat uptake and oxidation. The effects of NO on de novo lipogenesis (DNL), however, are less clear. Here we demonstrate that hepatic expression of endothelial nitric oxide synthase is reduced following prolonged administration of a hypercaloric high-fat diet. This results in marked reduction in the amount of S-nitrosylation of liver proteins including notably acetyl-CoA carboxylase (ACC), the rate-limiting enzyme in DNL. We further show that ACC S-nitrosylation markedly increases enzymatic activity. Diminished endothelial nitric oxide synthase expression and ACC S-nitrosylation may thus represent a physiological adaptation to caloric excess by constraining lipogenesis. Our findings demonstrate that S-nitrosylation of liver proteins is subject to dietary control and suggest that DNL is coupled to dietary and metabolic conditions through ACC S-nitrosylation.

A high-fat and fructose diet in dogs mirrors insulin resistance and β-cell dysfunction characteristic of impaired glucose tolerance in humans.

This study examined the impact of a hypercaloric high-fat high-fructose diet (HFFD) in dogs as a potential model for human impaired glucose tolerance (IGT) and type 2 diabetes mellitus (T2DM). The HFFD not only led to weight gain but also triggered metabolic alterations akin to the precursors of human T2DM, notably insulin resistance and β-cell dysfunction. Following the HFFD intervention, the dogs exhibited a 50% decrease in insulin sensitivity within the first four weeks, paralleling observations in the progression from normal to IGT in humans. Calculations of the insulinogenic index using both insulin and C-peptide measurements during oral glucose tolerance tests revealed a significant and sustained decrease in early-phase insulin release, with partial compensation in the later phase, predominantly stemming from reduced hepatic insulin clearance. In addition, the Disposition Index, representing the β-cell's capacity to compensate for diminished insulin sensitivity, fell dramatically. These results confirm that a HFFD can instigate metabolic changes in dogs akin to the early stages of progression to T2DM in humans. The study underscores the potential of using dogs subjected to a HFFD as a model organism for studying human IGT and T2DM.

Preventive effect of Ya'an Tibetan tea on obesity in rats fed with a hypercaloric high-fat diet revealed by gut microbiology and metabolomics studies

Ya'an Tibetan Tea (YATT) is a classic dark tea variety fermented with a unique geographical environment and traditional craftsmanship. Previous research indicates that it is beneficial for obesity and related metabolic disorders, but no systematic research currently reveals its precise mechanisms. This work investigated the preventive effect of YATT on obesity and the corresponding potential mechanisms by performing 16S rRNA gene sequencing and metabolomics studies. Our results demonstrated that YATT could significantly improve the body weight and fat deposition in hypercaloric high-fat diet (HFD)-induced obese rats, enhance antioxidant enzymes activity and reduce inflammation, and reverse the liver damage caused by an HFD. Moreover, 16S rRNA analysis showed that YATT could improve the intestinal microbial disorders caused by the HFD by significantly reversing the increase in Firmicutes/Bacteroidetes（F/B）ratio and the relative abundance of flora associated with the HFD, such as unclassified_Lachnospiraceae and Romboutsia flora. In addition, metabolomic analysis of cecum contents identified 121 differential metabolites, of which 19 were common to all experimental rats fed with and without a high-fat diet. Strikingly, 17 of the most prevalent 19 differential metabolites, including Theobromine, L-Valine, and Diisobutyl phthalate, were considerably reversed by YATT. Enrichment analysis of the metabolic pathways of these differential metabolites indicated that Caffeine metabolism, Phenylalanine metabolism, and Lysine degradation are the potential metabolic pathways responsible for the obesity prevention effect of YATT. Collectively, this work revealed that YATT has good potential for obesity prevention and the improvement of intestinal microbial communities, potentially due to the YATT-induced alterations in the metabolic pathways and functional metabolite levels of caffeine and amino acids. These results inform the material basis of YATT for obesity prevention and its mechanisms and provide essential insights for developing YATT as a healthy beverage for obesity prevention.

The impact of moderate endurance exercise on cardiac telomeres and cardiovascular remodeling in obese rats.

