J Seydoux

University of Geneva, Genève, Geneva, Switzerland

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Publications (110)462.37 Total impact

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    ABSTRACT: ‘Dieting Makes You Fat’ – the title of a book published in 1983 – embodies the notion that dieting to control body weight, with consequential weight cycling, predisposes the individual to acquire even more body fat. While this notion is controversial, its debate underscores the large gap, which exists in our understanding of basic physiological laws, which govern the regulation of human body composition. In addressing the plausibility and mechanistic basis by which dieting may predispose to increased fatness, this paper integrates the results derived from re-analysis of classic longitudinal studies of human starvation and refeeding. These suggest that feedback signals from both fat and lean tissues contribute to recovering body weight through effects on energy intake and thermogenesis, and that a faster rate of fat recovery relative to lean tissue recovery is a central outcome of body composition autoregulation that drives fat overshooting. A main implication of these findings is that the risk of becoming fatter in response to dieting is greater in lean than in obese individuals.
    Cahiers de Nutrition et de Diététique 03/2013; 48(1):15–25.
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    ABSTRACT: Catch-up growth, a risk factor for type 2 diabetes, is characterized by hyperinsulinemia and accelerated body fat recovery. Using a rat model of semistarvation-refeeding that exhibits catch-up fat, we previously reported that during refeeding on a low-fat diet, glucose tolerance is normal but insulin-dependent glucose utilization is decreased in skeletal muscle and increased in adipose tissue, where de novo lipogenic capacity is concomitantly enhanced. Here we report that isocaloric refeeding on a high-fat (HF) diet blunts the enhanced in vivo insulin-dependent glucose utilization for de novo lipogenesis (DNL) in adipose tissue. These are shown to be early events of catch-up growth that are independent of hyperphagia and precede the development of overt adipocyte hypertrophy, adipose tissue inflammation, or defective insulin signaling. These results suggest a role for enhanced DNL as a glucose sink in regulating glycemia during catch-up growth, which is blunted by exposure to an HF diet, thereby contributing, together with skeletal muscle insulin resistance, to the development of glucose intolerance. Our findings are presented as an extension of the Randle cycle hypothesis, whereby the suppression of DNL constitutes a mechanism by which dietary lipids antagonize glucose utilization for storage as triglycerides in adipose tissue, thereby impairing glucose homeostasis during catch-up growth.
    Diabetes 09/2012; · 7.90 Impact Factor
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    ABSTRACT: Obesity is associated with a chronic low-grade inflammation, and specific antiinflammatory interventions may be beneficial for the treatment of type 2 diabetes and other obesity-related diseases. The lipid kinase PI3Kγ is a central proinflammatory signal transducer that plays a major role in leukocyte chemotaxis, mast cell degranulation, and endothelial cell activation. It was also reported that PI3Kγ activity within hematopoietic cells plays an important role in obesity-induced inflammation and insulin resistance. Here, we show that protection from insulin resistance, metabolic inflammation, and fatty liver in mice lacking functional PI3Kγ is largely consequent to their leaner phenotype. We also show that this phenotype is largely based on decreased fat gain, despite normal caloric intake, consequent to increased energy expenditure. Furthermore, our data show that PI3Kγ action on diet-induced obesity depends on PI3Kγ activity within a nonhematopoietic compartment, where it promotes energetic efficiency for fat mass gain. We also show that metabolic modulation by PI3Kγ depends on its lipid kinase activity and might involve kinase-independent signaling. Thus, PI3Kγ is an unexpected but promising drug target for the treatment of obesity and its complications.
