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International audience; Hormones such as leptin and ghrelin can rapidly rewire hypothalamic feeding circuits when injected into rodent brains. These experimental manipulations suggest that the hypothalamus might reorganize continually in adulthood to integrate the metabolic status of the whole body. In this study, we examined whether hypothalamic plasticity occurs in naive animals according to their nutritional conditions. For this purpose, we fed mice with a short-term high-fat diet (HFD) and assessed brain remodeling through its molecular and functional signature. We found that HFD for 3 d rewired the hypothalamic arcuate nucleus, increasing the anorexigenic tone due to activated pro-opiomelanocortin (POMC) neurons. We identified the polysialic acid molecule (PSA) as a mediator of the diet-induced rewiring of arcuate POMC. Moreover, local pharmacological inhibition and genetic disruption of the PSA signaling limits the behavioral and metabolic adaptation to HFD, as treated mice failed to normalize energy intake and showed increased body weight gain after the HFD challenge. Altogether, these findings reveal the existence of physiological hypothalamic rewiring involved in the homeostatic response to dietary fat. Furthermore, defects in the hypothalamic plasticity-driven adaptive response to HFD are obesogenic and could be involved in the development of metabolic diseases.

International audience; Endoplasmic reticulum (ER) stress is proposed as a novel link between elevated fatty acids levels, obesity and insulin resistance in liver and adipose tissue. However, it is unknown whether ER stress also contributes to lipid-induced insulin resistance in skeletal muscle, the major tissue responsible of insulin-stimulated glucose disposal. Here, we investigated the possible role of ER stress in palmitate-induced alterations of insulin action, both in vivo, in gastrocnemius of high-palm diet fed mice, and in vitro, in palmitate-treated C(2)C(12) myotubes. We demonstrated that 8 weeks of high-palm diet increased the expression of ER stress markers in muscle of mice, whereas ex-vivo insulin-stimulated PKB phosphorylation was not altered in this tissue. In addition, exposure of C(2)C(12) myotubes to either tuncamycine or palmitate induced ER stress and altered insulin-stimulated PKB phosphorylation. However, alleviation of ER stress by either TUDCA or 4-PBA treatments, or by overexpressing Grp78, did not restore palmitate-induced reduction of insulin-stimulated PKB phosphorylation in C(2)C(12) myotubes. This work highlights that, even ER stress is associated with palmitate-induced alterations of insulin signaling, ER stress is likely not the major culprit of this effect in myotubes, suggesting that the previously proposed link between ER stress and insulin resistance is less important in skeletal muscle than in adipose tissue and liver.

This study investigates the effect of various dietary saturated fatty acid (SFA) profiles on plasma lipid parameters and tissue fatty acid composition in rats. The experiment was designed to monitor polyunsaturated fatty acids (PUFA) levels, while examining different amounts and types of SFA. Four isocaloric diets were prepared, containing 10-11 mol% of fatty acids (FA) as linoleic acid (LNA) and 2.5 mol% as α-linolenic acid (ALA), leading to an identical and well-balanced LNA/ALA ratio. The initial rapeseed oil/corn oil mixture providing ALA and LNA was enriched with olive oil to prepare the olive oil diet. The butterfat diet was supplemented with butterfat, containing short-chain SFA (C4:0-C10:0, 17 mol% of FA), lauric acid (C12:0, 3.2 mol%), myristic acid (C14:0, 10.5 mol%) and palmitic acid (C16:0, 14.5 mol%). The saturates diet was supplemented with trilaurin, trimyristin and tripalmitin to obtain the same level of lauric, myristic and palmitic acids as the butterfat diet, without the short-chain SFA. The trimyristin diet was enriched with trimyristin only. The results showed that the butterfat diet contributed to specific effects, compared to the olive oil diet and the saturates and trimyristin diets: a decrease in plasma total, LDL- and HDL-cholesterol, higher tissue storage of ALA and LNA, and a higher level of (n-3) highly unsaturated fatty acids in some tissues. This study supports the hypothesis that in diets with identical well-balanced LNA/ALA ratios, short chain SFA may decrease circulating cholesterol and increase tissue polyunsaturated fatty acid content in the rat.

International audience; The importance of dietary fat in human obesity remains a controversial issue as the prevalence of overweight and obesity has increased despite no dramatic change in the amount of ingested fats over the past few decades. However, qualitative changes (i.e. the fatty acid composition of fats) have been largely disregarded. In this review, we summarize experimental evidence which supports polyunsaturated fatty acids of the omega6 series as being potent promoters of both adipogenesis in vitro and adipose tissue development in vivo during the gestation/lactation period. This conclusion is also supported by epidemiological data from infant studies as well as by the assessment of the fatty acid composition of mature breast milk and formula milk. It is proposed that unnoticed changes in fatty acid composition of ingested fats over the last decades have been important determinants in the increasing prevalence of childhood overweight and obesity.

International audience; Diabetic cardiomyopathy is a secondary complication of diabetes with an unclear etiology. Based on a functional genomic evaluation of obesity-associated cardiac gene expression, we previously identified and cloned the gene encoding apolipoprotein O (APOO), which is overexpressed in hearts from diabetic patients. Here, we generated APOO-Tg mice, transgenic mouse lines that expresses physiological levels of human APOO in heart tissue. APOO-Tg mice fed a high-fat diet exhibited depressed ventricular function with reduced fractional shortening and ejection fraction, and myocardial sections from APOO-Tg mice revealed mitochondrial degenerative changes. In vivo fluorescent labeling and subcellular fractionation revealed that APOO localizes with mitochondria. Furthermore, APOO enhanced mitochondrial uncoupling and respiration, both of which were reduced by deletion of the N-terminus and by targeted knockdown of APOO. Consequently, fatty acid metabolism and ROS production were enhanced, leading to increased AMPK phosphorylation and Ppara and Pgc1a expression. Finally, we demonstrated that the APOO-induced cascade of events generates a mitochondrial metabolic sink whereby accumulation of lipotoxic byproducts leads to lipoapoptosis, loss of cardiac cells, and cardiomyopathy, mimicking the diabetic heart-associated metabolic phenotypes. Our data suggest that APOO represents a link between impaired mitochondrial function and cardiomyopathy onset, and targeting APOO-dependent metabolic remodeling has potential as a strategy to adjust heart metabolism and protect the myocardium from impaired contractility.

This review is respectfully dedicated to the memory of Michel Ollivon, Research Director at CNRS (Châtenay-Malabry, France), outstanding physico-chemist specialist of lipid organization, recipient of the Hilditch Memorial Lecture award, who was the initiator of the network RMT LISTRAL. We are also sadly paying tribute to Jean-Luc Vendeuvre, Food Engineer at the French Pork and Pig Institute (IFIP, Maisons-Alfort, France), outstanding expert in meat products who participated actively in RMT LISTRAL and provided unpublished data for figures in the present review, who passed away during review submission. RMT LISTRAL: Mixed Technological Network combining academic and industrial partners, devoted to the enhancement and divulgation of knowledge regarding structured dietary lipids.; International audience; On a nutritional standpoint, lipids are now being studied beyond their energy content and fatty acid (FA) profiles. Dietary FA are building blocks of a huge diversity of more complex molecules such as triacylglycerols (TAG) and phospholipids (PL), themselves organised in supramolecular structures presenting different thermal behaviours. They are generally embedded in complex food matrixes. Recent reports have revealed that molecular and supramolecular structures of lipids and their liquid or solid state at the body temperature influence both the digestibility and metabolism of dietary FA. The aim of the present review is to highlight recent knowledge on the impact on FA digestion, absorption and metabolism of: (i) the intramolecular structure of TAG; (ii) the nature of the lipid molecules carrying FA; (iii) the supramolecular organization and physical state of lipids in native and formulated food products and (iv) the food matrix. Further work should be accomplished now to obtain a more reliable body of evidence and integrate these data in future dietary recommendations. Additionally, innovative lipid formulations in which the health beneficial effects of either native or recomposed structures of lipids will be taken into account can be foreseen.