Hypercaloric nutrition and physical inactivity cause obesity, a potential driver of myocardial apoptosis and senescence that may accelerate cardiac aging. Although physical activity reduces mortality, its impact on myocardial aging is insufficiently understood. Here we investigated the effects of a hypercaloric high-fat diet (HFD) and regular exercise training on cardiac cells telomeres and histomorphometric indices of cardiac aging. Ninety-six 4-months old female Sprague-Dawley rats were fed for 10 months normal (ND) or a HFD diet. Half of the animals in each group performed 30 min treadmill-running sessions on 5 consecutive days per week. At study end, cardiomyocyte cross-sectional area (CSA), interstitial collagen content, vascular density, apoptotic and senescent cells, relative telomere length (RTL), and expression of telomerase-reverse transcriptase (Tert) as marker of telomere-related senescence and apoptosis were analyzed. Compared to ND, the HFD group developed obesity, higher CSA, lower capillary density and tended to have more apoptotic cardiomyocytes and interstitials cells. Myocardial RTL and the expression of Terf-1 and Terf-2 were comparable in sedentary HFD and ND animals. In the HFD group, regular moderate endurance exercise improved myocardial vascularization, but had no effect on CSA or apoptosis. Notably, the combination of exercise and HFD increased senescence when compared to sedentary ND or HFD, and reduced RTL when compared to exercise ND animals. Exercising HFD animals also showed a trend toward higher Tert expression compared to all other groups. In addition, exercise reduced Terf-1 expression regardless of diet. HFD-induced obesity showed no effects on myocardial telomeres and induced only mild morphologic alterations. Summarized, long-term moderate endurance exercise partially reverses HFD-induced effects but may even trigger cardiac remodeling in the context of obesity.

Combinations of Tibetan tea and medicine food homology herbs: A new strategy for obesity prevention.

Obesity has become a significant global public health problem. Functional drinks have been an essential direction for obesity prevention research. The present study investigated the preventive effect and safety of winter melon and lotus leaf Tibetan tea (WLTT, a compound tea drink based on Ya'an Tibetan Tea and medicine food homology herbs) on obesity. The rats' hypercaloric high-fat diet (HFD) obesity model was established to evaluate obesity prevention and explored the mechanism through intestinal flora regulation. The results showed that in obese rats with the intervention of WLTT (400, 800, and 1600 mg/kg BW), the body weight, fat accumulation, adipocyte cell size, serum lipid levels, and antioxidant enzyme activity (SOD, GSH-Px, and MDA) were progressively improved. 16S rRNA high-throughput sequencing showed that WLTT could improve intestinal flora disorders due to HFD, which significantly reversed the relative abundance of Firmicutes and the F/B ratio associated with an HFD, and significantly upregulated the relative abundance of Verrucomicrobia. At the genus level, the downregulation of the relative abundance of Akkermansia and unclassified_Lachnospiraceae groups, and the upregulation of the relative abundance of Romboutsia, Ruminococcus, Corynebacteriume, and Saccharibacteria_genera_incertae_sedis groups brought about by the HFD were significantly reversed. The results of the above experiments were compared favorably with those of a parallel experiment with Bi -Sheng -Yuan slimming tea (BSY, a functional drink based on green tea and medicine food homology herbs). Overall, the findings have provided that WLTT can prevent obesity owing to an HFD by regulating intestinal flora and has a good safety profile, and combinations of Tibetan tea and medicine food homology herbs could be a new option for obesity prevention.

Deleterious Effect of High-Fat Diet on Skeletal Muscle Performance Is Prevented by High-Protein Intake in Adult Rats but Not in Old Rats.

