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Aims: We analyze how the inflammatory state in adipose tissue caused by a condition of chronically positive energy balance can lead to insulin resistance first in adipose tissue, then in all insulin-sensitive tissues.Data synthesis: Chronic nutrient overload causes an increase in adipose depots that, if adipose tissue expandability is tow, are characterized by an increased presence of hypertrophic adipocytes. This adipocyte hypertrophy is a possible stress condition for the endoplasmic reticulum (ER) that would lead to a proinflammatory state in adipose tissue. In this condition, ER stress would activate metabolic pathways that trigger insulin resistance, release of macrophage chemoattractant proteins, and in chronic inflammation, the death of the hypertrophic adipocyte. The infiltrated macrophages in turn release inflammatory proteins causing further recruitment of macrophages to adipose tissue and the release of inflammatory cytokines. Following these events, insulin resistance becomes extended to all adipose tissue. Insulin-resistant adipocytes, characterized by low liposynthetic capacity and high lipolytic capacity, cause increased release of free fatty acids (FFA). FFA released by lipolitic adipocytes may also activate Toll-like receptors 4 and then chemokines and cytokines release amplifying insulin resistance, lipolysis and inflammation in all. adipose tissue. Moreover, increased circulating FFA levels, reduced circulating adiponectin levels and leptin resistance lead to decreased lipid oxidation in non-adipose tissues, thereby triggering ectopic accumulation of lipids, lipotoxicity and insulin resistance.Conclusion: All. the conditions that increase circulating fatty acids and cause lipid overloading (obesity, lipoatrophy, lipodystrophy, catabolic states, etc.) induce a lipotoxic state in non-adipose tissues that gives rise to insulin resistance.

Fatty liver disease is a serious complication of childhood obesity. Calorie-restricted regimen(RCR) is one of the e ective therapy for this condition. Aim of the study was to evaluate the effectof lycopene-rich tomato sauce with oregano and basil extracts in obese children with fatty liver onRCR. 61 obese children with fatty liver were enrolled, 52 completed the study. A randomized crossover clinical trial was performed. Participants were assigned to RCR alone or with a supplement oflycopene-rich tomato juice for 60 days; subsequently, the groups were switched to the alternativeregimen for the next 60 days. Reduction in BMI, HOMA-IR, cholesterol, triglycerides, liver size,and steatosis was more profound in tomato-supplemented group. Leptin decreased in both groupswhereas adiponectin raised only after tomato supplementation. RCR is associated with the impairedengagement of T-cells glycolysis and proliferation, tomato-supplementation resulted in glycolyticmetabolic activation of T-cells. Tomato juice ameliorates glucose and lipid metabolism in obesechildren, improve oxidative and inflammatory state and modulates the mitochondrial metabolismof T-cells contributing to a maintenance of a proper immune surveillance in children, impaired byRCR. The addition of tomato to RCR could be considered a protective and preventive support toobese child. Progetto giovani ricercatori[GR-2016-02363725] dal titolo: "Immune Tolerance, Metabolism and Multiple Sclerosis: Novel Molecular Tools to Monitor Disease Pathogenesis and Progression"

Fatty liver disease is a serious complication of childhood obesity. Calorie-restricted regimen (RCR) is one of the e ective therapy for this condition. Aim of the study was to evaluate the effect of lycopene-rich tomato sauce with oregano and basil extracts in obese children with fatty liver on RCR. 61 obese children with fatty liver were enrolled, 52 completed the study. A randomized cross over clinical trial was performed. Participants were assigned to RCR alone or with a supplement of lycopene-rich tomato juice for 60 days; subsequently, the groups were switched to the alternative regimen for the next 60 days. Reduction in BMI, HOMA-IR, cholesterol, triglycerides, liver size, and steatosis was more profound in tomato-supplemented group. Leptin decreased in both groups whereas adiponectin raised only after tomato supplementation. RCR is associated with the impaired engagement of T-cells glycolysis and proliferation, tomato-supplementation resulted in glycolytic metabolic activation of T-cells. Tomato juice ameliorates glucose and lipid metabolism in obese children, improve oxidative and inflammatory state and modulates the mitochondrial metabolism of T-cells contributing to a maintenance of a proper immune surveillance in children, impaired by RCR. The addition of tomato to RCR could be considered a protective and preventive support to obese child. Progetto giovani ricercatori [GR-2016-02363725] dal titolo: "Immune Tolerance, Metabolism and Multiple Sclerosis: Novel Molecular Tools to Monitor Disease Pathogenesis and Progression"