International audience; A relationship between orosensory detection of dietary lipids, regulation of fat intake, and body mass index was recently suggested. However, involved mechanisms are poorly understood. Moreover, whether obesity can directly modulate preference for fatty foods remains unknown. To address this question, exploration of the oral lipid sensing system was undertaken in diet-induced obese (DIO) mice. By using a combination of biochemical, physiological, and behavioral approaches, we found that i) the attraction for lipids is decreased in obese mice, ii) this behavioral change has an orosensory origin, iii) it is reversed in calorie-restricted DIO mice, revealing an inverse correlation between fat preference and adipose tissue size, iv) obesity suppresses the lipid-mediated downregulation of the lipid-sensor CD36 in circumvallate papillae, usually found during the refeeding of lean mice, and v) the CD36-dependent signaling cascade controlling the intracellular calcium levels ([Ca(2+)]i) in taste bud cells is decreased in obese mice. Therefore, obesity alters the lipid-sensing system responsible for the oral perception of dietary lipids. This phenomenon seems to take place through a CD36-mediated mechanism, leading to changes in eating behavior.

International audience; A relationship between orosensory detection of dietary lipids, regulation of fat intake, and body mass index was recently suggested. However, involved mechanisms are poorly understood. Moreover, whether obesity can directly modulate preference for fatty foods remains unknown. To address this question, exploration of the oral lipid sensing system was undertaken in diet-induced obese (DIO) mice. By using a combination of biochemical, physiological, and behavioral approaches, we found that i) the attraction for lipids is decreased in obese mice, ii) this behavioral change has an orosensory origin, iii) it is reversed in calorie-restricted DIO mice, revealing an inverse correlation between fat preference and adipose tissue size, iv) obesity suppresses the lipid-mediated downregulation of the lipid-sensor CD36 in circumvallate papillae, usually found during the refeeding of lean mice, and v) the CD36-dependent signaling cascade controlling the intracellular calcium levels ([Ca(2+)]i) in taste bud cells is decreased in obese mice. Therefore, obesity alters the lipid-sensing system responsible for the oral perception of dietary lipids. This phenomenon seems to take place through a CD36-mediated mechanism, leading to changes in eating behavior.

International audience; A relationship between orosensory detection of dietary lipids, regulation of fat intake, and body mass index was recently suggested. However, involved mechanisms are poorly understood. Moreover, whether obesity can directly modulate preference for fatty foods remains unknown. To address this question, exploration of the oral lipid sensing system was undertaken in diet-induced obese (DIO) mice. By using a combination of biochemical, physiological, and behavioral approaches, we found that i) the attraction for lipids is decreased in obese mice, ii) this behavioral change has an orosensory origin, iii) it is reversed in calorie-restricted DIO mice, revealing an inverse correlation between fat preference and adipose tissue size, iv) obesity suppresses the lipid-mediated downregulation of the lipid-sensor CD36 in circumvallate papillae, usually found during the refeeding of lean mice, and v) the CD36-dependent signaling cascade controlling the intracellular calcium levels ([Ca(2+)]i) in taste bud cells is decreased in obese mice. Therefore, obesity alters the lipid-sensing system responsible for the oral perception of dietary lipids. This phenomenon seems to take place through a CD36-mediated mechanism, leading to changes in eating behavior.

International audience; Stimulating conversion of white fat to metabolically active adipocytes (beige fat) constitutes a promising strategy against weight gain and its deleterious associated-disorders. We provide direct evidence that prolactin (PRL), best known for its actions on the mammary gland, plays a pivotal role in energy balance through the control of adipocyte differentiation and fate. Here we show that lack of prolactin receptor (PRLR) causes resistance to high-fat-diet-induced obesity due to enhanced energy expenditure and increased metabolic rate. Mutant mice displayed reduced fat mass associated with appearance of massive brown-like adipocyte foci in perirenal and subcutaneous but not in gonadal fat depots under a high-fat diet. Positron emission tomography imaging further demonstrated the occurrence of these thermogenic brown fat depots in adult mice, providing additional support for recruitable brown-like adipocytes (beigeing) in white fat depots. Consistent with the activation of brown adipose tissue, PRLR inactivation increases expression of master genes controlling brown adipocyte fate (PRDM16) and mitochondrial function (PGC1α, UCP1). Altered pRb/Foxc2 expression suggests that this PRL-regulated pathway may contribute to beige cell commitment. Together, these results provide direct genetic evidence that PRLR affects energy balance and metabolic adaptation in rodents via effects on brown adipose tissue differentiation and function.

International audience; Endoplasmic reticulum (ER) stress is proposed as a novel link between elevated fatty acids levels, obesity and insulin resistance in liver and adipose tissue. However, it is unknown whether ER stress also contributes to lipid-induced insulin resistance in skeletal muscle, the major tissue responsible of insulin-stimulated glucose disposal. Here, we investigated the possible role of ER stress in palmitate-induced alterations of insulin action, both in vivo, in gastrocnemius of high-palm diet fed mice, and in vitro, in palmitate-treated C(2)C(12) myotubes. We demonstrated that 8 weeks of high-palm diet increased the expression of ER stress markers in muscle of mice, whereas ex-vivo insulin-stimulated PKB phosphorylation was not altered in this tissue. In addition, exposure of C(2)C(12) myotubes to either tuncamycine or palmitate induced ER stress and altered insulin-stimulated PKB phosphorylation. However, alleviation of ER stress by either TUDCA or 4-PBA treatments, or by overexpressing Grp78, did not restore palmitate-induced reduction of insulin-stimulated PKB phosphorylation in C(2)C(12) myotubes. This work highlights that, even ER stress is associated with palmitate-induced alterations of insulin signaling, ER stress is likely not the major culprit of this effect in myotubes, suggesting that the previously proposed link between ER stress and insulin resistance is less important in skeletal muscle than in adipose tissue and liver.

International audience; Endoplasmic reticulum (ER) stress is proposed as a novel link between elevated fatty acids levels, obesity and insulin resistance in liver and adipose tissue. However, it is unknown whether ER stress also contributes to lipid-induced insulin resistance in skeletal muscle, the major tissue responsible of insulin-stimulated glucose disposal. Here, we investigated the possible role of ER stress in palmitate-induced alterations of insulin action, both in vivo, in gastrocnemius of high-palm diet fed mice, and in vitro, in palmitate-treated C(2)C(12) myotubes. We demonstrated that 8 weeks of high-palm diet increased the expression of ER stress markers in muscle of mice, whereas ex-vivo insulin-stimulated PKB phosphorylation was not altered in this tissue. In addition, exposure of C(2)C(12) myotubes to either tuncamycine or palmitate induced ER stress and altered insulin-stimulated PKB phosphorylation. However, alleviation of ER stress by either TUDCA or 4-PBA treatments, or by overexpressing Grp78, did not restore palmitate-induced reduction of insulin-stimulated PKB phosphorylation in C(2)C(12) myotubes. This work highlights that, even ER stress is associated with palmitate-induced alterations of insulin signaling, ER stress is likely not the major culprit of this effect in myotubes, suggesting that the previously proposed link between ER stress and insulin resistance is less important in skeletal muscle than in adipose tissue and liver.

International audience; Cardiovascular diseases and cancers are leading causes of morbidity and mortality. Reducing dietary saturated fat and replacing it with polyunsaturated fat is still the main dietary strategy to prevent cardiovascular diseases, although major flaws have been reported in the analyses supporting this approach. Recent studies introducing the concept of myocardial preconditioning have opened new avenues to understand the complex interplay between the various lipids and the risk of cardiovascular diseases. The optimal dietary fat profile includes a low intake of both saturated and omega-6 fatty acids and a moderate intake of omega-3 fatty acids. This profile is quite similar to the Mediterranean diet. On the other hand, recent studies have found a positive association between omega-6 and breast cancer risk. In contrast, omega-3 fatty acids do have anticancer properties. It has been shown that certain (Mediterranean) polyphenols significantly increase the endogenous synthesis of omega-3 whereas high intake of omega-6 decreases it. Finally, epidemiological studies suggest that a high omega-3 to omega-6 ratio may be the optimal strategy to decrease breast cancer risk. Thus, the present high intake of omega-6 in many countries is definitely not the optimal strategy to prevent cardiovascular disease and cancers. A moderate intake of plant and marine omega-3 in the context of the traditional Mediterranean diet (low in saturated and omega-6 fatty acids but high in plant monounsaturated fat) appears to be the best approach to reduce the risk of both cardiovascular diseases and cancers, in particular breast cancer.