    Proceedings of the National Academy of Sciences 09/2011; 108(42):E854-63. · 9.81 Impact Factor
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    ABSTRACT: The present study investigates whether excessive fat accumulation and hyperinsulinaemia during catch-up growth on high-fat diets are altered by n-6 and n-3 PUFA derived from oils rich in either linoleic acid (LA), α-linolenic acid (ALA), arachidonic acid (AA) or DHA. It has been shown that, compared with food-restricted rats refed a high-fat (lard) diet low in PUFA, those refed isoenergetically on diets enriched in LA or ALA, independently of the n-6:n-3 ratio, show improved insulin sensitivity, lower fat mass and higher lean mass, the magnitude of which is related to the proportion of total PUFA precursors (LA+ALA) consumed. These relationships are best fitted by quadratic regression models (r2>0·8, P < 0·001), with threshold values for an impact on body composition corresponding to PUFA precursors contributing 25–30 % of energy intake. Isoenergetic refeeding on high-fat diets enriched in AA or DHA also led to improved body composition, with increases in lean mass as predicted by the quadratic model for PUFA precursors, but decreases in fat mass, which are disproportionately greater than predicted values; insulin sensitivity, however, was not improved. These findings pertaining to the impact of dietary intake of PUFA precursors (LA and ALA) and their elongated–desaturated products (AA and DHA), on body composition and insulin sensitivity, provide important insights into the search for diets aimed at counteracting the pathophysiological consequences of catch-up growth. In particular, diets enriched in essential fatty acids (LA and/or ALA) markedly improve insulin sensitivity and composition of weight regained, independently of the n-6:n-3 fatty acid ratio.
    The British journal of nutrition 06/2011; 105(12):1750 - 1763. · 3.45 Impact Factor
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    ABSTRACT: Catch-up growth, a risk factor for later type 2 diabetes, is characterized by hyperinsulinemia, accelerated body-fat recovery (catch-up fat), and enhanced glucose utilization in adipose tissue. Our objective was to characterize the determinants of enhanced glucose utilization in adipose tissue during catch-up fat. White adipose tissue morphometry, lipogenic capacity, fatty acid composition, insulin signaling, in vivo glucose homeostasis, and insulinemic response to glucose were assessed in a rat model of semistarvation-refeeding. This model is characterized by glucose redistribution from skeletal muscle to adipose tissue during catch-up fat that results solely from suppressed thermogenesis (i.e., without hyperphagia). Adipose tissue recovery during the dynamic phase of catch-up fat is accompanied by increased adipocyte number with smaller diameter, increased expression of genes for adipogenesis and de novo lipogenesis, increased fatty acid synthase activity, increased proportion of saturated fatty acids in triglyceride (storage) fraction but not in phospholipid (membrane) fraction, and no impairment in insulin signaling. Furthermore, it is shown that hyperinsulinemia and enhanced adipose tissue de novo lipogenesis occur concomitantly and are very early events in catch-up fat. These findings suggest that increased adipose tissue insulin stimulation and consequential increase in intracellular glucose flux play an important role in initiating catch-up fat. Once activated, the machinery for lipogenesis and adipogenesis contribute to sustain an increased insulin-stimulated glucose flux toward fat storage. Such adipose tissue plasticity could play an active role in the thrifty metabolism that underlies glucose redistribution from skeletal muscle to adipose tissue.
    Diabetes 08/2009; 58(10):2228-37. · 7.90 Impact Factor
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    ABSTRACT: Energy conservation directed at accelerating body fat recovery (or catch-up fat) contributes to obesity relapse after slimming and to excess fat gain during catch-up growth after malnutrition. To investigate the mechanisms underlying such thrifty metabolism for catch-up fat, we tested whether during refeeding after caloric restriction rats exhibiting catch-up fat driven by suppressed thermogenesis have diminished skeletal muscle phosphatidylinositol-3-kinase (PI3K) activity or AMP-activated protein kinase (AMPK) signaling-two pathways required for hormone-induced thermogenesis in ex vivo muscle preparations. The results show that during isocaloric refeeding with a low-fat diet, at time points when body fat, circulating free fatty acids, and intramyocellular lipids in refed animals do not exceed those of controls, muscle insulin receptor substrate 1-associated PI3K activity (basal and in vivo insulin-stimulated) is lower than that in controls. Isocaloric refeeding with a high-fat diet, which exacerbates the suppression of thermogenesis, results in further reductions in muscle PI3K activity and in impaired AMPK phosphorylation (basal and in vivo leptin-stimulated). It is proposed that reduced skeletal muscle PI3K/AMPK signaling and suppressed thermogenesis are interdependent. Defective PI3K or AMPK signaling will reduce the rate of substrate cycling between de novo lipogenesis and lipid oxidation, leading to suppressed thermogenesis, which accelerates body fat recovery and furthermore sensitizes skeletal muscle to dietary fat-induced impairments in PI3K/AMPK signaling.