We studied attention orienting and reaching to remembered spatial locations in a patient (G.P.) with optic ataxia due to bilateral damage to the occipitoparietal areas. G.P. and healthy controls took part in three experiments. In the experiment 1, the participants performed a line bisection task with their right or left hand. The lines were oriented along radial, vertical and horizontal axes. G.P. bisected radial lines farther and vertical lines more above than the controls, consistent with near/lower space neglect and attentional bias toward the far/upper space. The experiment 2 consisted of two tasks: (1) an immediate reaching task, in which G.P. reached target locations under visual control; (2) a delayed visual reaching task, in which G.P. and healthy controls were asked to reach remembered target locations visually presented. Reaching was performed with the right or left hand; both G.P. and healthy controls could foveate target locations. We measured constant and variable distance and direction errors. In immediate reaching task, G.P. accurately reached target locations. In delayed reaching task, G.P. and the healthy participants exhibited an opposite patterns of constant distance errors: G.P. overshot remembered target locations, whereas the controls undershot them. Furthermore, variable errors were greater in G.P. than in the controls. In the experiment 3, G.P. and healthy controls performed a delayed proprioceptive reaching task. In it, participants were asked to reach with their right or left hand remembered target locations proprioceptively presented. Constant errors of G.P. did not differ from those of the controls, whereas variable direction errors were greater in G.P. than in the controls. We suggest that the occipitoparietal damage, and the relatively intact occipitotemporal region, produced in G.P. an attentional orienting bias toward the far/upper space (experiment 1). In turns, the attentional bias selectively shifted forward remembered visual (experiment 2), but not proprioceptive (experiment 3), target locations to-be-reached. Furthermore, the observation that in both delayed reaching tasks the variable errors were greater in G.P. than in the controls suggests that it is possible to detect in optic ataxia not only a visuo- but also a proprioceptivo-motor integration deficit.

The therapeutic approach of multifactorial complex diseases is always a challenge; Parkinson’s disease (PD) is a heterogeneous neurodegenerative disorder triggered by genetic and environmental factors, contributing to its etiology. Indeed, several pathogenic mechanisms lead to selective dopaminergic neuronal injury, including oxidative stress, mitochondrial dysfunction, alteration of endoplasmic reticulum-to-Golgi protein trafficking, excitotoxicity, and neuroinflammation. Current treatment approaches include mainly dopamine replacement therapy or optimizing dopaminergic transmission; however, these strategies that do not counteract the pathogenic mechanisms underlying PD symptoms and often are less effective over time. Recently, there has been growing interest in the therapeutic use of nutraceuticals, that could represent an integrative approach to the pharmacological standard therapy and specifically affect one or more pathogenic pathways. The intake of nutraceuticals or nutritional modifications are generally safe and can be combined with current common drug therapy in most cases to improve the patient’s quality of life and/or mitigate PD symptoms. The current review focuses on several key nutritional compounds and dietary modifications that are effective on several pathogenic pathways involved in PD onset and progression, and further highlights the rationale behind their potential use for the prevention and treatment of PD., Graphical abstract Image 1, Highlights • PD therapy has limited effectiveness acting only on mitigation of symptoms. • PD features include oxidative and ER stress, protein misfolding and inflammation. • Nutraceuticals own neuroprotective effect on PD with converging mechanisms. • Nutraceuticals may represent an adjuvant approach for PD management.

Ursodeoxycholic acid (UDCA) is considered the first-choice therapy for cholestatic disorders. To enhance solubility and exploit specific transporters in liver, we synthesized a new galactosyl pro-drug of UDCA (UDCAgal). Ethinylestradiol (EE)-induced cholestasis was used to study and compare the effects of UDCAgal with UDCA on bile flow, hepatic canalicular efflux transporter expression, and inflammation. UDCAgal resulted quite stable both at pH 7.4 and 1.2 and regenerated the parent drug after incubation in human plasma. Its solubility, higher than UDCA, was pH- and temperature-independent. UDCAgal displayed a higher cell permeation compared to UDCA in liver HepG2 cells. Moreover, in cholestatic rats, UDCAgal showed a higher potency compared to UDCA in reducing serum biomarkers (AST, ALT, and ALP) and cytokines (TNF-α and IL-1β). The higher effect of UDCAgal on the increase in bile salt export pump and multidrug resistance-associated protein 2 transcription indicated an improved spillover of bile acids from the liver. UDCAgal showed a reduction in CCL2, as well as TNF-α, IL-1β, and cyclooxygeanse-2 mRNAs, indicating a reduction in hepatic neutrophil accumulation and inflammation. Moreover, UDCAgal, similarly to UDCA, heightens bile flow and modulates biliary acids secretion. These results indicate that UDCAgal has a potential in the treatment of cholestatic disease.