WOS: 000285876900007; International audience; Coenzyme Q (CoQ) is not only the single antioxidant synthesized in humans but also an obligatory element of mitochondrial functions. We have previously reported CoQ deficiency in white adipose tissue of ob/ob mice. We sought to determine (i) whether this deficit exists in all species and its relevance in human obesity and (ii) to what extent CoQ could be involved in adipocyte differentiation. Here we identified in rodents as well as in humans a specific very strong nonlinear negative correlation between CoQ content in subcutaneous adipose tissue and obesity indexes. This striking correlation reveals a threshold value similar in both species. This relative deficit in CoQ content in adipose tissue rapidly took place during the time course of high-fat-diet-induced obesity in mice. Adipocyte differentiation was assessed in vitro using the preadipocyte 3T3-F442A cell line. When CoQ synthesis was inhibited by a pharmacological approach using chlorobenzoic acid, this strongly triggered adipose differentiation. In contrast, adipogenesis was strongly inhibited when a long-term increase in CoQ content was obtained by overexpressing human 4-hydroxy benzoate acid polyprenyltransferase gene. Altogether, these data suggest that a strict level of CoQ remains essential for adipocyte differentiation, and its impairment is associated with obesity.

International audience; BACKGROUND & AIMS: A high-fat diet affects liver metabolism, leading to steatosis, a complex disorder related to insulin resistance and mitochondrial alterations. Steatosis is still poorly understood since diverse effects have been reported, depending on the different experimental models used. METHODS: We hereby report the effects of an 8 week high-fat diet on liver energy metabolism in a rat model, investigated in both isolated mitochondria and hepatocytes. RESULTS: Liver mass was unchanged but lipid content and composition were markedly affected. State-3 mitochondrial oxidative phosphorylation was inhibited, contrasting with unaffected cytochrome content. Oxidative phosphorylation stoichiometry was unaffected, as were ATPase and adenine nucleotide translocator proteins and mRNAs. Mitochondrial acylcarnitine-related H(2)O(2) production was substantially higher and the mitochondrial quinone pool was smaller and more reduced. Cellular consequences of these mitochondrial alterations were investigated in perifused, freshly isolated hepatocytes. Ketogenesis and fatty acid-dependent respiration were lower, indicating a lower β-oxidation rate contrasting with higher RNA contents of CD36, FABP, CPT-1, and AcylCoA dehydrogenases. Concomitantly, the cellular redox state was more reduced in the mitochondrial matrix but more oxidized in the cytosol: these opposing changes are in agreement with a significantly higher in situ mitochondrial proton motive force. CONCLUSIONS: A high-fat diet results in both a decrease in mitochondrial quinone pool and a profound modification in mitochondrial lipid composition. These changes appear to play a key role in the resulting inhibition of fatty acid oxidation and of mitochondrial oxidative-phosphorylation associated with an increased mitochondrial ROS production. Mitochondrial quinone pool could have prospects as a crucial event, potentially leading to interesting therapeutic perspectives.

International audience; Low-grade inflammation is a risk factor for the onset of atherosclerosis. Little is known about the involvement of endotoxin absorption from the gut during the digestion of lipids. In the present study, we first investigated in humans the impact of a mixed meal containing dispersed lipids on postprandial endotoxemia and inflammation. We then investigated the effect of (i) oil emulsification in vivo in rats and (ii) fatty acid amounts in vitro using Caco-2 cells on postprandial endotoxemia. In humans, postprandial endotoxemia increased early after the meal. Moreover, we evidenced that the endotoxin receptor sCD14 increased during digestion and that chylomicrons could contribute to absorbed endotoxin transport. This could explain the significant peak of inflammatory cytokine IL-6 that we observed 2 h after the mixed meal. Interestingly, in rats, the emulsion led to both higher endotoxemia and hypertriglyceridemia than oil and compared to a control saline load. In vitro, incubation of Caco-2 cells with increasing fatty acid concentrations enhanced epithelial absorption of endotoxin. To our knowledge, this is the first study evidencing in healthy humans that, following a mixed meal containing lipids, increased endotoxemia is associated with raised sCD14 and a peak of IL-6. On a repeated basis, this may thus be a triggering cascade for the onset of atherosclerosis. In this respect, optimizing both dietary fat amount and structure could be a possible strategy to limit such low-grade endotoxemia and inflammation by the control of postprandial lipemia.

International audience; Metabolic diseases such as obesity are characterized by a subclinical inflammatory state that contributes to the development of insulin resistance and atherosclerosis. Recent reports also indicate that (i) there are alterations of the intestinal microbiota in metabolic diseases and (ii) absorption of endogenous endotoxins (namely lipopolysaccharides, LPS) can occur, particularly during the digestion of lipids. The aim of the present review is to highlight recently gained knowledge regarding the links between high fat diets, lipid digestion, intestinal microbiota and metabolic endotoxemia & inflammation.

WOS:000296521400044; International audience; Fatty-acids (FAs) are required in the diet of many animals throughout their life. However, the mechanisms involved in the perception of and preferences for dietary saturated and unsaturated FAs (SFAs and UFAs, respectively) remain poorly explored, especially in insects. Using the model species Drosophila melanogaster, we measured the responses of wild-type larvae and adults to pure SFAs (14, 16, and 18 carbons) and UFAs (C18 with 1, 2, or 3 double-bonds). Individual and group behavioral tests revealed different preferences in larvae and adults. Larvae preferred UFAs whereas SFAs tended to induce both a strong aversion and a persistent aggregation behavior. Adults generally preferred SFAs, and laid more eggs and had a longer life span when ingesting these substances as compared to UFAs. Our data suggest that insects can discriminate long-chain dietary FAs. The developmental change in preference shown by this species might reflect functional variation in use of FAs or stage-specific nutritional requirements, and may be fundamental for insect use of these major dietary components.

International audience; Low-grade inflammation is a risk factor for the onset of atherosclerosis. Little is known about the involvement of endotoxin absorption from the gut during the digestion of lipids. In the present study, we first investigated in humans the impact of a mixed meal containing dispersed lipids on postprandial endotoxemia and inflammation. We then investigated the effect of (i) oil emulsification in vivo in rats and (ii) fatty acid amounts in vitro using Caco-2 cells on postprandial endotoxemia. In humans, postprandial endotoxemia increased early after the meal. Moreover, we evidenced that the endotoxin receptor sCD14 increased during digestion and that chylomicrons could contribute to absorbed endotoxin transport. This could explain the significant peak of inflammatory cytokine IL-6 that we observed 2 h after the mixed meal. Interestingly, in rats, the emulsion led to both higher endotoxemia and hypertriglyceridemia than oil and compared to a control saline load. In vitro, incubation of Caco-2 cells with increasing fatty acid concentrations enhanced epithelial absorption of endotoxin. To our knowledge, this is the first study evidencing in healthy humans that, following a mixed meal containing lipids, increased endotoxemia is associated with raised sCD14 and a peak of IL-6. On a repeated basis, this may thus be a triggering cascade for the onset of atherosclerosis. In this respect, optimizing both dietary fat amount and structure could be a possible strategy to limit such low-grade endotoxemia and inflammation by the control of postprandial lipemia.

