Activités scientifiques

Transcription

1 Prof. Françoise Rohner-Jeanrenaud Activités scientifiques I. A role for adipose tissue de novo lipogenesis in glucose homeostasis during catch-up growth: A Randle cycle favoring fat storage Catch-up growth during infancy and childhood is now recognized as an important risk factor for the development of type 2 diabetes and cardiovascular diseases later in life. Although the mechanisms by which catch-up growth leads to these chronic diseases remain obscure, there is compelling evidence both in humans and other mammals that catch-up growth is characterized by an early occurrence of hyperinsulinemia, as well as by a disproportionately increased recovery rate of body fat over lean body mass. Using a rat model showing catch-up fat in response to semistarvation-refeeding, we previously showed that the insulin-resistant state of catch-up fat persists in the absence of hyperphagia and that it is associated with decreased in vivo glucose utilization in skeletal muscle, but enhanced glucose utilization in white adipose tissue (WAT). These data led to the proposal that the preferential catch-up fat during catch-up growth is characterized by glucose redistribution from skeletal muscle to WAT. In the present study, we provide evidence suggesting a major role for WAT de novo lipogenesis in glucose homeostasis during catch-up growth on a regular low-fat diet. Under these feeding conditions, the increased WAT de novo lipogenesis observed during catch-up growth not only contributes to the rapid recovery of fat in adipose tissue, but also acts as a glucose sink that allows glycemia to be maintained within the physiological range. In contrast, refeeding on an isocaloric high fat diet blunts the enhanced insulin-stimulated glucose utilization in WAT, while it has no additional impact on insulin-stimulated glucose utilization in skeletal muscle. This effect of dietary lipids is specific for catch-up growth, as spontaneously growing (fed control) rats on a high-fat diet show no significant difference in insulin-stimulated glucose utilization in WAT compared with controls fed a low-fat diet. Other data obtained by studying various refeeding times indicate that the loss of WAT insulin hyperresponsiveness during catch-up fat is an early and sustained response to dietary lipids, which is not initiated by excess caloric intake, adiposity or by adipocyte hypertrophy per se. It therefore appears that dietary fat offsets the ability of WAT to buffer against glucose spared from insulin resistance in skeletal muscle by blunting the enhanced capacity for glucose flux into WAT during catch-up fat. This represents an extension of the Randle cycle hypothesis, whereby the suppression of de novo lipogenesis 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. This could be of importance for the excessive fat storage encountered in obesity and for the accompanying metabolic defects involving impaired glucose tolerance as a first step toward the development of type 2 diabetes. Diabetes Feb;62(2): doi: /db II. Direct control of brown adipose tissue thermogenesis by central nervous system glucagon-like peptide-1 receptor signaling Agonism of the receptor for glucagon-like peptide-1 (GLP-1) is currently one of the most successfully and widely used therapies for type 2 diabetes. GLP-1 is a product of proglucagon that also gives rise to glucagon (GCG) and oxyntomodulin (OXM). Both GLP-1 and its receptor (GLP-1R) are expressed in peripheral tissues and in areas of the central 1