The potential mechanisms of action of polyphenols in nonalcoholic fatty liver disease (NAFLD) are overlooked. Here, we evaluate the beneficial therapeutic effects of hydroxytyrosol (HT), the major metabolite of the oleuropein, in a nutritional model of insulin resistance (IR) and NAFLD by high-fat diet. Young male rats were divided into three groups receiving (1) standard diet (STD; 10.5% fat), (2) high-fat diet (HFD; 58.0% fat) and (3) HFD+HT (10 mg/kg/day by gavage). After 5 weeks, the oral glucose tolerance test was performed, and at 6th week, blood sample and tissues (liver and duodenum) were collected for following determinations. The HT-treated rats showed a marked reduction in serum AST, ALT and cholesterol and improved glucose tolerance and insulin sensitivity, reducing homeostasis model assessment index. HT significantly corrected the metabolic impairment induced by HFD, increasing hepatic peroxisome proliferator activated receptor PPAR-α and its downstream-regulated gene fibroblast growth factor 21, the phosphorylation of acetyl-CoA carboxylase and the mRNA carnitine palmitoyltransferase 1a. HT also reduced liver inflammation and nitrosative/oxidative stress decreasing the nitrosylation of proteins, reactive oxygen species production and lipid peroxidation. Moreover, HT restored intestinal barrier integrity and functions (fluorescein isothiocyanate-dextran permeability and mRNA zona occludens ZO-1). Our data demonstrate the beneficial effect of HT in the prevention of early inflammatory events responsible for the onset of IR and steatosis, reducing hepatic inflammation and nitrosative/oxidative stress and restoring glucose homeostasis and intestinal barrier integrity.

Different nutritional components are able, by modulating mitochondrial function and gut microbiota composition, to influence body composition, metabolic homeostasis and inflammatory state. In this study, we aimed to evaluate the effects produced by the supplementation of different milks on energy balance, inflammatory state, oxidative stress and antioxidant/detoxifying enzyme activities and to investigate the role of the mitochondrial efficiency and the gut microbiota in the regulation of metabolic functions in an animal model. We compared the intake of human milk, gold standard for infant nutrition, with equicaloric supplementation of donkey milk, the best substitute for newborns due to its nutritional properties, and cow milk, the primary marketed product. The results showed a hypolipidemic effect produced by donkey and human milk intake in parallel with enhanced mitochondrial activity/proton leakage. Reduced mitochondrial energy efficiency and proinflammatory signals (tumor necrosis factor α, interleukin-1 and lipopolysaccharide levels) were associated with a significant increase of antioxidants (total thiols) and detoxifying enzyme activities (glutathione-S-transferase, NADH quinone oxidoreductase) in donkey- and human milk-treated animals. The beneficial effects were attributable, at least in part, to the activation of the nuclear factor erythroid-2-related factor-2 pathway. Moreover, the metabolic benefits induced by human and donkey milk may be related to the modulation of gut microbiota. In fact, milk treatments uniquely affected the proportions of bacterial phyla and genera, and we hypothesized that the increased concentration of fecal butyrate in human and donkey milk-treated rats was related to the improved lipid and glucose metabolism and detoxifying activities.

Fatty liver disease is a serious complication of childhood obesity. Calorie-restricted regimen (RCR) is one of the effective therapy for this condition. Aim of the study was to evaluate the effect of lycopene-rich tomato sauce with oregano and basil extracts in obese children with fatty liver on RCR. 61 obese children with fatty liver were enrolled, 52 completed the study. A randomized cross over clinical trial was performed. Participants were assigned to RCR alone or with a supplement of lycopene-rich tomato juice for 60 days, subsequently, the groups were switched to the alternative regimen for the next 60 days. Reduction in BMI, HOMA-IR, cholesterol, triglycerides, liver size, and steatosis was more profound in tomato-supplemented group. Leptin decreased in both groups whereas adiponectin raised only after tomato supplementation. RCR is associated with the impaired engagement of T-cells glycolysis and proliferation, tomato-supplementation resulted in glycolytic metabolic activation of T-cells. Tomato juice ameliorates glucose and lipid metabolism in obese children, improve oxidative and inflammatory state and modulates the mitochondrial metabolism of T-cells contributing to a maintenance of a proper immune surveillance in children, impaired by RCR. The addition of tomato to RCR could be considered a protective and preventive support to obese child.