International audience; Gender-based differences in the physiological response to exercise have been studied extensively for the last four decades, and yet the study of post-exercise, gender-specific recovery has only been developing in more recent years. This review of the literature aims to present the current state of knowledge in this field, focusing on some of the most pertinent aspects of physiological recovery in female athletes and how metabolic, thermoregulatory, or inflammation and repair processes may differ from those observed in male athletes. Scientific investigations on the effect of gender on substrate utilization during exercise have yielded conflicting results. Factors contributing to the lack of agreement between studies include differences in subject dietary or training status, exercise intensity or duration, as well as the variations in ovarian hormone concentrations between different menstrual cycle phases in female subjects, as all are known to affect substrate metabolism during sub-maximal exercise. If greater fatty acid mobilization occurs in females during prolonged exercise compared with males, the inverse is observed during the recovery phase. This could explain why, despite mobilizing lipids to a greater extent than males during exercise, females lose less fat mass than their male counterparts over the course of a physical training programme. Where nutritional strategies are concerned, no difference appears between males and females in their capacity to replenish glycogen stores; optimal timing for carbohydrate intake does not differ between genders, and athletes must consume carbohydrates as soon as possible after exercise in order to maximize glycogen store repletion. While lipid intake should be limited in the immediate post-exercise period in order to favour carbohydrate and protein intake, in the scope of the athlete's general diet, lipid intake should be maintained at an adequate level (30%). This is particularly important for females specializing in long-duration events. With protein balance, it has been shown that a negative nitrogen balance is more often observed in female athletes than in male athletes. It is therefore especially important to ensure that this remains the case during periods of caloric restriction, especially when working with female athletes showing a tendency to limit their caloric intake on a daily basis. In the post-exercise period, females display lower thermolytic capacities than males. Therefore, the use of cooling recovery methods following exercise, such as cold water immersion or the use of a cooling vest, appear particularly beneficial for female athletes. In addition, a greater decrease in arterial blood pressure is observed after exercise in females than in males. Given that the return to homeostasis after a brief intense exercise appears linked to maintaining good venous return, it is conceivable that female athletes would find a greater advantage to active recovery modes than males. This article reviews some of the major gender differences in the metabolic, inflammatory and thermoregulatory response to exercise and its subsequent recovery. Particular attention is given to the identification of which recovery strategies may be the most pertinent to the design of training programmes for athletic females, in order to optimize the physiological adaptations sought for improving performance and maintaining health.

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International audience; Docosahexaenoic acid (DHA), upon incorporation into tumor tissue, has the potential to sensitize tumors to the effects of chemotherapy or radiation therapy. Although DHA has usually been supplied to tumor tissue in the diet, appropriate dietary conditions required to obtain optimal tumor levels have not been established. Hence, we studied mammary tumor tissue responses in rats fed various durations and doses of DHA. Rats fed a palm oil enriched diet (diet 0) were switched to diets providing either 0.8 g DHA/day (diet 1) or 1.5 g DHA/day (diet 2). Tumor tissue fatty acid composition was analysed at baseline (diet 0), at weeks 1, 4 and 9 during diet 1 and at week 4 during diet 2. Dietary DHA supplementation differentially increased DHA within phospholipids (PL) and triacylglycerol (TAG) fractions in tumors. DHA level equilibrated between 2 and 4 weeks in PL while DHA increase was more progressive in TAG and did not reach a steady state. A higher dose of DHA further increased DHA content in tumor PL and TAG (P = 0.018 and P < 0.001, respectively). DHA concentration in plasma PL was positively correlated with DHA in tumor PL (r = 0.72; P = 0.0003) and TAG (r = 0.64; P = 0.003). We conclude that dietary DHA supplementation enhances tumor content of DHA in a time- and dose-dependent manner, and that the DHA level in plasma PL could be used as a proxy for tumor DHA. These findings have implications for dietary DHA supplementations in cancer patients.

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International audience; Age-related macular degeneration (AMD) represents the major cause of vision loss in industrialized nations. Laminar deposits in Bruch's membrane (BM) are among the first prominent histopathologic features, along with drusen formation, and have been found to contain oxidized lipids. Increases in concentrations of oxidized LDL (oxLDL) in plasma are observed with age and high fat high (HFHC) cholesterol diet. CD36 is the principal receptor implicated in uptake of oxLDL, and is expressed in the retinal pigment epithelium (RPE). We determined if CD36 participates in oxLDL uptake in RPE and correspondingly in clearance of sub-retinal deposits. Uptake of oxLDL by RPEin vitro and in vivo was CD36-dependent. CD36 deficiency in mice resulted in age-associated accumulation of oxLDL and sub-retinal BM thickening, despite fed a regular diet. Conversely, treatment of HFHC-fed ApoE null mice with a CD36 agonist, EP80317 (300 μg/kg/day), markedly diminished thickening of BM, and partially preserved (in part) photoreceptor function. In conclusion, our data uncover a new role for CD36 in the clearance of oxidized lipids from BM and in the prevention of age-dependent sub-retinal laminar deposits.

International audience; Dietary n-3 polyunsaturated fatty acids (PUFA) reduce coronary heart disease (CHD) complications, such as chronic arrhythmia and sudden cardiac death. Improved myocardial resistance to ischemia-reperfusion injury results in smaller myocardial infarction, which is a major factor in the occurrence of CHD complications. We hypothesized that a specific dietary fatty acid profile (low in saturated and n-6 PUFA but high in plant and marine n-3 PUFA) may improve myocardial resistance to ischemia-reperfusion injury and reduce infarct size. To test this assumption, we used a well-defined rat model of myocardial infarction. Based on our results, in comparison to a diet that is high in either saturated or n-6 PUFA but poor in plant and marine n-3 PUFA, a diet that is low in saturated fats and n-6 PUFA but rich in plant and marine n-3 PUFA results in smaller myocardial infarct size (P < .01). The effects of the 3 diets were also examined by analyzing the fatty acid composition of plasma, erythrocyte cell membranes, and the phospholipids of myocardial mitochondria. The results show a great accumulation of n-3 PUFA and a parallel decrease in arachidonic acid, the main n-6 PUFA, in plasma, cell membranes, and cardiac mitochondria (P < .0001). We conclude that improved myocardial resistance to ischemia-reperfusion may be one of the critical factors explaining the protective effects of dietary n-3 PUFA against CHD complications in humans. In addition to increasing n-3 PUFA intake, an optimal dietary pattern aimed at reducing cardiovascular mortality should include a reduction of the intake of both saturated and n-6 PUFA.

International audience; It has been suggested that high-protein (HP) diets may favor weight management by lowering energy intake and reducing body fat. Whether these effects result from changes in energy metabolism remains unclear. We measured the adaptation of energy metabolism components during 2 wk of HP feeding. Fifty male Wistar rats were switched from a control diet to an HP diet (14 and 55% of protein, respectively) for 1, 3, 6, or 14 d. Energy expenditure (EE) and substrate oxidation were measured by indirect calorimetry in feed-deprived rats and after consumption of a test meal. EE components, including the thermic effect of feeding and activity, were not modified during adaptation to an HP diet. Nutrient oxidation in feed-deprived rats was not affected by HP feeding, except for an early increase in protein oxidation. After 1 d, the postprandial inhibition of lipid oxidation (Lox) was blunted, carbohydrate (CHO) oxidation decreased by one-half, and urea clearance decreased by 66%. Thereafter, CHO oxidation gradually rose, resulting in a null CHO balance. Lox and urea clearance recovered after 3 d of adaptation to an HP diet, while protein oxidation reached a plateau. The postprandial oxidation of CHO counterbalanced the amount of ingested CHO as soon as 3 d, leading to a null postprandial CHO balance. We conclude that the inhibition of de novo lipogenesis from dietary CHO, but not EE and Lox, may participate in limiting the adiposity induced by HP feeding. The transient changes occurring during the period of adaptation to the diet highlight that the duration of the diet is critical in HP diet studies.

International audience; Acute leptin increase as well as endogenous hyperleptinemia evoked by high-fat diets (HF) activate fatty acid metabolism in nonadipose tissues. This supports the notion that hyperleptinemia is pivotal to prevent/delay steatosis during periods of positive energy balance. We have previously shown that long-term HF spares ectopic accumulation of lipids specifically in the miocardium. Because carnitine palmitoyltransferase I (CPT-I) allows mitochondrial uptake/oxidation of fatty acids, we have hypothesized that leptin drives cardiac CPT-I activity. In the current study, hyperleptinemia was induced in C57BL/6J mice either by exogenous leptin administration or by means of HF, and the ability of malonyl-coenzyme A (malonyl-CoA) (the main endogenous inhibitor of CPT-I) to inhibit cardiac CPT was analyzed. IC(50) values of malonyl-CoA were 8.1 +/- 1.5 micromol/liter in controls vs. 69.3 +/- 5.2 micromol/liter (P < 0.01) in leptin-treated mice. This effect was also observed in cardiac explants incubated with leptin and was blocked by triciribine, a compound shown to inhibit protein kinase B (Akt) phosphorylation (pAkt). In accordance, acute leptin evoked an increase of cardiac pAkt levels, which correlated with CPT sensitivity to malonyl-CoA. Otherwise, the inhibitory effect of malonyl-CoA was hindered in HF hyperleptinemic mice, and in this case, pAkt levels also correlated with CPT sensitivity to malonyl-CoA. Our data show that leptin reduces the sensitivity of cardiac CPT-I to malonyl-CoA and suggest the involvement of an Akt-related signaling pathway in this effect. This mechanism appears to be sensitive to both acute and chronic hyperleptinemia. We conclude that this action of leptin is pivotal to drive cardiac metabolism under situations associated to hyperleptinemia.

