The Adipose Renin-Angiotensin System Modulates Systemic Markers of Insulin Sensitivity and Activates the Intrarenal Renin-Angiotensin System

Background. The adipose tissue renin-angiotensin system (RAS) contributes to regulation of fat mass and may also impact systemic functions such as blood pressure and metabolism. Methods and results. A panel of mouse models including mice lacking angiotensinogen, Agt (Agt-KO), mice expressing Agt solely in adipose tissue (aP2-Agt/Agt-KO), and mice overexpressing Agt in adipose tissue (aP2-Agt) was studied. Total body weight, epididymal fat pad weight, and circulating levels of leptin, insulin, and resistin were significantly decreased in Agt-KO mice, while plasma adiponectin levels were increased. aP2-Agt mice exhibited increased adiposity and plasma leptin and insulin levels compared to wild type (WT) controls. Angiotensinogen and type I Ang II receptor protein levels were also elevated in kidney of aP2-Agt mice. Conclusion. These findings demonstrate that alterations in adipose RAS activity significantly impact both local and systemic physiology in a way that may contribute to the detrimental health effects of obesity

Rôle de l'angiotensinogène adipocytaire dans le développement du tissu adipeux et de l'hypertension

Le tissu adipeux est un important site extra-hépatique de production de l'angiotensinogène, le précurseur de l'hormone angiotensine II qui possède des activités paracrines au sein de ce tissu. En effet, différentes approches in-vitro ont mis en évidence un rôle de l'ang II sur la différenciation et la maturation adipocytaire. De plus des données épidémiologiques ont montré une corrélation entre les niveaux plasmatiques d'angiotensinogène, la pression artérielle et l'indice de masse corporelle. Au cours de ma thèse j'ai réalisé une étude in-vivo concernant le rôle de l'angiotensinogène adipocytaire, au niveau local, sur le développement du tissu adipeux ainsi qu'au niveau endocrine, sur la régulation de la pression artérielle. Pour cela j'ai réalisé dans un premier temps une étude complète du tissu adipeux de souris déficientes en angiotensinogène (agt-/-) en comparaison à des souris témoins. Les souris agt-/- présentent des altérations dans le développement du tissu adipeux, un défaut de prise de poids en réponse à un régime hyperlipidique ainsi qu'une augmentation de l'activité locomotrice. Dans un second temps j'ai généré des souris transgéniques soit qui sur-expriment l'angiotensinogène adipocytaire, soit chez lesquelles l'expression de l'angiotensinogène est restreinte au tissu adipeux. Dans les deux cas, une expression ciblée de l'angiotensinogène dans le tissu adipeux permet un augmentation de la masse adipeuse ainsi que de la pression artérielle. Au terme de ces études, nos résultats ont montré que l'angiotensinogène adipocytaire joue à la fois un rôle local et un rôle endocrine, en faveur de son implication chez les patients obèses hypertendus.NICE-BU Sciences (060882101) / SudocSudocFranceF

Prebiotics Supplementation Impact on the Reinforcing and Motivational Aspect of Feeding.

Energy homeostasis is tightly regulated by the central nervous system which responds to nervous and circulating inputs to adapt food intake and energy expenditure. However, the rewarding and motivational aspect of food is tightly dependent of dopamine (DA) release in mesocorticolimbic (MCL) system and could be operant in uncontrolled caloric intake and obesity. Accumulating evidence indicate that manipulating the microbiota-gut-brain axis through prebiotic supplementation can have beneficial impact of the host appetite and body weight. However, the consequences of manipulating the implication of the microbiota-gut-brain axis in the control motivational and hedonic/reinforcing aspects of food are still underexplored. In this study, we investigate whether and how dietary prebiotic fructo-oligosaccharides (FOS) could oppose, or revert, the change in hedonic and homeostatic control of feeding occurring after a 2-months exposure to high-fat high-sugar (HFHS) diet. The reinforcing and motivational components of food reward were assessed using a two-food choice paradigm and a food operant behavioral test in mice exposed to FOS either during or after HFHS exposure. We also performed mRNA expression analysis for key genes involved in limbic and hypothalamic control of feeding. We show in a preventive-like approach, FOS addition of HFHS diet had beneficial impact of hypothalamic neuropeptides, and decreased the operant performance for food but only after an overnight fast while it did not prevent the imbalance in mesolimbic markers for DA signaling induced by palatable diet exposure nor the spontaneous tropism for palatable food when given the choice. However, when FOS was added to control diet after chronic HFHS exposure, although it did not significantly alter body weight loss, it greatly decreased palatable food tropism and consumption and was associated with normalization of MCL markers for DA signaling. We conclude that the nature of the diet (regular chow or HFHS) as well as the timing at which prebiotic supplementation is introduced (preventive or curative) greatly influence the efficacy of the gut-microbiota-brain axis. This crosstalk selectively alters the hedonic or motivational drive to eat and triggers molecular changes in neural substrates involved in the homeostatic and non-homeostatic control of body weight