The term &ldquo, pain threshold&rdquo, refers to the measurement of the intensity of a physical stimulus that evokes pain. To estimate the pain threshold, a mechanical or electrical stimulus with increasing intensity is usually applied until the subject under evaluation refers to a pain sensation. This study aims to evaluate the autoalgometric pain threshold as a perfect technique to determine the effects of stimulation rate in relation to both gender and the site of stimulation. In this experimental model, pressure algometry was applied: the subject under evaluation pushed a finger against a small round metal tip, producing and at the same time controlling the intensity of the noxious stimulus. Through autoalgometry, the stimulus intensity was recorded over time, measuring the force change rate applied and studying the subject&rsquo, s behavior on approaching pain. This test was performed with 50 healthy volunteers on two days, applying a fast or slow rate of stimulation. The results described demonstrate that there is a positive correlation between the pressure increase rate and the pressure threshold evaluation. In light of these findings, autoalgometry can be proposed as an objective measure of pressure pain threshold for clinical and research use.

Non-dioxin-like (NDL) polychlorinated biphenyls (PCBs) are persistent organic pollutants, associated with a range of adverse health effects, including interference with the immune system. In this study, we investigate the capability of NDL-PCBs 101, 153, and 180, 3 of the 6 NDL-PCBs defined as indicators, to impair the immune response in lipopolysaccharide (LPS)-activated J774A.1 and primary murine macrophages. Our results clearly demonstrate that the exposure of J774A.1 and primary macrophages to NDL-PCB 153 or 180 or all NDL-PCBs mixtures causes a significant reduction in LPS-induced cytokine/chemokine synthesis, such as tumor necrosis factor-α and interleukin-6, together with monocyte chemoattractant protein-1, involved in cell recruitment. Moreover, PCBs were found to suppress LPS-stimulated NO production, and to reduce cyclooxygenase-2 and inducible nitric oxide synthase expression in J774A.1 and primary macrophages. At mechanistic level, PCBs significantly counteract the LPS-driven toll-like receptor (TLR) 4 and CD14 upregulation, therefore inhibiting downstream nuclear factor-κB (NF-κB) activation in J774A.1. Furthermore, PCBs determine a significant loss of macrophage endocytic capacity, a prerequisite for efficient antigen presentation. Taken together, these data indicate that NDL-PCBs reduce macrophage responsiveness, particularly when they are combined at concentrations per se inactive, impairing the capability to orchestrate a proper immune response to an infectious stimulus, disrupting TLR4/NF-κB pathway.

The orexin-A/hypocretin-1 and orexin-B/hypocretin-2 are neuropeptides synthesized by a cluster of neurons in the lateral hypothalamus and perifornical area. Orexin neurons receive a variety of signals related to environmental, physiological and emotional stimuli, and project broadly to the entire CNS. Orexin neurons are “multi-tasking” neurons regulating a set of vital body functions, including sleep/wake states, feeding behavior, energy homeostasis, reward systems, cognition and mood. Furthermore, a dysfunction of orexinergic system may underlie different pathological conditions. A selective loss orexin neurons was found in narcolepsia, supporting the crucial role of orexins in maintaining wakefulness. In animal models, orexin deficiency lead to obesity even if the consume of calories is lower than wildtype counterpart. Reduced physical activity appears the main cause of weight gain in these models resulting in energy imbalance. Orexin signaling promotes obesity resistance via enhanced spontaneous physical activity and energy expenditure regulation and the deficiency/dysfunction in orexins system lead to obesity in animal models despite of lower calories intake than wildtype associated with reduced physical activity. Interestingly, orexinergic neurons show connections to regions involved in cognition and mood regulation, including hippocampus. Orexins enhance hippocampal neurogenesis and improve spatial learning and memory abilities, and mood. Conversely, orexin deficiency results in learning and memory deficits, and depression.

Fatty liver, oxidative stress, and mitochondrial dysfunction are key pathophysiological features of insulin resistance and obesity. Butyrate, produced by fermentation in the large intestine by gut microbiota, and its synthetic derivative, the N-(1-carbamoyl-2-phenyl-ethyl) butyramide, FBA, have been demonstrated to be protective against insulin resistance and fatty liver. Here, hepatic mitochondria were identified as the main target of the beneficial effect of both butyrate-based compounds in reverting insulin resistance and fat accumulation in diet-induced obese mice. In particular, butyrate and FBA improved respiratory capacity and fatty acid oxidation, activated the AMPK–acetyl-CoA carboxylase pathway, and promoted inefficient metabolism, as shown by the increase in proton leak. Both treatments consistently increased utilization of substrates, especially fatty acids, leading to the reduction of intracellular lipid accumulation and oxidative stress. Finally, the shift of the mitochondrial dynamic toward fusion by butyrate and FBA resulted in the improvement not only of mitochondrial cell energy metabolism but also of glucose homeostasis. In conclusion, butyrate and its more palatable synthetic derivative, FBA, modulating mitochondrial function, efficiency, and dynamics, can be considered a new therapeutic strategy to counteract obesity and insulin resistance.