International audience; BACKGROUND: Transcription factor 7-like 2 (TCF7L2) rs7903146 associates with type 2 diabetes and may operate via impaired glucagon-like peptide 1 secretion, which is stimulated more by fat than by carbohydrate ingestion. OBJECTIVE: The objective was to examine the interaction between TCF7L2 rs7903146 and dietary fat and carbohydrate [high-fat, low-carbohydrate: 40-45% of energy as fat (HF); compared with low-fat, high-carbohydrate: 20-25% of energy as fat (LF)] in obese individuals' responses to a 10-wk hypoenergetic diet (-600 kcal/d). DESIGN: European, obese participants (n = 771) were randomly assigned to receive an HF or an LF diet. Body weight, fat mass (FM), fat-free mass (FFM), waist circumference (WC), resting energy expenditure (REE), fasting fat oxidation in percentage of REE (FatOx), homeostasis model assessed insulin release (HOMA-beta), and HOMA-insulin resistance (HOMA-IR) were determined at baseline and after the intervention; 739 individuals were genotyped for rs7903146. RESULTS: Average weight loss was 6.9 kg with the LF and 6.6 kg with the HF (difference between diets, NS) diet. Among individuals who were homozygous for the T-risk allele, those in the HF diet group experienced smaller weight losses (Deltaweight) (2.6 kg; P = 0.009; n = 622), smaller DeltaFFM (1.6 kg; P = 0.027; n = 609), smaller DeltaWC (3.3 cm; P = 0.010; n = 608), and a smaller DeltaHOMA-IR (1.3 units; P = 0.004; n = 615) than did the LF diet group. For C allele carriers, there were no differences between the HF and LF diet groups. For the HF diet group, each additional T allele was associated with a reduced loss of FM (0.67 kg; P = 0.019; n = 609). TCF7L2 rs7903146 was not associated with DeltaREE, DeltaFatOx, DeltaHOMA-beta, or dropout. CONCLUSION: Our results suggest that obese individuals who are homozygous for the TCF7L2 rs7903146 T-risk allele are more sensitive to LF than to HF weight-loss diets.

International audience; Polyphenols from cinnamon (CN) have been described recently as insulin sensitizers and antioxidants but their effects on the glucose/insulin system in vivo have not been totally investigated. The aim of this study was to determine the effects of CN on insulin resistance and body composition, using an animal model of the metabolic syndrome, the high fat/high fructose (HF/HF) fed rat. Four groups of 22 male Wistar rats were fed for 12 weeks with: (i) (HF/HF) diet to induce insulin resistance, (ii) HF/HF diet containing 20 g cinnamon/kg of diet (HF/HF + CN), (iii) Control diet (C) and (iv) Control diet containing 20 g cinnamon/kg of diet (C + CN). Data from hyperinsulinemic euglycemic clamps showed a significant decrease of the glucose infusion rates in rats fed the HF/HF diet. Addition of cinnamon to the HF/HF diet increased the glucose infusion rates to those of the control rats. The HF/HF diet induced a reduction in pancreas weight which was prevented in HF/HF+CN group (p

Invited Review Article; International audience; Large controlled trials have shown that intake of fish oil (marine n-3 fatty acids, eicosapentaenoic acid, and docosahexaenoic acid), whether from dietary sources or fish oil supplements, may exhibit beneficial effects on total and cardiovascular disease mortality. Stabilization of cell membranes and suppression of cardiac arrhythmias have been identified as possible mechanisms. Moreover, n-3 fatty acids have anti-inflammatory effects, reduce blood pressure, and may also be antiatherogenic. Finally, high doses of n-3 fatty acids can lower elevated serum triglyceride levels. The n-3 index (erythrocyte eicosapentaenoic acid plus docosahexaenoic acid) may be considered as a potential risk marker for coronary heart disease mortality, especially sudden cardiac death. The balance of n-6 to n-3 fatty acids is an important determinant in decreasing the risk for coronary heart disease, both in the primary and in the secondary prevention of coronary heart disease. Patients with known coronary heart disease should be recommended to consume n-3 fatty acid supplements at 1 g per day, without raising concerns for interactions with other medications or side effects. On the other hand, fish in the diet (preferably oily fish, 1-2 meals/week) should be considered as part of a healthy diet low in saturated fat.

International audience; Pancreatic lipase (PL) and pancreatic lipase-related proteins 1 and 2 (PLRP1 and PLRP2) display different functional properties, despite close structures. The aim of the study was to compare the kinetic properties of recombinant human PLRP1, PLRP2, and PL on a physiological substrate: the milk fat under native and homogenized structures. No lipolytic activity is measured for PLRP1. PLRP2 hydrolyses milk fat with a lower catalytic efficiency than that of PL. PLRP2 activity, higher on homogenized than on native milk fat, is differently influenced by fatty acids (FA) and colipase depending on a proteolytic cleavage in the lid domain. FA enhance the activity on both milks. A colipase positive effect on the non-proteolyzed PLRP2 is observed on homogenized milk and with FA on native milk fat. Bile salts are necessary. An original observation is a synergic effect between PL and PLRP2 on the two milks. An inhibitory effect of PLRP1 on PL activity is also demonstrated. The combined action of pancreatic lipases on milk fat digestion proposes PLRPs as modulators of PL. Our study supports the hypothesis of a major role of PLRP2 in fat digestion in newborns and brings new insights to understand the physiological role of PLRPs.

International audience; This study investigated the extent to which the increase in torpor expression in the grey mouse lemur, due to graded food restriction, is modulated by a trade-off between a whole body sparing of polyunsaturated dietary fatty acids and the related oxidative stress generated during daily torpor. We measured changes in torpor frequency, total energy expenditure (TEE), linoleate (polyunsaturated fatty acid) and palmitate (saturated fatty acid) oxidation, hexanoyl-lysine (HEL; the product of linoleate peroxidation), and 8-hydroxydeoxyguanosine (8OHdG; a marker of DNA damage). Animals under summer-acclimated long days (LD) or winter-acclimated short days (SD) were exposed to a 40% (LD40 and SD40) and 80% (LD80 and SD80) 35-day calorie restriction (CR). During CR, all groups reduced their body mass, but LD80 animals reached survival-threatened levels at day 22 and were then excluded from the CR trial. Only SD mouse lemurs increased their torpor frequency with CR and displayed a decrease in their TEE adjusted for fat-free mass. After CR, SD40 mouse lemurs shifted the dietary fatty acid oxidation toward palmitate and spared linoleate. Such a shift was not observed in LD animals and during severe CR, during which oxidation of both dietary fatty acids was increased. Concomitantly, HEL increased in both LD40 and SD80 groups, whereas DNA damage was only seen in SD80 food-restricted animals. HEL correlated positively with linoleate oxidation confirming in vivo the substrate/product relationship demonstrated in vitro, and negatively with TEE adjusted for fat-free mass, suggesting higher oxidative stress associated with increased torpor expression. This suggests a seasonal-dependant, cost-benefit trade-off between maximizing torpor propensity and minimizing oxidative stress that is associated with a shift toward sparing of dietary polyunsaturated fatty acids that is dependent upon the expression of a winter phenotype.