    The FASEB Journal 04/2008; 22(3):774-85. · 5.70 Impact Factor
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    ABSTRACT: Mice lacking beta-adrenoceptors, which mediate the thermogenic effects of norepinephrine and epinephrine, show diminished thermogenesis and high susceptibility to obesity, whereas mice lacking stearoyl-CoA desaturase 1 (SCD1), which catalyzes the synthesis of monounsaturated fatty acids, show enhanced thermogenesis and high resistance to obesity. In testing whether beta-adrenergic control of thermogenesis might be mediated via repression of the SCD1 gene, we found that in mice lacking beta-adrenoceptors, the gene expression of SCD1 is elevated in liver, skeletal muscle and white adipose tissue. In none of these tissues/organs, however, could a link be found between increased sympathetic nervous system activity and diminished SCD1 gene expression when thermogenesis is increased in response to diet or cold, nor is the SCD1 transcript repressed by the administration of epinephrine. Taken together, these studies suggest that the elevated SCD1 transcript in tissues of mice lacking beta-adrenoceptors is not a direct effect of blunted beta-adrenergic signalling, and that beta-adrenergic control of SCD1 repression is unlikely to be a primary effector mechanism in sympathoadrenal regulation of thermogenesis. Whether approaches that target both SCD1 and molecular effectors of thermogenesis under beta-adrenergic control might be more effective than targeting SCD1 alone are potential avenues for future research in obesity management.
    International Journal of Obesity 03/2007; 31(2):378-81. · 5.22 Impact Factor
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    ABSTRACT: The analyses of large epidemiological databases have suggested that infants and children who show catch-up growth, or adiposity rebound at a younger age, are predisposed to the development of obesity, type 2 diabetes and cardiovascular diseases later in life. The pathophysiological mechanisms by which these growth trajectories confer increased risks for these diseases are obscure, but there is compelling evidence that the dynamic process of catch-up growth per se , which often overlaps with adiposity rebound at a younger age, is characterized by hyperinsulinemia and by a disproportionately higher rate in the recovery of body fat than lean tissue (i.e. preferential 'catch-up fat'). This paper first focuses upon the almost ubiquitous nature of this preferential 'catch-up fat' phenotype across the life cycle as a risk factor for obesity and insulin-related complications – not only in infants and children who experienced catch-up growth after earlier fetal or neonatal growth retardation, or after preterm birth, but also in adults who show weight recovery after substantial weight loss owing to famine, disease-cachexia or periodic dieting. It subsequently reviews the evidence indicating that such preferential catch-up fat is primarily driven by energy conservation (thrifty) mechanisms operating via suppressed thermogenesis, with glucose thus spared from oxidation in skeletal muscle being directed towards de novo lipogenesis and storage in white adipose tissue. A molecular–physiological framework is presented which integrates emerging insights into the mechanisms by which this thrifty 'catch-up fat' phenotype crosslinks with early development of insulin and leptin resistance. In the complex interactions between genetic constitution of the individual, programming earlier in life, and a subsequent lifestyle of energy dense foods and low physical activity, this thrifty 'catch-up fat' phenotype – which probably evolved to increase survival capacity in a hunter–gatherer lifestyle of periodic food shortages – is a central event in growth trajectories to obesity and to diseases that cluster into the insulin resistance (metabolic) syndrome.