2 nervous system (CNS) involved in the control of energy balance. Treatment with GLP-1R agonists improves glycemic control and reduces body weight in diabetic humans. Studies in animals have demonstrated that CNS GLP-1R signaling contributes to the body weight reducing effect of these agonists. OXM can bind to and activate both GLP-1R and GCGR, and studies with rodents and humans suggest that it may be efficient in treating obesity and diabetes. OXM regulates feeding, at least in part, through GLP-1R. There is evidence that OXM action in the CNS also reduces body weight by increasing energy expenditure. This may involve activation of brown adipose tissue (BAT) metabolism, since intracerebroventricular administration of OXM reduces the weight of interscapular BAT (ibat) pads and increases body temperature in rats. Altogether, these observations led us to hypothesize that activation of the CNS GCGR and GLP-1R signaling regulates BAT thermogenesis. We further postulated that such a control is mediated by activation of the sympathetic nervous system. To verify these hypotheses, we studied ibat activity in wild-type (WT) and glucagon-like peptide 1 receptor (GLP-1R) deficient mice after the administration of the proglucagonderived peptides (PGDPs) glucagon-like peptide (GLP-1), glucagon (GCG), and oxyntomodulin (OXM) directly into the brain. Intracerebroventricular injection of PGDPs reduced body weight and increased ibat thermogenesis. This was independent of changes in feeding and insulin responsiveness, but correlated with increased activity of sympathetic fibers innervating brown adipose tissue. Despite being a GCG receptor agonist, OXM required GLP-1R activation to induce ibat thermogenesis. The increase in thermogenesis in WT mice correlated with increased expression of genes upregulated by adrenergic signaling and required for ibat thermogenesis, including PGC1a and UCP-1. In spite of the increase in ibat thermogenesis induced by GLP-1R activation in WT mice, Glp1r / mice exhibited a normal response to cold exposure, demonstrating that endogenous GLP-1R signaling is not essential for appropriate thermogenic response after cold exposure. Our data suggest that the increase in BAT thermogenesis may be an additional mechanism whereby pharmacological GLP-1R activation controls energy balance. Diabetes 61, , III. Central Melanin-Concentrating Hormone Influences Liver and Adipose Metabolism Via Specific Hypothalamic Nuclei and Efferent Autonomic/JNK1 Pathways Specific neuronal circuits modulate autonomic outflow to liver and white adipose tissue. Melanin-concentrating hormone (MCH)-deficient mice are hypophagic, lean and do not develop hepatosteatosis when fed a high-fat diet. In the present study, we aimed at investigating the role of MCH, an orexigenic neuropeptide specifically expressed in the lateral hypothalamic area, on hepatic and adipocyte metabolism. To this end, the effects of chronic central administration of MCH and adenoviral vectors increasing MCH signaling were studied in rats and mice. Vagal denervation was carried out to assess its effect on liver metabolism. The peripheral effects on lipid metabolism were studied by real-time polymerase chain reaction and Western blot. We observed that the activation of MCH receptors promotes nonalcoholic fatty liver disease through the parasympathetic nervous system, whereas it increases fat deposition in white adipose tissue via the suppression of sympathetic traffic. These metabolic actions are independent of parallel changes in food intake and energy expenditure. In the liver, MCH triggers lipid accumulation and lipid uptake, with c-jun N-terminal kinase being an essential player, whereas in adipocytes MCH induces metabolic pathways that promote lipid storage and decreases lipid mobilization. Genetic activation of MCH receptors or infusion of MCH specifically in the lateral hypothalamic area modulated hepatic lipid metabolism, whereas the specific activation of this receptor in the arcuate nucleus affected adipocyte metabolism. 2