International audience; Diet is an important environmental factor modulating the onset of atherosclerosis. The aim of this study was to evaluate the effects of different dairy-based food products on early atherogenesis using both conventional and metabonomic approaches in hyperlipidemic hamsters. The hamsters received up to 200 g/kg of fat as anhydrous butter or cheese made from various milk fats or canola-based oil (CV), in addition to a non-atherogenic low-fat diet. Aortic cholesteryl ester loading was considered to be an early atherogenic point, and metabolic changes linked to atherogenesis were measured using plasma (1)H NMR-based metabonomics. The lowest atherogenicity was obtained with the plant-oil cheese diet, followed by the dairy fat cheese diet, while the greatest atherogenicity was observed with the butter diet (P

International audience; Although corroborating data indicate that estrogens influence glucose metabolism through the activation of the estrogen receptor alpha (ERalpha), it has not been established whether this pathway could represent an effective therapeutic target to fight against metabolic disturbances induced by a high-fat diet (HFD). To this end, we first evaluated the influence of chronic 17beta-estradiol (E2) administration in wild-type ovariectomized mice submitted to either a normal chow diet or a HFD. Whereas only a modest effect was observed in normal chow diet-fed mice, E2 administration exerted a protective effect against HFD-induced glucose intolerance, and this beneficial action was abolished in ERalpha-deficient mice. Furthermore, E2 treatment reduced HFD-induced insulin resistance by 50% during hyperinsulinemic euglycemic clamp studies and improved insulin signaling (Akt phosphorylation) in insulin-stimulated skeletal muscles. Unexpectedly, we found that E2 treatment enhanced cytokine (IL-6, TNF-alpha) and plasminogen activator inhibitor-1 mRNA expression induced by HFD in the liver and visceral adipose tissue. Interestingly, although the proinflammatory effect of E2 was abolished in visceral adipose tissue from chimeric mice grafted with bone marrow cells from ERalpha-deficient mice, the beneficial effect of the hormone on glucose tolerance was not altered, suggesting that the metabolic and inflammatory effects of estrogens can be dissociated. Eventually comparison of sham-operated with ovariectomized HFD-fed mice demonstrated that endogenous estrogens levels are sufficient to exert a full protective effect against insulin resistance and glucose intolerance. In conclusion, the regulation of the ERalpha pathway could represent an effective strategy to reduce the impact of high-fat diet-induced type 2 diabetes.

Myristic acid is a 14 carbon saturated fatty acid, which is mostly found in milk fat. In industrialized countries, its excessive consumption is correlated with an increase in plasma cholesterol and mortality due to cardiovascular diseases. Nevertheless, one feature of this fatty acid is its ability to acylate proteins, a reaction which is called N-terminal myristoylation. This article describes various examples of important cellular regulations where the intervention of myristic acid is proven. Modulations of the cellular concentration of this fatty acid and its associated myristoylation function might be used as regulators of these metabolic pathways.

International audience; Glucagon-like peptide-1 (GLP-1) is a peptide released by the intestine and the brain. We previously demonstrated that brain GLP-1 increases glucose-dependent hyperinsulinemia and insulin resistance. These two features are major characteristics of the onset of type 2 diabetes. Therefore, we investigated whether blocking brain GLP-1 signaling would prevent high-fat diet (HFD)-induced diabetes in the mouse. Our data show that a 1-month chronic blockage of brain GLP-1 signaling by exendin-9 (Ex9), totally prevented hyperinsulinemia and insulin resistance in HFD mice. Furthermore, food intake was dramatically increased, but body weight gain was unchanged, showing that brain GLP-1 controlled energy expenditure. Thermogenesis, glucose utilization, oxygen consumption, carbon dioxide production, muscle glycolytic respiratory index, UCP2 expression in muscle, and basal ambulatory activity were all increased by the exendin-9 treatment. Thus, we have demonstrated that in response to a HFD, brain GLP-1 signaling induces hyperinsulinemia and insulin resistance and decreases energy expenditure by reducing metabolic thermogenesis and ambulatory activity.

International audience; OBJECTIVE: The first objective was to evaluate the influence of caloric intake on liver mitochondrial properties. The second objective was aimed at determining the impact of increasing fat intake on these properties. DESIGN: Lou/C rats, displaying an inborn low caloric intake and resistant to diet-induced obesity, were compared to Wistar rats fed either ad libitum or pair-fed. An additional group of Lou/C rats were allowed to increase their fat intake by adjusting their diet from a standard high carbohydrate low-fat diet to a high-fat carbohydrate-free diet. MEASUREMENTS: Hydrogen peroxide (H(2)O(2)) generation, oxygen consumption rate (J(O(2))), membrane potential (DeltaPsi), activity of respiratory chain complexes, cytochrome contents, oxidative phosphorylation efficiency (OPE) and uncoupling protein 2 (UCP2) expression were determined in liver mitochondria. RESULTS: H(2)O(2) production was higher in Lou/C than Wistar rats with glutamate/malate and/or succinate, octanoyl-carnitine, as substrates. These mitochondrial features cannot be mimicked by pair-feeding Wistar rats and remained unaltered by increasing fat intake. Enhanced H(2)O(2) production by mitochondria from Lou/C rats is due to an increased reverse electron flow through the respiratory-chain complex I and a higher medium-chain acyl-CoA dehydrogenase activity. While J(O(2)) was similar over a large range of DeltaPsi in both strains, Lou/C rats were able to sustain higher membrane potential and respiratory rate. In addition, mitochondria from Lou/C rats displayed a decrease in OPE that cannot be explained by increased expression of UCP2 but rather to a slip in proton pumping by cytochrome oxidase. CONCLUSIONS: Liver mitochondria from Lou/C rats display higher reactive oxygen species (ROS) generation but to deplete upstream electron-rich intermediates responsible for ROS generation, these animals increased intrinsic uncoupling of cytochrome oxidase. It is likely that liver mitochondrial properties allowed this strain of rat to display higher insulin sensitivity and resist diet-induced obesity.

OBJECTIVE-Kinins mediate pathophysiological processes related to hypertension, pain, and inflammation through the activation of two G-protein-coupled receptors, named B(1) and B(2). Although these peptides have been related to glucose homeostasis, their effects on energy balance are still unknown.RESEARCH DESIGN and METHODS-Using genetic and pharmacological strategies to abrogate the kinin B(1) receptor in different animal models of obesity, here we present evidence of a novel role for kinins in the regulation of satiety and adiposity.RESULTS-Kinin B(1) receptor deficiency in mice (B(1)(-/-)) resulted in less fat content, hypoleptinemia, increased leptin sensitivity, and robust protection against high-fat diet-induced weight gain. Under high-fat diet, B(1)(-/-) also exhibited reduced food intake, improved lipid oxidation, and increased energy expenditure. Surprisingly, B(1) receptor deficiency was not able to decrease food intake and adiposity in obese mice lacking leptin (ob/ob-B(1)(-/-)). However, ob/ob-B(1)(-/-) mice were more responsive to the effects of exogenous leptin on body weight and food intake, suggesting that B(1) receptors may be dependent on leptin to display their metabolic roles. Finally, inhibition of weight gain and food intake by B(1) receptor ablation was pharmacologically confirmed by long-term administration of the kinin B(1) receptor antagonist SSR240612 to mice under high-fat diet.CONCLUSIONS-Our data suggest that kinin B(1) receptors participate in the regulation of the energy balance via a mechanism that could involve the modulation of leptin sensitivity. Universidade Federal de São Paulo, Dept Biophys, BR-04023062 São Paulo, Brazil Univ Mogi das Cruzes, Mogi Das Cruzes, Brazil Universidade Federal de São Paulo, Dept Physiol, BR-04023062 São Paulo, Brazil Sanofi Aventis, Montpellier, France Universidade Federal de São Paulo, Dept Med, BR-04023062 São Paulo, Brazil Inst Natl Sante & Rech Med, Dept Renal & Cardiac Remodeling, U858 I2MR, Toulouse, France Univ Toulouse 3, Inst Med Mol Rangueil, F-31062 Toulouse, France Inst Natl Rech Agron AgroParisTech, UMR914 Nutr Physiol & Ingest Behav, Paris, France Max Delbruck Ctr Mol Med, Berlin, Germany Universidade Federal de São Paulo, Dept Biophys, BR-04023062 São Paulo, Brazil Universidade Federal de São Paulo, Dept Physiol, BR-04023062 São Paulo, Brazil Universidade Federal de São Paulo, Dept Med, BR-04023062 São Paulo, Brazil Web of Science

International audience; Processed meat intake may be involved in the etiology of colorectal cancer, a major cause of death in affluent countries. The epidemiologic studies published to date conclude that the excess risk in the highest category of processed meat-eaters is comprised between 20% and 50% compared with non-eaters. In addition, the excess risk per gram of intake is clearly higher than that of fresh red meat. Several hypotheses, which are mainly based on studies carried out on red meat, may explain why processed meat intake is linked to cancer risk. Those that have been tested experimentally are (i) that high-fat diets could promote carcinogenesis via insulin resistance or fecal bile acids; (ii) that cooking meat at a high temperature forms carcinogenic heterocyclic amines and polycyclic aromatic hydrocarbons; (iii) that carcinogenic N-nitroso compounds are formed in meat and endogenously; (iv) that heme iron in red meat can promote carcinogenesis because it increases cell proliferation in the mucosa, through lipoperoxidation and/or cytotoxicity of fecal water. Nitrosation might increase the toxicity of heme in cured products. Solving this puzzle is a challenge that would permit to reduce cancer load by changing the processes rather than by banning processed meat.