    International Journal of Obesity 12/2006; · 5.22 Impact Factor
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    ABSTRACT: Activation of the peroxisome proliferator-activated receptor (PPAR)-alpha increases lipid catabolism and lowers the concentration of circulating lipid, but its role in the control of glucose metabolism is not as clearly established. Here we compared PPARalpha knockout mice with wild type and confirmed that the former developed hypoglycemia during fasting. This was associated with only a slight increase in insulin sensitivity but a dramatic increase in whole-body and adipose tissue glucose use rates in the fasting state. The white sc and visceral fat depots were larger due to an increase in the size and number of adipocytes, and their level of GLUT4 expression was higher and no longer regulated by the fed-to-fast transition. To evaluate whether these adipocyte deregulations were secondary to the absence of PPARalpha from liver, we reexpresssed this transcription factor in the liver of knockout mice using recombinant adenoviruses. Whereas more than 90% of the hepatocytes were infected and PPARalpha expression was restored to normal levels, the whole-body glucose use rate remained elevated. Next, to evaluate whether brain PPARalpha could affect glucose homeostasis, we activated brain PPARalpha in wild-type mice by infusing WY14643 into the lateral ventricle and showed that whole-body glucose use was reduced. Hence, our data show that PPARalpha is involved in the regulation of glucose homeostasis, insulin sensitivity, fat accumulation, and adipose tissue glucose use by a mechanism that does not require PPARalpha expression in the liver. By contrast, activation of PPARalpha in the brain stimulates peripheral glucose use. This suggests that the alteration in adipocyte glucose metabolism in the knockout mice may result from the absence of PPARalpha in the brain.
    Endocrinology 10/2006; 147(9):4067-78. · 4.72 Impact Factor
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    ABSTRACT: An enhanced metabolic efficiency for accelerating the recovery of fat mass (or catch-up fat) is a characteristic feature of body weight regulation after weight loss or growth retardation and is the outcome of an "adipose-specific" suppression of thermogenesis, i.e., a feedback control system in which signals from the depleted adipose tissue fat stores exert a suppressive effect on thermogenesis. Using a previously described rat model of semistarvation-refeeding in which catch-up fat results from suppressed thermogenesis per se, we report here that the gene expression of stearoyl-coenzyme A desaturase 1 (SCD1) is elevated in skeletal muscle after 2 wk of semistarvation and remains elevated in parallel to the phase of suppressed thermogenesis favoring catch-up fat during refeeding. These elevations in the SCD1 transcript are skeletal muscle specific and are associated with elevations in microsomal Delta9 desaturase enzyme activity, in the Delta9 desaturation index, and in the relative content of SCD1-derived monounsaturates in several lipid fractions extracted from skeletal muscle. An elevated skeletal muscle SCD1, by desaturating the products of de novo lipogenesis and diverting them away from mitochondrial oxidation, would inhibit substrate cycling between de novo lipogenesis and lipid oxidation, thereby leading to a state of suppressed thermogenesis that regulates the body's fat stores.
    The FASEB Journal 09/2006; 20(10):1751-3. · 5.70 Impact Factor
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    ABSTRACT: The mechanisms by which CRH and related peptides (i.e. the CRH/urocortin system) exert their control over thermogenesis and weight regulation have until now focused only upon their effects on brain centers controlling sympathetic outflow. Using a method that involves repeated oxygen uptake determinations in intact mouse skeletal muscle, we report here that CRH can act directly on skeletal muscle to stimulate thermogenesis, an effect that is more pronounced in oxidative than in glycolytic muscles and that can be inhibited by a selective CRH-R2 antagonist or blunted by a nonselective CRH receptor antagonist. This thermogenic effect of CRH can also be blocked by interference along pathways of de novo lipogenesis and lipid oxidation, as well as by inhibitors of phosphatidylinositol 3-kinase or AMP-activated protein kinase. Taken together, these studies demonstrate that CRH can directly stimulate thermogenesis in skeletal muscle, and in addition raise the possibility that this thermogenic effect, which requires both phosphatidylinositol 3-kinase and AMP-activated protein kinase signaling, might occur via substrate cycling between de novo lipogenesis and lipid oxidation. The effect of CRH in directly stimulating thermogenesis in skeletal muscle underscores a potentially important peripheral role for the CRH/urocortin system in the control of thermogenesis in this tissue, in its protection against excessive intramyocellular lipid storage, and hence against skeletal muscle lipotoxicity and insulin resistance.