Arachidonic acid and prostacyclin signaling promote adipose tissue development: a human health concern

Abstract High fat intake is associated with fat mass gain through fatty acid activation of peroxisome proliferator-activated receptors � and �, which promote adipogenesis. We show herein that, compared to a combination of specific agonists to both receptors or to saturated, monounsaturated, and �-3 polyunsaturated fatty acids, arachidonic acid (C20:4, �-6) promoted substantially the differentiation of clonal preadipocytes. This effect was blocked by cyclooxygenase inhibitors and mimicked by carbacyclin, suggesting a role for the prostacyclin receptor and activation of the cyclic AMPdependent pathways that regulate the expression of the CCAAT enhancer binding proteins � and � implicated in adipogenesis. During the pregnancy-lactation period, mother mice were fed either a high-fat diet rich in linoleic acid, a precursor of arachidonic acid (LO diet), or the same isocaloric diet enriched in linoleic acid and �-linolenic acid (LO/ LL diet). Body weight from weaning onwards, fat mass, epididymal fat pad weight, and adipocyte size at 8 weeks of age were higher with LO diet than with LO/LL diet. In contrast, prostacyclin receptor-deficient mice fed either diet were similar in this respect, indicating that the prostacyclin signaling contributes to adipose tissue development. These results raise the issue of the high content of linoleic acid of i) ingested lipids during pregnancy and lactation, and ii) formula milk and infant foods in relation to the epidemic of childhood obesity.—Massiera, F., P. Saint-Marc, J. Seydoux

A Western-like fat diet is sufficient to induce a gradual enhancement in fat mass over generations[S]

The prevalence of obesity has steadily increased over the last few decades. During this time, populations of industrialized countries have been exposed to diets rich in fat with a high content of linoleic acid and a low content of α-linolenic acid compared with recommended intake. To assess the contribution of dietary fatty acids, male and female mice fed a high-fat diet (35% energy as fat, linoleic acid:α-linolenic acid ratio of 28) were mated randomly and maintained after breeding on the same diet for successive generations. Offspring showed, over four generations, a gradual enhancement in fat mass due to combined hyperplasia and hypertrophy with no change in food intake. Transgenerational alterations in adipokine levels were accompanied by hyperinsulinemia. Gene expression analyses of the stromal vascular fraction of adipose tissue, over generations, revealed discrete and steady changes in certain important players, such as CSF3 and Nocturnin. Thus, under conditions of genome stability and with no change in the regimen over four generations, we show that a Western-like fat diet induces a gradual fat mass enhancement, in accordance with the increasing prevalence of obesity observed in humans

image_1_Prebiotics Supplementation Impact on the Reinforcing and Motivational Aspect of Feeding.tif

<p>Energy homeostasis is tightly regulated by the central nervous system which responds to nervous and circulating inputs to adapt food intake and energy expenditure. However, the rewarding and motivational aspect of food is tightly dependent of dopamine (DA) release in mesocorticolimbic (MCL) system and could be operant in uncontrolled caloric intake and obesity. Accumulating evidence indicate that manipulating the microbiota–gut–brain axis through prebiotic supplementation can have beneficial impact of the host appetite and body weight. However, the consequences of manipulating the implication of the microbiota–gut–brain axis in the control motivational and hedonic/reinforcing aspects of food are still underexplored. In this study, we investigate whether and how dietary prebiotic fructo-oligosaccharides (FOS) could oppose, or revert, the change in hedonic and homeostatic control of feeding occurring after a 2-months exposure to high-fat high-sugar (HFHS) diet. The reinforcing and motivational components of food reward were assessed using a two-food choice paradigm and a food operant behavioral test in mice exposed to FOS either during or after HFHS exposure. We also performed mRNA expression analysis for key genes involved in limbic and hypothalamic control of feeding. We show in a preventive-like approach, FOS addition of HFHS diet had beneficial impact of hypothalamic neuropeptides, and decreased the operant performance for food but only after an overnight fast while it did not prevent the imbalance in mesolimbic markers for DA signaling induced by palatable diet exposure nor the spontaneous tropism for palatable food when given the choice. However, when FOS was added to control diet after chronic HFHS exposure, although it did not significantly alter body weight loss, it greatly decreased palatable food tropism and consumption and was associated with normalization of MCL markers for DA signaling. We conclude that the nature of the diet (regular chow or HFHS) as well as the timing at which prebiotic supplementation is introduced (preventive or curative) greatly influence the efficacy of the gut–microbiota–brain axis. This crosstalk selectively alters the hedonic or motivational drive to eat and triggers molecular changes in neural substrates involved in the homeostatic and non-homeostatic control of body weight.</p