Diet is a major aspect of glycaemic control in type 2 diabetes, particularly among the elderly. The objective of this study was to describe the food habits of elderly diabetic subjects compared with non-diabetic ones and to examine the difference between their nutritional behavior and nutritional recommendations. This study was based on the Three City (3C) community-based cohort. The food habits of 1336 participants aged 65 or over, including 149 diabetic subjects, were evaluated using a food frequency questionnaire and a 24-hour recall of food consumption. For both sexes, intake of carbohydrates was lower for diabetic compared to non diabetic subjects, essentially due to lower intake of mono-/disaccharides. For ddiabetic men, this was compensated for by a higher intake of protein whereas women had a lower energy intake overall. Fibre intake was also higher in diabetic men. There was no absolute increase in fats intake, neither for men nor for women and distribution of subtypes of fats (saturated, mono-unsaturated, and poly-unsaturated) did not differ between diabetic and non-diabetic subjects. In mean, carbohydrates provided 40.5% of energy intake in diabetic men and 43.9% in diabetic women. Contrary to nutritional recommendations for diabetic subjects, for approximately two thirds of the diabetic subjects carbohydrates represented less than 45% of daily calories. Although food habits of elderly diabetic subjects differed from those of non-diabetic ones these habits are not totally in line with nutritional recommendations. These results should be taken into account to adapt nutritional advice given to the diabetic population.

International audience; Mitochondrial dysfunction in skeletal muscle has been implicated in the development of type 2 diabetes. However, whether these changes are a cause or a consequence of insulin resistance is not clear. We investigated the structure and function of muscle mitochondria during the development of insulin resistance and progression to diabetes in mice fed a high-fat, high-sucrose diet. Although 1 month of high-fat, high-sucrose diet feeding was sufficient to induce glucose intolerance, mice showed no evidence of mitochondrial dysfunction at this stage. However, an extended diet intervention induced a diabetic state in which we observed altered mitochondrial biogenesis, structure, and function in muscle tissue. We assessed the role of oxidative stress in the development of these mitochondrial abnormalities and found that diet-induced diabetic mice had an increase in ROS production in skeletal muscle. In addition, ROS production was associated with mitochondrial alterations in the muscle of hyperglycemic streptozotocin-treated mice, and normalization of glycemia or antioxidant treatment decreased muscle ROS production and restored mitochondrial integrity. Glucose- or lipid-induced ROS production resulted in mitochondrial alterations in muscle cells in vitro, and these effects were blocked by antioxidant treatment. These data suggest that mitochondrial alterations do not precede the onset of insulin resistance and result from increased ROS production in muscle in diet-induced diabetic mice.

When using 13C tracer to measure plasma fat oxidation, an acetate recovery factor should be determined in every subject to correct for label sequestration. Less is known regarding the acetate recovery factor for dietary fatty acid oxidation. We compiled data from six studies to investigate the determinants of the dietary acetate recovery factor (dARF) at rest and after physical activity interventions and compared the effects of different methods of dARF calculation on both the fat oxidation and its variability. In healthy lean subjects, dARF was 50.6 ± 5.4% dose ( n = 56) with an interindividual coefficient of variation of 10.6% at rest and 9.2% after physical activity modifications. The physical activity interventions did not impact dARF, and the intraindividual coefficient of variation was 4.6%. No major anthropological or physiological determinants were detected except for resting metabolic rate, which explains 7.4% of the dARF variability. Applying an individual or an average group dARF did not affect the mean and the variability of the derived dietary lipid oxidation at rest or after physical activity interventions. Using a mean dARF for a group leads to over- or underestimation of fat oxidation of less than 10% in individual subjects. Moreover, the use of a group or individual correction did not affect the significant relationship found between fasting respiratory exchange ratio and dietary fat oxidation. These data indicate that an average dARF can be applied for longitudinal and cross-sectional studies investigating dietary lipid metabolism.

Obesity is a major public health problem and is often associated with type 2 diabetes mellitus, cardiovascular disease, and metabolic syndrome. Leptin is the crucial adipostatic hormone that controls food intake and body weight through the activation of specific leptin receptors (OB-R) in the hypothalamic arcuate nucleus (ARC). However, in most obese patients, high circulating levels of leptin fail to bring about weight loss. The prevention of this “leptin resistance” is a major goal for obesity research. We report here a successful prevention of diet-induced obesity (DIO) by silencing a negative regulator of OB-R function, the OB-R gene-related protein (OB-RGRP), whose transcript is genetically linked to the OB-R transcript. We provide in vitro evidence that OB-RGRP controls OB-R function by negatively regulating its cell surface expression. In the DIO mouse model, obesity was prevented by silencing OB-RGRP through stereotactic injection of a lentiviral vector encoding a shRNA directed against OB-RGRP in the ARC. This work demonstrates that OB-RGRP is a potential target for obesity treatment. Indeed, regulators of the receptor could be more appropriate targets than the receptor itself. This finding could serve as the basis for an approach to identifying potential new therapeutic targets for a variety of diseases, including obesity.

0012-186X (Print) 0012-186X (Linking) Journal Article Research Support, Non-U.S. Gov't; International audience; AIMS/HYPOTHESIS: Uncoupling protein (UCP) 3 is a mitochondrial inner membrane protein expressed predominantly in glycolytic skeletal muscles. Its role in vivo remains poorly understood. The aim of the present work was to produce a mouse model with moderate overproduction and proper fibre-type distribution of UCP3. METHODS: Transgenic mice were created with a 16 kb region encompassing the human UCP3 gene. Mitochondrial uncoupling was investigated on permeabilised muscle fibres. Changes in body weight, adiposity and glucose or insulin tolerance were assessed in mice fed chow and high-fat diets. Indirect calorimetry was used to determine whole-body energy expenditure and substrate utilisation. RESULTS: Transgenic mice showed a twofold increase in UCP3 protein levels specifically in glycolytic muscles. Mitochondrial respiration revealed an increase of uncoupling in glycolytic but not in oxidative muscles. Transgenic mice gained less weight than wild-type littermates due to lower adipose tissue accretion when fed a high-fat diet. Animals showed a sexual dimorphism in metabolic responses. Female transgenic mice were more glucose-sensitive than wild-type animals, while male transgenic mice with high body weights had impaired glucose and insulin tolerance. Measurements of RQs in mice fed chow and high-fat diets suggested an impairment of metabolic flexibility in transgenic male mice. CONCLUSIONS/INTERPRETATION: Our data show that physiological overproduction of UCP3 in glycolytic muscles results in mitochondrial uncoupling, resistance to high-fat diet-induced obesity and sex specificity regarding insulin sensitivity and whole-body substrate utilisation.

The role of the tumor suppressor retinoblastoma protein (pRb) has been firmly established in the control of cell cycle, apoptosis, and differentiation. Recently, it was demonstrated that lack of pRb promotes a switch from white to brown adipocyte differentiation in vitro . We used the Cre-Lox system to specifically inactivate pRb in adult adipose tissue. Under a high-fat diet, pRb-deficient (pRb ad−/− ) mice failed to gain weight because of increased energy expenditure. This protection against weight gain was caused by the activation of mitochondrial activity in white and brown fat as evidenced by histologic, electron microscopic, and gene expression studies. Moreover, pRb −/− mouse embryonic fibroblasts displayed higher proliferation and apoptosis rates than pRb +/+ mouse embryonic fibroblasts, which could contribute to the altered white adipose tissue morphology. Taken together, our data support a direct role of pRb in adipocyte cell fate determination in vivo and suggest that pRb could serve as a potential therapeutic target to trigger mitochondrial activation in white adipose tissue and brown adipose tissue, favoring an increase in energy expenditure and subsequent weight loss.