The phenotype of sarcopenic obesity is frequently associated with impaired muscle strength and performance. Ectopic lipid deposition may interfere with muscle anabolic response especially during aging. Evidence is scarce concerning the potential interplay among aging and nutrient imbalance on skeletal muscle functionality. The objective of the present study was to investigate the impact of protein intake in the context of an obesogenic diet on skeletal muscle functional properties and intramuscular lipid infiltration. Two groups of forty-two adult and thirty-seven old male Wistar rats were randomly divided into four groups: isocaloric standard diet (12% protein, 14% lipid, as ST12); isocaloric standard (high-protein) diet (25% protein, 14% lipid, ST25); hypercaloric high-fat (normal-protein) diet (12% protein, 45% lipid, HF12); and hypercaloric high-fat (high-protein) diet (25% protein, 45% lipid, HF25). The nutritional intervention lasted 10 weeks. Total body composition was measured through Echo-MRI. Lipids were extracted from tibialis anterior muscle and analyzed by gas-liquid chromatography. The functional properties of the plantarflexor muscles were evaluated in vivo on an isokinetic dynamometer. Maximal torque was assessed from the torque-frequency relationship in isometric condition and maximal power was evaluated from the torque-velocity relationship in concentric condition. In adult rats high-protein intake combined with high-fat diet determined a lower decrease in relative isometric torque, normalized to either FFM or body weight, compared with adult rats fed a high-fat normal-protein diet. High-fat diet was also detrimental to relative muscle power, as normalized to body weight, that decreased to a larger extent in adult rats fed a high-fat normal-protein diet than their counterparts fed a normal-fat, high-protein diet. The effect of high-fat diet observed in adults, with the enhanced protein intake (25%) conferring some kind of protection against the negative effects of HFD, may be linked to the reduced intramuscular fat in this group, which may have contributed to preserve, at least partly, the contractile properties. A potential role for high-protein diet in preventing ectopic lipid deposition needs to be explored in future research. Detrimental effects of high- fat diet on skeletal muscle performance are mitigated by high- protein intake in adult rats but not in old rats.

Modification of a model of non-alcoholic fat liver disease in rats with a сombination of a hypercaloric diet and hypodynamia

Introduction. Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the world, and non-alcoholic steatohepatitis is the second most common cause of liver transplantation in the adult population. An urgent task is to find and develop an optimal model of NAFLD in laboratory animals, which would reproduce all the features of this disease in the clinic.Aim. Modification of the NAFLD model in laboratory animals (rats), which allows the obtained data to be transmitted to humans as fully as possible.Materials and methods. The study was conducted on 52 outbred white male rats of the same age. As the basis of the model, a hypercaloric high-fat diet was used with the addition of food appeal enhancers (sodium glutamate and liquid shrimp extract) and for the first-time conditions of hypodynamia were used – restriction of the motor activity of animals using specially designed cells, in which an individual 11 × 18 cm cell was allocated for each individual. The duration of the study was 12 months. In the course of the experiment, body weight, physical performance, biochemical parameters of blood serum and urine in dynamics were assessed, and lethality was recorded. After the end of the study, the mass of internal organs, visceral and epididymal fat was analyzed, and a histological examination of the liver was performed.Results and discussion. In the course of the experimental study, the development of NAFLD in rats of the control group of animals was histologically confirmed. A high mortality rate was revealed in the group of animals with pathology. Compared with animals of the intact group, a statistically significant increase in their body weight, liver weight, visceral and epididymal fat, a decrease in physical performance, disturbances in lipid, carbohydrate and protein metabolism were revealed, as well as signs of deterioration of the protein synthesis and excretory functions of the liver.Conclusion. A number of advantages of the NAFLD model with a combination of a hypercaloric diet and hypodynamic conditions were revealed, including the similarity of the conditions for the formation and pathogenesis of the disease in experimental animals and humans, which ensures the adequacy of data translation from preclinical practice to clinical practice.

Changes in rat liver fatty acid profile in experimental non-alcoholic steatohepatitis