    Endocrinology 02/2006; 147(1):31-8. · 4.72 Impact Factor
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    ABSTRACT: Catch-up growth, a risk factor for later obesity, type 2 diabetes, and cardiovascular diseases, is characterized by hyperinsulinemia and an accelerated rate for recovering fat mass, i.e., catch-up fat. To identify potential mechanisms in the link between hyperinsulinemia and catch-up fat during catch-up growth, we studied the in vivo action of insulin on glucose utilization in skeletal muscle and adipose tissue in a previously described rat model of weight recovery exhibiting catch-up fat caused by suppressed thermogenesis per se. To do this, we used euglycemic-hyperinsulinemic clamps associated with the labeled 2-deoxy-glucose technique. After 1 week of isocaloric refeeding, when body fat, circulating free fatty acids, or intramyocellular lipids in refed animals had not yet exceeded those of controls, insulin-stimulated glucose utilization in refed animals was lower in skeletal muscles (by 20-43%) but higher in white adipose tissues (by two- to threefold). Furthermore, fatty acid synthase activity was higher in adipose tissues from refed animals than from fed controls. These results suggest that suppressed thermogenesis for the purpose of sparing glucose for catch-up fat, via the coordinated induction of skeletal muscle insulin resistance and adipose tissue insulin hyperresponsiveness, might be a central event in the link between catch-up growth, hyperinsulinemia and risks for later metabolic syndrome.
    Diabetes 04/2005; 54(3):751-6. · 7.90 Impact Factor
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    ABSTRACT: Life is a combustion, but how the major fuel substrates that sustain human life compete and interact with each other for combustion has been at the epicenter of research into the pathogenesis of insulin resistance ever since Randle proposed a 'glucose-fatty acid cycle' in 1963. Since then, several features of a mutual interaction that is characterized by both reciprocality and dependency between glucose and lipid metabolism have been unravelled, namely: the inhibitory effects of elevated concentrations of fatty acids on glucose oxidation (via inactivation of mitochondrial pyruvate dehydrogenase or via desensitization of insulin-mediated glucose transport),the inhibitory effects of elevated concentrations of glucose on fatty acid oxidation (via malonyl-CoA regulation of fatty acid entry into the mitochondria), and more recentlythe stimulatory effects of elevated concentrations of glucose on de novo lipogenesis, that is, synthesis of lipids from glucose (via SREBP1c regulation of glycolytic and lipogenic enzymes). This paper first revisits the physiological significance of these mutual interactions between glucose and lipids in skeletal muscle pertaining to both blood glucose and intramyocellular lipid homeostasis. It then concentrates upon emerging evidence, from calorimetric studies investigating the direct effect of leptin on thermogenesis in intact skeletal muscle, of yet another feature of the mutual interaction between glucose and lipid oxidation: that of substrate cycling between de novo lipogenesis and lipid oxidation. It is proposed that this energy-dissipating substrate cycling that links glucose and lipid metabolism to thermogenesis could function as a 'fine-tuning' mechanism that regulates intramyocellular lipid homeostasis, and hence contributes to the protection of skeletal muscle against lipotoxicity.
    International Journal of Obesity 01/2005; 28 Suppl 4:S29-37. · 5.22 Impact Factor
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    Abdul G Dulloo, Josiane Seydoux, Jean Jacquet
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    ABSTRACT: After decades of controversies about the quantitative importance of autoregulatory adjustments in energy expenditure in weight regulation, there is now increasing recognition that even subtle variations in thermogenesis could, in dynamic systems and over the long term, be important in determining weight maintenance in some and obesity in others. The main challenge nowadays is to provide a mechanistic explanation for the role of adaptive thermogenesis in attenuating and correcting deviations of body weight and body composition, and in the identification of molecular mechanisms that constitute its effector systems. This workshop paper reconsiders what constitutes adaptive changes in thermogenesis and reassesses the role of the sympathetic nervous system (SNS) and uncoupling proteins (UCP1, UCP2, UCP3, UCP5/BMCP1) as the efferent and effector components of the classical one-control system for adaptive thermogenesis and fat oxidation. It then reviews the evidence suggesting that there are in fact two distinct control systems for adaptive thermogenesis, the biological significance of which is to satisfy--in a lifestyle of famine-and-feast--the needs to suppress thermogenesis for energy conservation during weight loss and weight recovery even under environmental stresses (e.g., cold, infection, nutrient imbalance) when sympathetic activation of thermogenesis has equally important survival value.