Obesity and dietary fats are well known risk factors for the pathogenesis of neurodegenerative diseases. The analysis of specific markers, whose brain level can be affected by diet, might contribute to unveil the intersection between inflammation/obesity and neurodegeneration. Haptoglobin (Hpt) is an acute phase protein, which acts as antioxidant by binding free haemoglobin (Hb), thus neutralizing its pro-oxidative action. We previously demonstrated that Hpt plays critical functions in brain, modulating cholesterol trafficking in neuroblastoma cell lines, beta-amyloid (Aβ) uptake by astrocyte, and limiting Aβ toxicity on these cells. A major aim of this study was to evaluate whether a long term (12 or 24 weeks) high-fat diet (HFD) influences Hpt and Hb expression in rat hippocampus. We also assessed the development of obesity-induced inflammation by measuring hippocampal level of TNF-alpha, and the extent of protein oxidation by titrating nitro-tyrosine (N-Tyr). Hpt concentration was lower (p < 0.001) in hippocampus of HFD rats than in control animals, both in the 12 and in the 24 weeks fed groups. HFD was also associated in hippocampus with the increase of Hb level (p < 0.01), inflammation and protein oxidative modification, as evidenced by the increase in the concentration of TNF-alpha and nitro-tyrosine. In fact, TNF-alpha concentration was higher in rats receiving HFD for 12 (p < 0.01) or 24 weeks (p < 0.001) compared to those receiving the control diet. N-Tyr concentration was more elevated in hippocampus of HFD than in control rats in both 12 weeks (p = 0.04) and 24 weeks groups (p = 0.01), and a positive correlation between Hb and N-Tyr concentration was found in each group. Finally, we found that the treatment of the human glioblastoma-astrocytoma cell line U-87 MG with cholesterol and fatty acids, such as palmitic and linoleic acid, significantly impairs (p < 0.001) Hpt secretion in the extracellular compartment. We hypothesize that the HFD-dependent decrease of Hpt in hippocampus, as associated with Hb increase, might enhance the oxidative stress induced by free Hb. Altogether our data, identifying Hpt as a molecule modulated in the brain by dietary fats, may represent one of the first steps in the comprehension of the molecular mechanisms underlying the diet-related effects in the nervous system.

An accelerated rate of fat recovery (catch-up fat) and insulin resistance are characteristic features of weight recovery after caloric restriction, with implications for the pathophysiology of catch-up growth and weight fluctuations. Using a previously described rat model of weight recovery in which catch-up fat and skeletal muscle insulin resistance have been linked to suppressed thermogenesis per se, we investigated alterations in mitochondrial energetics and oxidative stress in subsarcolemmal (SS) and intermyofibrillar (IMF) skeletal muscle mitochondria. After 2 weeks of semistarvation followed by 1 week of refeeding, the refed rats show persistent and selective reductions in SS mitochondrial mass (assessed from citrate synthase activity in tissue homogenate and isolated mitochondria) and oxidative capacity. Furthermore, the refed rats show, in both SS and IMF muscle mitochondria, a lower aconitase activity (whose inactivation is an index of increased reactive oxygen species [ROS]), associated with higher superoxide dismutase activity and increased proton leak. Taken together, these studies suggest that diminished skeletal muscle mitochondrial mass and function, specifically in the SS mitochondrial compartment, contribute to the high metabolic efficiency for catch-up fat after caloric restriction and underscore a potential link between diminished skeletal muscle SS mitochondrial energetics, increased ROS concentration, and insulin resistance during catch-up fat.

The effect of treatment with acetyl-L-carnitine on hepatic mitochondrial respiration and biosynthetic function in perfused liver from young (90 days) and old (22-24 months) rats was studied. Rats were given a 1.5% (w/v) solution of acetyl-L-carnitine in their drinking water for 1 month and oxygen consumption together with the rate of gluconeogenesis, urea synthesis, and ketogenesis with and without added substrates were measured in perfused liver. Mitochondrial oxygen consumption was also assessed in liver homogenate and isolated mitochondria to determine the maximal capacity for oxidative phosphorylation. Acetyl-L-carnitine treatment almost completely restored the age-dependent decline in oxygen consumption, gluconeogenesis, urea synthesis, and ketogenesis found in perfused liver of old rats to the levels found in young rats. In addition, acetyl-L-carnitine treatment increased oxygen consumption and biosynthetic function in perfused liver from young rats. After acetyl-L-carnitine treatment, we found detectable 3-oxoacyl-CoA-transferase activity associated with a consumption of ketone bodies in young and old rats. Finally, oxygen consumption measured in homogenate and isolated mitochondria did not change with age and acetyl-L-carnitine treatment. Our results show that in perfused liver, acetyl-L-carnitine treatment slows the age-associated decline in mitochondrial respiration and biosynthetic function. In addition, treatment of young rats with acetyl-L-carnitine has a stimulating effect on liver metabolism, probably through an increase in ATP production.