Introduction. Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the world. Non-alcoholic steatohepatitis (NASH), a clinically progressive morphological form of NAFLD, ranks second in the list of reasons for liver transplantation in the adult population. In the pathogenesis of this disease, metabolism and distribution of free fatty acids (FFA) play an important role. A large number of studies have established that the level of FFA in peripheral blood directly correlates with the severity of NASH, but it is still unclear what effect fluctuations in the profile of fatty acids (FA) in the liver have in steatohepatitis.Aim. Study of changes in the profile of fatty acids in the liver of laboratory animals with experimental non-alcoholic steatohepatitis.Materials and methods. The study was carried out on 17 white outbred male rats, which were randomized into two groups – intact (n = 6) and control (steatohepatitis) (n = 11). Steatohepatitis was modeled by 12-month use of a hypercaloric high-fat diet against the background of hypodynamia. The content of fatty acids in the liver was determined in the reaction of methanolysis and extraction with a hexane mixture of their methyl esters. The LC was separated by gas chromatography-mass spectrometry. Calibration for quantitative calculation was carried out with deuterated tridecanoic acid. The content of saturated and monounsaturated higher FAs, their aldehydes and hydroxy derivatives, as well as sterols were studied.Results and discussion. A total decrease in the content of FFA in the liver of animals with steatohepatitis was revealed. The most significant decrease occurred mainly in the class of monounsaturated fatty acids and cholesterol. Also, a significant decrease in the activity of Δ9-desaturase, a key enzyme in the synthesis of monounsaturated FAs from their precursor with the same carbon chain length, was revealed, which was manifested by a significant decrease in their amount in the liver. There were no statistically significant changes in the levels of aldehydes and hydroxy acids between the study groups, as well as in the level of sterols (except for cholesterol, the content of which decreased significantly).Conclusion. Thus, in the liver of rats with steatohepatitis caused by a combination of a hypercaloric diet and hypodynamia, statistically significant changes in the profile and concentration of fatty acids were found in comparison with healthy animals. The demonstrated shifts in FA composition may reflect both adaptive and pathological changes in the liver of animals with NAFLD and require further study.

Small Amounts of Dietary Medium-Chain Fatty Acids Protect Against Insulin Resistance During Caloric Excess in Humans.

Medium-chain fatty acids (MCFAs) have in rodents been shown to have protective effects on glucose homeostasis during high-fat overfeeding. In this study, we investigated whether dietary MCFAs protect against insulin resistance induced by a hypercaloric high-fat diet in humans. Healthy, lean men ingested a eucaloric control diet and a 3-day hypercaloric high-fat diet (increase of 75% in energy, 81-83% energy [E%] from fat) in randomized order. For one group (n = 8), the high-fat diet was enriched with saturated long-chain FAs (LCSFA-HFD), while the other group (n = 9) ingested a matched diet, but with ∼30 g (5E%) saturated MCFAs (MCSFA-HFD) in substitution for a corresponding fraction of the saturated long-chain fatty acids (LCFAs). A hyperinsulinemic-euglycemic clamp with femoral arteriovenous balance and glucose tracer was applied after the control and hypercaloric diets. In LCSFA-HFD, whole-body insulin sensitivity and peripheral insulin-stimulated glucose disposal were reduced. These impairments were prevented in MCSFA-HFD, accompanied by increased basal fatty acid oxidation, maintained glucose metabolic flexibility, increased nonoxidative glucose disposal related to lower starting glycogen content, and increased glycogen synthase activity, together with increased muscle lactate production. In conclusion, substitution of a small amount of dietary LCFAs with MCFAs rescues insulin action in conditions of lipid-induced energy excess.

MTORC1 and CB1 receptor signaling regulate excitatory glutamatergic inputs onto the hypothalamic paraventricular nucleus in response to energy availability

ObjectiveThe hypothalamic paraventricular nucleus (PVN) is a key target of the melanocortin system, which orchestrates behavioral and metabolic responses depending on energy availability. The mechanistic target of rapamycin complex 1 (mTORC1) and the endocannabinoid type 1 receptor (CB1R) pathways are two key signaling systems involved in the regulation of energy balance whose activity closely depends upon energy availability. Here we tested the hypothesis that modulation of mTORC1 and CB1R signaling regulates excitatory glutamatergic inputs onto the PVN. MethodsPatch-clamp recordings in C57BL/6J mice, in mice lacking the mTORC1 component Rptor or CB1R in pro-opio-melanocortin (POMC) neurons, combined with pharmacology targeting mTORC1, the melanocortin receptor type 4 (MC4R), or the endocannabinoid system under chow or a hypercaloric diet. ResultsAcute pharmacological inhibition of mTORC1 in C57BL/6J mice decreased glutamatergic inputs onto the PVN via a mechanism requiring modulation of MC4R, endocannabinoid 2-AG mobilization by PVN parvocellular neurons, and retrograde activation of presynaptic CB1R. Further electrophysiology studies using mice lacking mTORC1 activity or CB1R in POMC neurons indicated that the observed effects involved mTORC1 and CB1R-dependent regulation of glutamate release from POMC neurons. Finally, energy surfeit caused by hypercaloric high-fat diet feeding, rapidly and time-dependently altered the glutamatergic inputs onto parvocellular neurons and the ability of mTORC1 and CB1R signaling to modulate such excitatory activity. ConclusionsThese findings pinpoint the relationship between mTORC1 and endocannabinoid-CB1R signaling in the regulation of the POMC-mediated glutamatergic inputs onto PVN parvocellular neurons and its rapid alteration in conditions favoring the development of obesity.