    Physiology & Behavior 01/2005; 83(4):587-602. · 3.16 Impact Factor
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    ABSTRACT: We report here studies that integrate data of respiration rate from mouse skeletal muscle in response to leptin and pharmacological interference with intermediary metabolism, together with assays for phosphatidylinositol 3-kinase (PI3K) and AMP-activated protein kinase (AMPK). Our results suggest that the direct effect of leptin in stimulating thermogenesis in skeletal muscle is mediated by substrate cycling between de novo lipogenesis and lipid oxidation, and that this cycle requires both PI3K and AMPK signaling. This substrate cycling linking glucose and lipid metabolism to thermogenesis provides a novel thermogenic mechanism by which leptin protects skeletal muscle from excessive fat storage and lipotoxicity.
    FEBS Letters 12/2004; 577(3):539-44. · 3.58 Impact Factor
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    ABSTRACT: The peroxisome proliferator-activated receptor gamma (PPARgamma) plays a major role in fat tissue development and physiology. Mutations in the gene encoding this receptor have been associated to disorders in lipid metabolism. A thorough investigation of mice in which one PPARgamma allele has been mutated reveals that male PPARgamma heterozygous (PPARgamma +/-) mice exhibit a reduced body size associated with decreased body weight, reflecting lean mass reduction. This phenotype is reproduced when treating the mice with a PPARgamma- specific antagonist. Monosodium glutamate treatment, which induces weight gain and alters body growth in wild-type mice, further aggravates the growth defect of PPARgamma +/- mice. The levels of circulating GH and that of its downstream effector, IGF-I, are not altered in mutant mice. However, the IGF-I mRNA level is decreased in white adipose tissue (WAT) of PPARgamma +/- mice and is not changed by acute administration of recombinant human GH, suggesting an altered GH action in the mutant animals. Importantly, expression of the gene encoding the suppressor of cytokine signaling-2, which is an essential negative regulator of GH signaling, is strongly increased in the WAT of PPARgamma +/- mice. Although the relationship between the altered GH signaling in WAT and reduced body size remains unclear, our results suggest a novel role of PPARgamma in GH signaling, which might contribute to the metabolic disorder affecting insulin signaling in PPARgamma mutant mice.
    Molecular Endocrinology 11/2004; 18(10):2363-77. · 4.75 Impact Factor
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    ABSTRACT: The ability of a retinoid X receptor (RXR) to heterodimerize with many nuclear receptors, including LXR, PPAR, NGF1B and RAR, underscores its pivotal role within the nuclear receptor superfamily. Among these heterodimers, PPAR:RXR is considered an important signalling mediator of both PPAR ligands, such as fatty acids, and 9-cis retinoic acid (9-cis RA), an RXR ligand. In contrast, the existence of an RXR/9-cis RA signalling pathway independent of PPAR or any other dimerization partner remains disputed. Using in vivo chromatin immunoprecipitation, we now show that RXR homodimers can selectively bind to functional PPREs and induce transactivation. At the molecular level, this pathway requires stabilization of the homodimer-DNA complexes through ligand-dependent interaction with the coactivator SRC1 or TIF2. This pathway operates both in the absence and in the presence of PPAR, as assessed in cells carrying inactivating mutations in PPAR genes and in wild-type cells. In addition, this signalling pathway via PPREs is fully functional and can rescue the severe hypothermia phenotype observed in fasted PPARalpha-/- mice. These observations have important pharmacological implications for the development of new rexinoid-based treatments.