OBJECTIVE: To study the influence of thyroid hormones on the relationship between serum leptin and fat mass, as well as on energy and macronutrient balance. DESIGN: Rats with different thyroid states were obtained by 7 and 15 days of treatment with the antithyroid drug propylthiouracil or with triiodothyronine (T3). MEASUREMENTS: Energy balance, macronutrient balance and serum leptin concentrations. RESULTS: In hypothyroid rats we found a decrease in metabolizable energy (ME) intake and energy expenditure together with an increase in lipid gain/lipid intake ratio and a decrease in protein gain/protein intake ratio. Consequently, body lipid percentage significantly increased compared to euthyroid rats. Hyperthyroid rats first increased energy expenditure and later ME intake, so that increased metabolism was balanced by increased intake, and energy gain was similar to that found in euthyroid rats. CONCLUSION: These results indicate that T3 plays a major role in the maintenance of energy and lipid balance. Our results also indicate that an inverse relationship exists between T3 and leptin serum concentrations, and that this relationship is not only the result of changes in body fat stores induced by changed T3 concentrations.

cope Virgin olive oil is an essential component of the Mediterranean diet. Its antioxidant and anti-inflammatory properties are mainly linked to phenolic contents. This study aims to evaluate the beneficial effects of a polyphenol-rich virgin olive oil (HPCOO) or olive oil without polyphenols (WPOO) in rats fed high-fat diet (HFD). Methods and results Male Sprague-Dawley rats were divided into four groups based on the different types of diet: (I) standard diet (STD); (II) HFD; (III) HFD containing WPOO, and (IV) HFD containing HPCOO. HPCOO and WPOO induced a significant improvement of HFD-induced impaired glucose homeostasis (by hyperglycemia, altered oral glucose tolerance, and HOMA-IR) and inflammatory status modulating pro- and anti-inflammatory cytokines (TNF-α, IL-1, and IL-10) and adipokines. Moreover, HPCOO and less extensively WPOO, limited HFD-induced liver oxidative and nitrosative stress and increased hepatic fatty acid oxidation. To study mitochondrial performance, oxidative capacity and energy efficiency were also evaluated in isolated liver mitochondria. HPCOO, but not WPOO, reduced H2O2 release and aconitase activity by decreasing degree of coupling, which plays a major role in the control of mitochondrial reactive oxygen species emission. Conclusion HPCOO limits HFD-induced insulin resistance, inflammation, and hepatic oxidative stress, preventing nonalcoholic fatty liver disease progression.

Variations in energy balance, body composition, and nutrient partitioning induced by high-fat feeding, cold exposure or by concomitant high-fat feeding and cold exposure were studied in young Wistar rats. Changes in hepatic metabolism as well as in serum free triiodothyronine and leptin levels were also evaluated. Rats were exposed to either 24 or 4 degrees C and fed either a low- or high-fat diet (10 % or 50 % energy respectively) for 2 weeks. Relative to low-fat feeding at 24 degrees C, both energy intake and expenditure were increased by high-fat feeding or by cold exposure, and these changes were accompanied by increased serum triiodothyronine levels. In response to concomitant high-fat feeding and cold exposure, serum triiodothyronine tended to be further elevated, but no further increases in energy intake or energy expenditure were observed. Independently of diet, the increased energy expenditure in cold-exposed rats was not completely balanced by adaptive hyperphagia, with consequential reductions in protein and fat gain, accompanied by marked decreases in serum leptin. Furthermore, unlike high-fat feeding at 24 degrees C, cold exposure enhanced hepatic mitochondrial oxidative capacity both in the low-fat- and high-fat-fed groups. It is concluded that in this strain of young Wistar rats, despite similarly marked stimulation of energy expenditure by high-fat feeding at 24 degrees C, by cold exposure and by concomitant high-fat feeding and cold exposure, an increased hepatic oxidative capacity occurred only in the presence of the cold stimulus.

In the present study we investigated the changes in hepatic mitochondrial function in the transition from weaning to adulthood in the rat. We measured mitochondrial respiration using FAD- and NAD-linked substrates in 25 and 60 day old rats. The results show that adult rats exhibited significantly higher respiratory rates with all the substrates used except pyruvate. Our results indicate that the transition from weaning to adulthood induces important changes in hepatic mitochondrial function.