LC-MS/MS Analysis and Hepatoprotective Activity of Artichoke (Cynara scolymus L.) Leaves Extract against High Fat Diet-Induced Obesity in Rats.

Cynara scolymus L. (Artichoke) has been used for the treatment of metabolic disorders. The purpose of the present study was to investigate the hepatoprotective effect of Cynara scolymus leaves extract against a high fat diet (HFD) induced rats. This study investigated the most abundant phenolic compounds rich Cynara scolymus leaves extract and it is antihypercholesterolemic and antioxidative effects in vivo. The hypercaloric high fat diet (HFD) was treated with 200 mg/kg and 400 mg/kg of ethanol extract (EEA) from leaves of Cynara and atorvastatin (ATOR) (10 mg/kg/day) during an 8-week period. Lipid profile was measured and oxidative stress systematic in hepatic tissue was determined. Our data revealed that HFD-induced hepatic dysfunction manifested by significant abnormal levels of AST, ALT, ALP, LDH, and OCT was accompanied by increasing levels of oxidative stress biomarker (ROS, MDA, and AOPP) while decreasing in antioxidant status. Coadministration of EEA significantly reduced serum lipid profile and hepatic disorders which was confirmed to be histological by reducing the fatty liver deposition in hepatic lobule. These findings suggest that Cynara leaves exert antiobesity and antioxidant liver effects in HFD-induced obese rats.

Effects of nutritional status on acetaminophen measurement and exposure

Introduction: Fasting, as well as a high-fat diet, might increase the risk on acetaminophen-induced toxicity after an acute overdose. Therefore, it has been suggested to lower the threshold for acetylcysteine treatment to prevent liver injury in case of fasting. This study aims to investigate the effects of 36 hours of fasting and three days of a hypercaloric high-fat diet on acetaminophen measurement and exposure.Methods: Nine healthy male subjects were enrolled in a randomized crossover intervention study. Subjects received 1000mg oral acetaminophen after an overnight fast following: (1) regular diet,(2) 36h of fasting and (3) three days of a hypercaloric high-fat diet consisting of 500ml of cream (1715 kcal) supplemented to their regular diet. Pharmacokinetic parameters were determined by non-compartmental analysis. Samples were analyzed by an enzymatic colorimetric method used in routine practice and by LC-MS/MS being the gold standard. Agreement between these methods was assessed by the Bland–Altman method.Results: Short-term fasting increased acetaminophen exposure by 20% (ΔAUC0-8 hours, p = .04) in comparison with the control diet. Three days of hypercaloric high-fat diet did not affect acetaminophen exposure (ΔAUC0–8 hours= 9%, p = .67). The intraclass correlation coefficient between the enzymatic assay and LC-MS/MS methods of the fasting samples was 0.46 (0.28–0.61), compared to 0.87 (0.81–0.92) and 0.87 (0.79–0.91) in the control and high-fat samples respectively.Conclusions: Short-term fasting increases acetaminophen exposure in healthy subjects, whereas no effect is observed after a high-fat diet. Furthermore, short-term fasting decreases the accuracy of the enzymatic colorimetric method when measuring relatively low acetaminophen concentrations. This suggests considering nutritional status when assessing the risk of acetaminophen-induced toxicity, although further research at toxic doses is needed.