    The EMBO Journal 06/2004; 23(10):2083-91. · 9.82 Impact Factor
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    ABSTRACT: To assess the role of the alpha1b-adrenergic receptor (AR) in glucose homeostasis, we investigated glucose metabolism in knockout mice deficient of this receptor subtype (alpha1b-AR-/-). Mutant mice had normal blood glucose and insulin levels, but elevated leptin concentrations in the fed state. During the transition to fasting, glucose and insulin blood concentrations remained markedly elevated for at least 6 h and returned to control levels after 24 h whereas leptin levels remained high at all times. Hyperinsulinemia in the post-absorptive phase was normalized by atropine or methylatropine indicating an elevated parasympathetic activity on the pancreatic beta cells, which was associated with increased levels of hypothalamic NPY mRNA. Euglycemic clamps at both low and high insulin infusion rates revealed whole body insulin resistance with reduced muscle glycogen synthesis and impaired suppression of endogenous glucose production at the low insulin infusion rate. The liver glycogen stores were 2-fold higher in the fed state in the alpha1b-AR-/- compared with control mice, but were mobilized at the same rate during the fed to fast transition or following glucagon injections. Finally, high fat feeding for one month increased glucose intolerance and body weight in the alpha1b-AR-/-, but not in control mice. Altogether, our results indicate that in the absence of the alpha1b-AR the expression of hypotalamic NPY and the parasympathetic nervous activity are both increased resulting in hyperinsulinemia and insulin resistance as well as favoring obesity and glucose intolerance development during high fat feeding.
    Journal of Biological Chemistry 02/2004; 279(2):1108-15. · 4.65 Impact Factor
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    ABSTRACT: We investigated, in skeletal muscle mitochondria isolated from semistarved and refed rats, the relation between the protein expression of uncoupling protein 3 (UCP3) and mitochondrial oxidative capacity, assessed as state 4 and state 3 respiration rates in presence of substrates that are either non-lipids (glutamate, succinate) or lipids (palmitoyl CoA, palmitoylcarnitine). During semistarvation, when whole-body thermogenesis is diminished, state 3 respiration was lower than in fed controls by about 30% independently of substrate types, while state 4 respiration was lower by 20% only during succinate oxidation, but UCP3 was unaltered. After 5 days of refeeding, when thermogenesis is still diminished, neither state 4, state 3 nor UCP3 were lower than in controls. Refeeding on a high-fat diet, which exacerbates the suppression of thermogenesis, resulted in a two-fold elevation in UCP3 but no change in state 4 or state 3 respiration. These results during semistarvation and refeeding, in line with those previously reported for fasting, are not in support of the hypothesis that UCP3 is a mediator of adaptive thermogenesis pertaining to weight regulation, and underscore the need for caution in interpreting parallel changes in UCP3 and mitochondrial oxidative capacity as the reflection of mitochondrial uncoupling by UCP3.
    FEBS Letters 07/2003; 544(1-3):138-42. · 3.58 Impact Factor

Publication Stats

5k Citations
462.37 Total Impact Points

Institutions

  • 1968–2013
    • University of Geneva
      • • Department of Basic Neurosciences (NEUFO)
      • • Faculty of Medicine
      • • Department of Internal Medicine
      • • Department of Biochemistry
      • • Department of Anaesthesiology, Pharmacology and Surgery Intensive Care (APSIC)
      Genève, Geneva, Switzerland
  • 2001–2012
    • Université de Fribourg
      • Département de médecine
      Fribourg, FR, Switzerland
  • 1988–2003
    • University Hospital of Lausanne
      Lausanne, Vaud, Switzerland
  • 1998
    • Paul Sabatier University - Toulouse III
      Tolosa de Llenguadoc, Midi-Pyrénées, France
  • 1988–1996
    • Centre universitaire romand de médecine légale Lausanne - Genève (CURML)
      Genève, Geneva, Switzerland
  • 1992–1993
    • École Polytechnique Fédérale de Lausanne
      • Laboratoire de nanophotonique et métrologie
      Lausanne, VD, Switzerland