We have carried out measurements of energy balance in hypothyroid rats fed a low-fat or a high-fat diet for eighteen days. We have also measured cephalic and processing thermic effect of food (TEF) after a low-fat or a high-fat meal. Body lipid gain, carcass lipid content and gross efficiency were significantly (P < 0·05) higher in hypothyroid rats fed a high-fat diet compared with hypothyroid rats fed a low-fat diet, while metabolizable energy intake and energy expenditure remained unchanged. Cephalic TEF after a low-fat meal was significantly (P < 005) lower in hypothyroid rats fed a high-fat diet compared with hypothyroid rats fed a low-fat diet, while it was significantly (P Our results indicate that hypothyroid rats are unable to develop increased energy expenditure and increased TEF in response to a high-fat diet. European Journal of Endocrinology 136 309–315

Dietary PUFA, mainly those of the n-3 family, are known to play essential roles in the maintenance of energy balance and in the reduction of body fat deposition through the up regulation of mitochondrial uncoupling that is the main source of reactive oxygen species. We hypothesized that rat supplementation with raw donkey's milk (DM), characterized by low-fat content and higher n3:n6 ratio, may affect energy balance, lipid metabolism, and pro oxidant status as compared to animals treated with cow's milk. In the present study, the effects of drinking raw DM (for 4 weeks) on energy balance, lipid metabolism, antiinflammatory, and antioxidant/ detoxifying defences was compared to that produced by rat intake of an iso-energetic amount of raw cow's milk. The hypolipidemic effect produced by DM paralleled with the enhanced mitochondrial activity/proton leakage and with the increased activity or expression of mitochondrial markers namely, carnitine palmitoyl transferase and uncoupling protein 2. The association of decreased energy efficiency with reduced proinflammatory signs (TNF- and LPS levels) with the significant increase antioxidant (total thiols) and detoxifying enzyme activities (glutathione-S-transferase NADH quinone oxidoreductase) in DM-treated animals, indicated that beneficial effects were attributable, at least in part, to the activation of nuclear factor 2 erythroid-related factor 2 pathway.

This study was designed to examine energetic behaviour of skeletal muscle subsarcolemmal and intermyofibrillar mitochondrial populations. The data show that subsarcolemmal mitochondria exhibited a lower degree of coupling and efficiency than intermyofibrillar ones, and can therefore be considered less efficient at producing ATP. In addition, subsarcolemmal mitochondria showed an increased sensitivity to palmitate-induced uncoupling, in line with high adenine nucleotide translocator content and decreased oxidative damage. We then determined the effect of 24 h fasting on energetic characteristics of skeletal muscle mitochondrial populations. We found that fasting enhanced proton leak and decreased the degree of coupling and efficiency, both in the absence and in the presence of palmitate only in subsarcolemmal mitochondria. Moreover, this mitochondrial population showed lower oxidative damage, probably due to a counter-regulatory mechanism mediated by uncoupling protein 3. Subsarcolemmal and intermyofibrillar mitochondria appear to exhibit different energetic characteristics and can be differently affected by physiological stimuli.

This study deals with mitochondrial energy efficiency in liver and skeletal muscle mitochondria in 15 days cold exposed rats. Cold exposure strongly increases the sensitivity to uncoupling by added palmitate of skeletal muscle but not liver mitochondria, while mitochondrial energy coupling in the absence of fatty acids is only slightly affected by cold in liver and skeletal muscle. In addition, uncoupling protein 3 content does not follow changes in skeletal muscle mitochondrial coupling. It is therefore concluded that skeletal muscle could play a direct thermogenic role based on fatty acid-induced mild uncoupling of mitochondrial oxidative phosphorylation.

This study was designed to examine the effect of youth-adulthood transition on hepatic mitochondrial energy efficiency. The changes in basal and palmitate-induced proton leak, which contribute to mitochondrial efficiency, were evaluated in mitochondria isolated from the liver of young and adult rats. Alterations in mitochondrial cytochrome oxidase and aconitase specific activities, and in adenine nucleotide translocator content were also assessed. There was no difference in basal proton leak or thermodynamic coupling and efficiency of oxidative phosphorylation in liver mitochondria between the two rat groups. On the other hand, palmitate-induced proton leak increased significantly in adult rats. The function of this uncoupling could be avoidance of elevated formation of reactive oxygen species, which are known to accelerate ageing.