3 To conclude, our findings show that central MCH directly controls hepatic and adipocyte metabolism through different pathways. Gastroenterology Nov 6. pii: S (12) doi: /j.gastro IV. Central glucocorticoid administration promotes weight gain and increased 11βhydroxysteroid dehydrogenase type 1 expression in white adipose tissue Glucocorticoids (GCs) are involved in multiple metabolic processes, including the regulation of insulin sensitivity and adipogenesis. Their action partly depends on their intracellular activation by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). We previously demonstrated that central GC administration promotes hyperphagia, body weight gain, hyperinsulinemia and marked insulin resistance at the level of skeletal muscles. Similar dysfunctions have been reported to occur upon specific overexpression of 11β-HSD1 in adipose tissue. The aim of the present study was therefore to determine whether the effects of central GC infusion may enhance local GC activation in white adipose tissue. Male Wistar and Sprague Dawley (SD) rats were intracerebroventricularly infused with GCs for 2 to 3 days. Body weight, food intake and metabolic parameters were measured, and expression of enzymes regulating 11β-HSD1, as well as that of genes regulated by GCs, was quantified. Central GC administration induced a significant increase in body weight gain and in 11β- HSD1 and resistin expression in adipose tissue. A decrease 11β-HSD1 expression was noticed in the liver of SD rats, as a partial compensatory mechanism. Such effects of GCs are centrally elicited. This model of icv dexamethasone infusion thus appears to be a valuable acute model that helps delineating the initial metabolic defects occurring in obesity. An impaired downregulation of intracellular GC activation in adipose tissue may be important for the development of insulin resistance. PLoS One. 2012;7(3):e doi: /journal.pone V. Oxytocin treatment in obese and diabetic leptin-deficient mice Oxytocin has been demonstrated to be effective in the treatment of obesity, glucose intolerance and insulin resistance present in diet-induced obese rats and mice. The aim of this project was to examine its effectiveness in a more marked model of obesity and diabetes (leptin-deficient ob/ob mice). To this end, ob/ob and lean control mice were treated with oxytocin subcutaneously for 2 weeks. Pair-fed animal groups were included. Food, water, body weight and glycemia were measured daily; Body composition was determined by magnetic resonance imaging before and after the treatment, and glucose tolerance was assessed at the end of the treatment. Gene, protein and enzyme activities were measured in the adipose tissue and the hypothalamus. Finally, macrophage infiltration was studied in adipose tissue. We observed that in lean mice, the effects of the treatment lasted for only one day. In the obese group, the treatment prevented the animals from gaining weight, partially due to a decrease in food intake. It also prevented fat mass gain, due to a decrease in the expression of key genes involved in lipid uptake (Lpl) and lipogenesis (Fas) and to an increase in lipolysis (Hsl). These gene expression changes were food intake-independent. Adipose tissue inflammation was reduced through a decrease in the M1 pro-inflammatory macrophage population. Surprisingly, glucose tolerance failed to be improved by the treatment. It can therefore be concluded that oxytocin prevents body weight gain in leptin-deficient mice, partially due to a decrease in food intake and partially to direct effects on adipose tissue. 3

4 Manuscript in preparation. VI. Presence of brown adipocytes in white adipose tissue and its role in obesity resistance and insulin sensitivity Brown adipose tissue, characterised by the expression of uncoupling protein 1 (UCP1), has recently been described as metabolically active in adult humans. It induces an increase in energy expenditure and its presence seems to be inversely correlated with body weight. Compared to Wistar, the Lou/C rat (which originates from the Wistar strain) is resistant to obesity and more insulin sensitive. These characteristics could be mediated by the presence of UCP1, as well as of an overexpression of the β3- adrenoreceptor (main UCP1 activator) observed in the subcutaneous white adipose tissue depot (WATi). The aim of this project was to determine the consequences of UCP1 activation via the β3- adrenergic pathway on various metabolic parameters, including overall and tissue-specific insulin sensitivity. A β3 agonist treatment (CL , s.c, 1mg/kg/j, 2 wks) was administered in Wistar