International audience; Head-down bed rest (HDBR) increases plasma levels of atrial natriuretic peptide (ANP) and decreases norepinephrine levels. We previously demonstrated that ANP promotes lipid mobilization and utilization, an effect independent of sympathetic nervous system activation, when infused into lean healthy men at pharmacological doses. The purpose of the present study was to demonstrate that a physiological increase in ANP contributes to lipid mobilization and oxidation in healthy young men. Eight men were positioned for 4 h in a sitting (control) or in a HDBR position. Indexes of lipid mobilization and hormonal changes were measured in plasma. Extracellular glycerol, an index of lipolysis, was determined in subcutaneous adipose tissue (SCAT) with a microdialysis technique. A twofold increase in plasma ANP concentration was observed after 60 min of HDBR, and a plateau was maintained thereafter. Plasma norepinephrine decreased by 30-40% during HDBR, while plasma insulin and glucose levels did not change. The level of plasma nonesterified fatty acids was higher during HDBR. SCAT lipolysis, as reflected by interstitial glycerol, as well as interstitial cGMP, the second messenger of the ANP pathway, increased during HDBR. This was associated with an increase in blood flow observed throughout HDBR. Significant changes in respiratory exchange ratio and percent use of lipid and carbohydrate were seen only after 3 h of HDBR. Thus the proportion of lipid oxidized increased by 40% after 3 h of HDBR. The rise in plasma ANP during HDBR was associated with increased lipolysis in SCAT and whole body lipid oxidation. In this physiological setting, independent of increasing catecholamines, our study suggests that ANP contributes to lipid mobilization and oxidation in healthy young men.

International audience; Diminished mitochondrial oxidative phosphorylation and aerobic capacity are associated with reduced longevity. We tested whether resveratrol (RSV), which is known to extend lifespan, impacts mitochondrial function and metabolic homeostasis. Treatment of mice with RSV significantly increased their aerobic capacity, as evidenced by their increased running time and consumption of oxygen in muscle fibers. RSV's effects were associated with an induction of genes for oxidative phosphorylation and mitochondrial biogenesis and were largely explained by an RSV-mediated decrease in PGC-1alpha acetylation and an increase in PGC-1alpha activity. This mechanism is consistent with RSV being a known activator of the protein deacetylase, SIRT1, and by the lack of effect of RSV in SIRT1(-/-) MEFs. Importantly, RSV treatment protected mice against diet-induced-obesity and insulin resistance. These pharmacological effects of RSV combined with the association of three Sirt1 SNPs and energy homeostasis in Finnish subjects implicates SIRT1 as a key regulator of energy and metabolic homeostasis.

International audience; The importance of a high fat intake in the increasing prevalence of childhood and adult obesity remains controversial. Moreover, qualitative changes (i.e. the fatty acid composition of fats) have been largely disregarded. Herein is reviewed the role of polyunsaturated fatty acids (PUFAs) of the n-6 series in promoting adipogenesis in vitro and favouring adipose tissue development in rodents during the gestation/suckling period. Epidemiological data from infant studies as well as the assessment of the fatty acid composition of mature breast milk and infant formulas over the last decades in the Western industrialized world are revisited and appear consistent with animal data. Changes over decades in the intake of n-6 and n-3 PUFAs, with a striking increase in the linoleic acid/alpha-linolenic ratio, are observed. In adults, using a consumption model based upon production data, similar changes in the PUFA content of ingested lipids have been found for France, and are associated with an increase of fat consumption over the last 40 years. These profound quantitative and qualitative alterations can be traced in the food chain and shown to be due to changes in human dietary habits as well as in the feeding pattern of breeding stock. If prevention of obesity is a key issue for future generations, agricultural and food industry policies should be thoroughly reevaluated.

International audience; While bile acids (BAs) have long been known to be essential in dietary lipid absorption and cholesterol catabolism, in recent years an important role for BAs as signalling molecules has emerged. BAs activate mitogen-activated protein kinase pathways, are ligands for the G-protein-coupled receptor (GPCR) TGR5 and activate nuclear hormone receptors such as farnesoid X receptor alpha (FXR-alpha; NR1H4). FXR-alpha regulates the enterohepatic recycling and biosynthesis of BAs by controlling the expression of genes such as the short heterodimer partner (SHP; NR0B2) that inhibits the activity of other nuclear receptors. The FXR-alpha-mediated SHP induction also underlies the downregulation of the hepatic fatty acid and triglyceride biosynthesis and very-low-density lipoprotein production mediated by sterol-regulatory-element-binding protein 1c. This indicates that BAs might be able to function beyond the control of BA homeostasis as general metabolic integrators. Here we show that the administration of BAs to mice increases energy expenditure in brown adipose tissue, preventing obesity and resistance to insulin. This novel metabolic effect of BAs is critically dependent on induction of the cyclic-AMP-dependent thyroid hormone activating enzyme type 2 iodothyronine deiodinase (D2) because it is lost in D2-/- mice. Treatment of brown adipocytes and human skeletal myocytes with BA increases D2 activity and oxygen consumption. These effects are independent of FXR-alpha, and instead are mediated by increased cAMP production that stems from the binding of BAs with the G-protein-coupled receptor TGR5. In both rodents and humans, the most thermogenically important tissues are specifically targeted by this mechanism because they coexpress D2 and TGR5. The BA-TGR5-cAMP-D2 signalling pathway is therefore a crucial mechanism for fine-tuning energy homeostasis that can be targeted to improve metabolic control.

As shown by huge amount of assays in human as well as in animal models, w-3 polyunsaturated fatty acids play important role in the development and maintenance of different organs, primarily the brain, and could be useful in the prevention of different pathologies, mainly the cardiovascular diseases, and, as proposed recently, some psychiatric, dermatological or rheumatological disorders. For ALA, the major and cheapest source for human is rapeseed oil (canola oil), and walnut "noix de Grenoble" oil). The actual goal is first to identify which foods are naturally rich in w-3 fatty acids, and, second, to determine the true impact of the formulations (enriched in w-3 fatty acids) in chows used on farms and breeding centres on the nutritional value of the products and thus their effect on the health of consumers, thanks to quantities of either ALA, or EPA or DHA or both. This concern fish (in proportion of their lipid content, mainly mackerel, salmon, sardine and herring), eggs (wildly naturally rich in w-3 fatty acids, both ALA and DHA, or from laying hen fed ALA from linseed or rapeseed), meat from birds, mammals (from the highest concentration : rabbit, then pig and monogastrics, then polygastrics such as beef, mutton and goat) \; in butter, milk, dairy products, cheese (all naturally poor in w-3 fatty acids)... Indeed, the nature of fatty acids of reserve triglycerides (found in more or less large amounts depending on the anatomical localisation, that is to say the butcher's cuts) can vary mainly as a function of the food received by the animal. EPA and DHA are mainly present in animal's products. The impact (qualitative and quantitative) of alterations in the lipid composition of animal foods on the nutritional value of derived products (in terms of EPA and DHA content) eaten by humans are more important in single-stomach animals than multi-stomach animals (due to their hydrogenating intestinal bacteria). The intestinal physiology of birds results in the relatively good preservation of their dietary w-3 fatty acids. The enrichment in eggs is proportional to the amount of w-3 fatty acids in the hen's diet and can be extremely important. Including ALA in fish feeds is effective only if they are, like carp, vegetarians, as they have the enzymes required to transform ALA into EPA and DHA \; in contrast, it is probably less effective for carnivorous fish (75 % of the fish used for human), which have little of these enzymes : their feed must contain marine animals, mainly fish or fish oil. Analysis of the published results shows that, under the best conditions, feeding animals with extracts of linseed and rapeseed grains, for example, increases the level of ALA acid by 20 to 40-fold in eggs (according to the low or high level of ALA in commercial eggs), 10-fold in chicken, 6-fold in pork and less than 2-fold in beef. By feeding animals with fish extracts or algae (oils), the level of DHA is increased by 20-fold in fish, 7-fold in chicken, 3 to 6-fold in eggs, less than 2-fold in beef. In practise, the effect is considerable for fish and egg, interesting for poultry and rabbit, extremely low for beef, mutton and sheep. The effect on the price paid by the consumer is very low compared to the considerable gain in nutritional value.