The changes in metabolic efficiency, body composition, and nutrient partitioning induced by high-fat feeding were evaluated in adult rats (90d of age). The alterations in serum free triiodothyronine, insulin, and leptin levels, as well as in hepatic and skeletal muscle metabolism, were also assessed. Rats were fed either a low- or a high-fat diet for 2 weeks. Relative to the low-fat feeding, energy intake and expenditure, as well as body-energy gain, lipid gain, and energetic efficiency, were increased by the high-fat feeding. Increased serum leptin levels accompanied these variations. A positive correlation between serum leptin levels and percentage of body fat was found in the rats fed the low- or high-fat diet, with a significant divergence between the slope of the regression lines. Furthermore, a negative correlation between serum leptin level and energy intake was found in the rats fed the low-fat diet, while a positive correlation was found in the rats fed the high-fat diet. Finally, the high-fat feeding decreased the hepatic and skeletal muscle mitochondrial oxidative capacity. It is concluded that, in adult rats, a nutritional factor such as a high level of fat in the diet induces obesity, leptin resistance, and impairment of mitochondrial capacity, all phenomena typical of unrestrained aged rats.

The purpose of this study was to investigate the decline in rat liver mitochondria respiration found in adult rats compared to younger ones, and to find a link between this respiratory impairment and a tissue hypothyroidism state. To this end, hepatic concentration and serum levels of triiodothyronine were measured in postpubertal rats (60 days old) and adult rats (180 days old). In addition, in these rats we measured oxidative phosphorylation in homogenate together with coupled and uncoupled respiration in isolated mitochondria using succinate or durohydroquinone as substrate. We found that mitochondria from adult rats consumed less oxygen compared to younger rats due to lower electron transport chain and phosphorylating system activity. In addition, we found that in state 4 condition, mitochondria from adult rats consumed less oxygen than mitochondria from young rats. Finally, we found a decrease in liver triiodothyronine concentration in adult rats. In conclusion, the results of this study show that hepatic mitochondria in adult rats have a decreased ATP synthesis capacity and proton permeability, both consistent with the tissue hypothyroidism found in the liver of adult rats.

The purpose of this work was to study the effect of early long-term high-fat feeding on energy balance and liver oxidative activity. To this end, rats aged about 30 d were fed a high-fat or a low-fat diet for 15, 30 or 60 d. Full energy balance and energy partitioning measurements were carried out. In addition, we measured hepatic mitochondrial and peroxisomal oxidative capacities. Serum levels of free triiodothyronine (T3) and leptin were also determined. Rats fed a high-fat diet showed an increase in metabolizable energy intake as well as in energy expenditure, while lipid gain over the whole period was lower than that expected due to a decrease in metabolic efficiency. An increase in serum free T3levels was also found in rats fed a high-fat diet after 15 and 30 d. Statistically significant correlations between serum leptin levels and body fat mass were found after 15, 30 and 60 d of high-fat feeding. Finally, no variation in hepatic mitochondrial and peroxisomal fatty acid oxidation capacity was found in rats fed a high-fat diet for 15, 30 or 60 d. In conclusion, the results of the present study show that young Wistar rats fed a high-fat diet for up to 60 d are able to counteract, at least in part, obesity development.

OBJECTIVE: To study the effects of fat feeding on fat balance and hepatic mitochondrial function in postpubertal male rats. DESIGN: Rats were fed low fat, medium fat or high fat diet for 15 days. MEASUREMENTS: Energy balance, body composition, resting metabolic rate (RMR), mitochondrial state 3 and state 4 oxygen consumption rates, succinic dehydrogenase (EC 1.3.99.1) and mitochondrial α-glycerophosphate dehydrogenase (EC 1.1.1.8) activities. RESULTS: Rats fed medium fat or high fat diet, in comparison with rats fed low fat diet, showed a significantly greater metabolisable energy intake and energy expenditure. In addition, body energy and lipid gains were significantly higher in rats fed medium fat or high fat diet than in rats fed low fat diet. Mitochondrial respiration and enzymatic activities were not affected by fat feeding. CONCLUSION: These results indicate that in postpubertal rats fed high fat diets, the increase in energy expenditure counteracts only in part the excess fat deposition. This is probably due to the impairment in regulatory responses, and enhances thermogenesis.

Energy intake, utilization, and partitioning were determined in male Wistar rats from 25 to 180 d of age. Serum free triiodothyronine, leptin, and free fatty acid concentrations were also measured. Energy balance measurements allowed us to identify a period from 25 to 90 d, characterized by a rapid body growth rate and another from 90 to 180 d, during which body growth rate slowed. From 25 to 180 d, we found decreases in daily energy intake and expenditure, which were faster before 90 d. The first period was characterized by storage of lipid and protein. In the second period, protein deposition approached zero and the excess of ingested energy was entirely stored as fat, so that age-associated obesity began to develop. The inability of rats to maintain a stable body weight after the cessation of growth of lean body mass is not due to decreased resting metabolism but rather to a partial leptin resistance. J.