A short-term high fat diet increases exposure to midazolam and omeprazole in healthy subjects

ABSTRACTObjectives: Knowledge of factors contributing to variation in drug metabolism is of vital importance to optimize drug treatment. This study assesses the effects of a short-term hypercaloric high fat diet on metabolism of five oral drugs, which are each specific for a single P450 isoform: midazolam (CYP3A4), omeprazole (CYP2C19), metoprolol (CYP2D6), S-warfarin (CYP2C9) and caffeine (CYP1A2).Methods: In 9 healthy volunteers, pharmacokinetics of the five drugs were assessed after an overnight fast at two separate occasions: after a regular diet and after 3 days of a hypercaloric high fat diet (i.e. regular diet supplemented with 500 mL cream [1715 kcal, 35% fat]). Pharmacokinetic parameters (mean [SEM]) were estimated by non-compartmental analysis.Results: The high fat diet increased exposure to midazolam by 19% from 24.7 (2.6) to 29.5 (3.6) ng ml-1h-1 (p=0.04) and exposure to omeprazole by 31% from 726 (104) to 951 (168) ng ml-1h-1 (p=0.05). Exposure to metoprolol, caffeine and S-warfarin was not affected by the high fat diet.Conclusion: A short-term hypercaloric high fat diet increases exposure to midazolam and omeprazole, possibly reflecting modulation of CYP3A4 and CYP2C19.

Myocardial Structural and Biological Anomalies Induced by High Fat Diet in Psammomys obesus Gerbils.

BackgroundPsammomys obesus gerbils are particularly prone to develop diabetes and obesity after brief period of abundant food intake. A hypercaloric high fat diet has been shown to affect cardiac function. Here, we sought to determine whether a short period of high fat feeding might alter myocardial structure and expression of calcium handling proteins in this particular strain of gerbils.MethodsTwenty Psammomys obesus gerbils were randomly assigned to receive a normal plant diet (controls) or a high fat diet. At baseline and 16-week later, body weight, plasma biochemical parameters (including lipid and carbohydrate levels) were evaluated. Myocardial samples were collected for pathobiological evaluation.ResultsSixteen-week high fat dieting resulted in body weight gain and hyperlipidemia, while levels of carbohydrates remained unchanged. At myocardial level, high fat diet induced structural disorganization, including cardiomyocyte hypertrophy, lipid accumulation, interstitial and perivascular fibrosis and increased number of infiltrating neutrophils. Myocardial expressions of pro-apoptotic Bax-to-Bcl-2 ratio, pro-inflammatory cytokines [interleukin (IL)-1β and tumor necrosis factor (TNF)-α], intercellular (ICAM1) and vascular adhesion molecules (VCAM1) increased, while gene encoding cardiac muscle protein, the alpha myosin heavy polypeptide (MYH6), was downregulated. Myocardial expressions of sarco(endo)plasmic calcium-ATPase (SERCA2) and voltage-dependent calcium channel (Cacna1c) decreased, while protein kinase A (PKA) and calcium-calmodulin-dependent protein kinase (CaMK2D) expressions increased. Myocardial expressions of ryanodine receptor, phospholamban and sodium/calcium exchanger (Slc8a1) did not change.ConclusionsWe conclude that a relative short period of high fat diet in Psammomys obesus results in severe alterations of cardiac structure, activation of inflammatory and apoptotic processes, and altered expression of calcium-cycling determinants.

CB1R antagonist increases hepatic insulin clearance in fat-fed dogs likely via upregulation of liver adiponectin receptors.

The improvement of hepatic insulin sensitivity by the cannabinoid receptor 1 (CB1R) antagonist rimonabant (RIM) has been recently been reported to be due to upregulation of adiponectin. Several studies demonstrated that improvement in insulin clearance accompanies the enhancement of hepatic insulin sensitivity. However, the effects of RIM on hepatic insulin clearance (HIC) have not been fully explored. The aim of this study was to explore the molecular mechanism(s) by which RIM affects HIC, specifically to determine whether upregulation of liver adiponectin receptors (ADRs) and other key genes regulated by adiponectin mediate the effects. To induce insulin resistance in skeletal muscle and liver, dogs were fed a hypercaloric high-fat diet (HFD) for 6 wk. Thereafter, while still maintained on a HFD, animals received RIM (HFD+RIM; n = 11) or placebo (HFD+PL; n = 9) for an additional 16 wk. HIC, calculated as the metabolic clearance rate (MCR), was estimated from the euglycemic-hyperinsulinemic clamp. The HFD+PL group showed a decrease in MCR; in contrast, the HFD+RIM group increased MCR. Consistently, the expression of genes involved in HIC, CEACAM-1 and IDE, as well as gene expression of liver ADRs, were increased in the HFD+RIM group, but not in the HFD+PL group. We also found a positive correlation between CEACAM-1 and the insulin-degrading enzyme IDE with ADRs. Interestingly, expression of liver genes regulated by adiponectin and involved in lipid oxidation were increased in the HFD+RIM group. We conclude that in fat-fed dogs RIM enhances HIC, which appears to be linked to an upregulation of the adiponectin pathway.