and Lou/C rats. Measurements of insulin sensitivity, as well as of energy expenditure were obtained by euglycemic hyperinsulinemic clamps and indirect calorimetry, respectively. In Lou/C rats only, the treatment induced a lower food efficiency and a decreased fat mass. The treatment also induced a higher energy expenditure and insulin sensitivity in Lou/C than in Wistar animals. BAT was similarly activated (mrna, protein and glucose intake) in both strains. Both glucose uptake and UCP1 expression were markedly enhanced in WATi of Lou/C rats. Adipose tissue was the only tissue that could explain the β3 agonist-induced increase in insulin sensitivity. Obesity resistance and improvement of insulin sensitivity in Lou/C rats may therefore be linked to UCP1 expression in subcutaneous fat depots. Manuscript in preparation. Publications Marcelino H., Veyrat-Durebex C., Summermatter S., Sarafian D., Miles-Chan J., Arsenijevic D., Zani F., Montani J.-P., Seydoux J., Solinas G., Rohner-Jeanrenaud F., Dulloo A.G. A role for adipose tissue de-novo lipogenesis in glucose homeostasis during catch-up growth: A Randle cycle favouring fat storage. Diabetes, doi: /db Lockie S.H., Heppner K.M., Chaudhary N., Chabenne J.R., Morgan D.A., Veyrat-Durebex C., Ananthakrishnan G., Rohner-Jeanrenaud F., Drucker D.J., DiMarchi R., Rahmouni K., Oldfield B.J., Tschöp M.H., Perez-Tilve D. Direct control of brown adipose tissue thermogenesis by central nervous system glucagon-like peptide-1 receptor signaling. Diabetes 61 : , Imbernon M., Beiroa D., Vázquez M. J., Morgan D. A., Veyrat-Durebex C., Porteiro B., Díaz- Arteaga A., Senra A., Busquets S., Velásquez D. A., Al-Massadi O., Varela L., Gandara M., López-Soriano F.J., Gallego R., Seoane L.M., Argiles J.M., López M., Davis R.J., Sabio G., Rohner-Jeanrenaud F., Rahmouni K., Dieguez C., Nogueiras R. Central Melanin- Concentrating Hormone Influences Liver and Adipose Metabolism Via Specific Hypothalamic Nuclei and Efferent Autonomic/JNK1 Pathways. Gastroenterology Nov 6. doi:pii: S (12) /j.gastro Veyrat-Durebex C., Deblon N., Caillon A., Andrew R., Altirriba J., Odermatt A. Rohner- Jeanrenaud F. Central glucocorticoid administration promotes weight gain and increased 4

5 11β-hydroxysteroid dehydrogenase type 1 expression in white adipose tissue. PLoS ONE 7(3) : e34002, Bourgoin L., Deblon N., Peyrou M., Ramadori P., Rohner-Jeanrenaud F., Foti M. mtor Inhibitors in Chronic Liver Diseases and Cancer. In "Rapamycin: Effectiveness, Safety and Drug Interactions". M. J. Blanco and A. M. Torres eds, Nova Science Publishers, pp 1-30, Submitted for publication Veyrat-Durebex C., Poher A.-L., Caillon A., Somm E., Vallet P., Charnay Y., Rohner-Jeanrenaud F. Improved leptin sensitivity as a potential candidate responsible for the spontaneous food restriction of the Lou/C rat. Submitted to PLoS ONE. Peyrou M., Bourgoin L., Maeder C., Caillon A., Rohner-Jeanrenaud F., Foti M. Hepatic PTEN deficiency triggers steatosis development but improves glucose tolerance by inhibiting hepatic gluconeogenesis and inducing muscle insulin hypersensitivity. Submitted to Diabetes. Lehr L., Somm E., Léger B., Paoloni-Giacobino A., Rohner-Jeanrenaud F., Meda P., Giacobino J.-P. Invalidation of the 4E-BP1 gene induces a complex dysregulation of glucose homeostasis in the absence of endoplasmic reticulum stress. Submitted to Diabetes/Metabolism Research and Reviews. Altirriba-Gutierrez J., Deblon N., Garrido-Urbani S., Caillon A., Veyrat-Durebex C., Disse E., Cristino G., Wahli W., Di Marzo V., Rohner-Jeanrenaud F. Central oxytocin regulates feeding behavior by increasing oleoylethanolamide production in the hypothalamus. In preparation. Altirriba-Gutierrez J., Garrido-Urbani S., Caillon A., Wahli W., Rohner-Jeanrenaud F. Oxytocin treatment in obese and diabetic leptin-deficient mice. In preparation. Poher A.-L., Veyrat-Direbex C., Altirriba-Gutierrez J., Caillon A., Rohner-Jeanrenaud F. Presence of brown adipocytes in white adipose tissue and its role in obesity resistance and insulin sensitivity. In preparation. 5