Effects Of Training In The Fasted State In Conjunction With Fat-rich diet On Muscle Metabolism

A high turnover rate of intramyocellular lipids (IMCL) is proposed to reduce high-fat diet-induced accumulation of toxic lipid intermediates interfering with insulin action. It has been shown that an acute exercise bout in the fasted state stimulates IMCL breakdown compared with postprandial exercise. PURPOSE: To compare the effect of an exercise training program in the fasted state versus the postprandial state on insulin sensitivity and IMCL content during a period of hypercaloric fat-rich diet, and to explore the underlying cellular mechanisms. METHODS: Moderately active males (18-25y) consumed a hyper-caloric (normal diet +30% kcal/day) high-fat (50%) diet (HFD) during 6 weeks, alone (CON; n=7) or in conjunction with endurance training (1-1.5h @70% VO2max, 4d/week) in either the fasted state (F; n=10) or with carbohydrate intake before and during exercise (CHO; n=10). Needle biopsies were taken from m. vastus lateralis. Glucose tolerance was measured by a 2h oral glucose tolerance test. RESULTS: In CON, body weight on average increased by ∼3kg. This weight gain was largely, if not entirely accounted for by fat accretion as evidenced by the 15% increase in sum of skinfolds, reflecting elevated subcutaneous fat deposit. The HFD-induced increase in body weight and skinfolds was largely negated by training in F (P<0.05).Compared with CON, both glucose tolerance and whole-body insulin sensitivity were improved after training in F (P<0.05), but not in CHO. HFD increased IMCL content to the same degree in all groups in both type I and type IIa fibers. Muscle diacylglycerol, ceramide, and phospholipid content were not significantly different between the groups at any time. The training-induced upregulation (+28%) of muscle GLUT4 content was greater in F than in CHO (P=0.05). Furthermore, compared with CON, the phosphorylated fraction of AMPKa increased by ∼25% in F (P<0.05) but not in CHO. Endoplasmatic reticulum stress occurred only in F, as indicated by elevated protein content of the unfolded protein response markers IRE1a and BiP (P<0.05). CONCLUSION: Exercise training in the fasted state during a period of HFD is more effective than similar training in the carbohydrate-fed state to promote metabolic adaptations in muscles that enhance glucose tolerance and insulin action.

The two-edged sword

The two-edged sword

High protein intake reduces intrahepatocellular lipid deposition in humans

Background:High sugar and fat intakes are known to increase intrahepatocellular lipids (IHCLs) and to cause insulin resistance. High protein intake may facilitate weight loss and improve glucose homeostasis in insulin-resistant patients, but its effects on IHCLs remain unknown.Objective:The aim was to assess the effect of high protein intake on high-fat diet–induced IHCL accumulation and insulin sensitivity in healthy young men.Design:Ten volunteers were studied in a crossover design after 4 d of either a hypercaloric high-fat (HF) diet; a hypercaloric high-fat, high-protein (HFHP) diet; or a control, isocaloric (control) diet. IHCLs were measured by 1H-magnetic resonance spectroscopy, fasting metabolism was measured by indirect calorimetry, insulin sensitivity was measured by hyperinsulinemic-euglycemic clamp, and plasma concentrations were measured by enzyme-linked immunosorbent assay and gas chromatography–mass spectrometry; expression of key lipogenic genes was assessed in subcutaneous adipose tissue biopsy specimens.Results:The HF diet increased IHCLs by 90 ± 26% and plasma tissue-type plasminogen activator inhibitor-1 (tPAI-1) by 54 ± 11% (P< 0.02 for both) and inhibited plasma free fatty acids by 26 ± 11% and β-hydroxybutyrate by 61 ± 27% (P< 0.05 for both). The HFHP diet blunted the increase in IHCLs and normalized plasma β-hydroxybutyrate and tPAI-1 concentrations. Insulin sensitivity was not altered, whereas the expression of sterol regulatory element-binding protein-1c and key lipogenic genes increased with the HF and HFHP diets (P< 0.02). Bile acid concentrations remained unchanged after the HF diet but increased by 50 ± 24% after the HFHP diet (P= 0.14).Conclusions:Protein intake significantly blunts the effects of an HF diet on IHCLs and tPAI-1 through effects presumably exerted at the level of the liver. Protein-induced increases in bile acid concentrations may be involved. This trial was registered at www.clinicaltrials.govas NCT00523562.

Rimonabant prevents additional accumulation of visceral and subcutaneous fat during high-fat feeding in dogs

We investigated whether rimonabant, a type 1 cannabinoid receptor antagonist, reduces visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) in dogs maintained on a hypercaloric high-fat diet (HHFD). To determine whether energy expenditure contributed to body weight changes, we also calculated resting metabolic rate. Twenty male dogs received either rimonabant (1.25 mg.kg(-1).day(-1), orally; n = 11) or placebo (n = 9) for 16 wk, concomitant with a HHFD. VAT, SAT, and nonfat tissue were measured by magnetic resonance imaging. Resting metabolic rate was assessed by indirect calorimetry. By week 16 of treatment, rimonabant dogs lost 2.5% of their body weight (P = 0.029), whereas in placebo dogs body weight increased by 6.2% (P < 0.001). Rimonabant reduced food intake (P = 0.027), concomitant with a reduction of SAT by 19.5% (P < 0.001). In contrast with the VAT increase with placebo (P < 0.01), VAT did not change with rimonabant. Nonfat tissue remained unchanged in both groups. Body weight loss was not associated with either resting metabolic rate (r(2) = 0.24; P = 0.154) or food intake (r(2) = 0.24; P = 0.166). In conclusion, rimonabant reduced body weight together with a reduction in abdominal fat, mainly because of SAT loss. Body weight changes were not associated with either resting metabolic rate or food intake. The findings provide evidence of a peripheral effect of rimonabant to reduce adiposity and body weight, possibly through a direct effect on adipose tissue.

Reduced Access to Insulin-Sensitive Tissues in Dogs With Obesity Secondary to Increased Fat Intake

Physiological hyperinsulinemia provokes hemodynamic actions and augments access of macromolecules to insulin-sensitive tissues. We investigated whether induction of insulin resistance by a hypercaloric high-fat diet has an effect on the extracellular distribution of macromolecules to insulin-sensitive tissues. Male mongrel dogs were randomly selected into two groups: seven dogs were fed an isocaloric control diet ( approximately 3,900 kcal, 35% from fat), and six dogs were fed a hypercaloric high-fat diet ( approximately 5,300 kcal, 54% from fat) for a period of 12 weeks. During hyperinsulinemic-euglycemic clamps, we determined transport parameters and distribution volumes of [(14)C]inulin by applying a three-compartment model to the plasma clearance data of intravenously injected [(14)C]inulin (0.8 microCi/kg). In another study with direct cannulation of the hindlimb skeletal muscle lymphatics, we investigated the effect of physiological hyperinsulinemia on the appearance of intravenously injected [(14)C]inulin in skeletal muscle interstitial fluid and compared the effect of insulin between control and high-fat diet groups. The hypercaloric high-fat diet resulted in significant weight gain (18%; P<0.001) associated with marked increases of subcutaneous (140%; P<0.001) and omental (83%; P<0.001) fat depots, as well as peripheral insulin resistance, measured as a significant reduction of insulin-stimulated glucose uptake during clamps (-35%; P<0.05). Concomitantly, we observed a significant reduction of the peripheral distribution volume of [(14)C]inulin (-26%; P<0.05), whereas the vascular distribution volume and transport and clearance parameters did not change as a cause of the diet. The second study directly confirmed our findings, suggesting a marked reduction of insulin action to stimulate access of macromolecules to insulin-sensitive tissues (control diet 32%, P<0.01; high-fat diet 18%, NS). The present results indicate that access of macromolecules to insulin-sensitive tissues is impaired during diet-induced insulin resistance and suggest that the ability of insulin itself to stimulate tissue access is diminished. We speculate that the observed diet-induced defects in stimulation of tissue perfusion contribute to the development of peripheral insulin resistance.