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International audience; High-protein-low-carbohydrate (HP-LC) diets have become widespread. Yet their deleterious consequences, especially on glucose metabolism and arteries, have already been underlined. Our previous study (2) has already shown glucose intolerance with major arterial dysfunction in very old mice subjected to an HP-LC diet. The hypothesis of this work was that this diet had an age-dependent deleterious metabolic and cardiovascular outcome. Two groups of mice, young and adult (3 and 6 mo old), were subjected for 12 wk to a standard or to an HP-LC diet. Glucose and lipid metabolism was studied. The cardiovascular system was explored from the functional stage with Doppler-echography to the molecular stage (arterial reactivity, mRNA, immunohistochemistry). Young mice did not exhibit any significant metabolic modification, whereas adult mice presented marked glucose intolerance associated with an increase in resistin and triglyceride levels. These metabolic disturbances were responsible for cardiovascular damages only in adult mice, with decreased aortic distensibility and left ventricle dysfunction. These seemed to be the consequence of arterial dysfunctions. Mesenteric arteries were the worst affected with a major oxidative stress, whereas aorta function seemed to be maintained with an appreciable role of cyclooxygenase-2 to preserve endothelial function. This study highlights for the first time the age-dependent deleterious effects of an HP-LC diet on metabolism, with glucose intolerance and lipid disorders and vascular (especially microvessels) and cardiac functions. This work shows that HP-LC lead to equivalent cardiovascular alterations, as observed in very old age, and underlines the danger of such diet.

International audience; Loss-of-function mutations in BSCL2 are responsible for Berardinelli-Seip congenital lipodystrophy, a rare disorder characterized by near absence of adipose tissue associated with insulin resistance. Seipin-deficient (Bscl2 −/−) mice display an almost total loss of white adipose tissue (WAT) with residual brown adipose tissue (BAT). Previous cellular studies have shown that seipin deficiency alters white adipocyte differentiation. In this study, we aimed to decipher the consequences of seipin deficiency in BAT. Using a brown adipocyte cell-line, we show that seipin knockdown had very little effect on adipocyte differentiation without affecting insulin sensitivity and oxygen consumption. However, when submitted to cold acclimation or chronic β3 agonist treatment, Bscl2 −/− mice displayed altered thermogenic capacity, despite several signs of BAT remodeling. Under cold activation, Bscl2 −/− mice were able to maintain their body temperature when fed ad libitum, but not under short fasting. At control temperature (i.e. 21 °C), fasting worsened Bscl2 −/− BAT properties. Finally, Bscl2 −/− BAT displayed obvious signs of insulin resistance. Our results in these lipodystrophic mice strongly suggest that BAT activity relies on WAT as an energetic substrate provider and adipokine-producing organ. Therefore, the WAT/BAT dialogue is a key component of BAT integrity in guaranteeing its response to insulin and cold-activated adrenergic signals. Berardinelli and Seip congenital lipodystrophy (BSCL) is a rare autosomal genetic disease characterized by an almost complete lack of white adipose tissue (WAT) 1,2. BSCL is associated with metabolic disturbances, including insulin resistance, hypertriglyceridaemia, and liver steatosis. The most severe form of BSCL is caused by bi-allelic mutations in BSCL2, which encodes seipin, an endoplasmic reticulum (ER) protein of unknown function 3. Seipin deficiency strongly impairs adipocyte differentiation in vitro 4,5. In yeast and in cultured human cells, seipin deficiency alters lipid droplet (LD) morphology, with either a few giant or multiple small LDs 6–9. Recently, seipin was reported to be essential for the initiation of LD formation in yeast 10. In accordance with a potential role in triglyc-eride (TG) synthesis pathway, seipin was shown to interact with 1-acylglycerol-3-phosphate O-acyltransferase 2 (AGPAT2) and lipin 1 11,12. Finally, seipin has been shown to promote TG storage through an interaction with the calcium pump SERCA2 in drosophila 13. Nevertheless, the precise biological role of seipin and the exact pathways in which it is implicated remain unclear. A major breakthrough in the understanding of the pathophysiology of BSCL2 came with the generation of global knockout (KO) mice for Bscl2. Bscl2 −/− mice display severe lipodystrophy, with at least a 90% decrease in WAT mass and the development of insulin resistance and hepatic steatosis, thus recapitulating the main features of the human BSCL phenotype 14–16. Adipose-specific Bscl2 −/− mice exhibit progressive lipodystrophy associated with similar metabolic complications 17 , whereas the transgenic overexpression of Bscl2 in WAT from Bscl2 −/− mice is sufficient to rescue the phenotype 18. Finally, thiazolidinedione (TZD) treatment in global or adipose-specific Bscl2 KO mice promotes an increase in WAT mass, leading to an improvement of the metabolic 1

Introduction Les chirurgies bariatriques representent une alternative therapeutique de choix chez les patients obeses morbides. Outre la perte de poids, elles reduisent les complications metaboliques frequemment associes, notamment les dyslipidemies. Bien que l'effet hypocholesterolemiant soit dependant de la procedure chirurgicale utilisee, les mecanismes moleculaires impliques demeurent mal definis. Cette etude vise a mesurer les consequences de deux chirurgies bariatriques (la sleeve gastrectomie et le by-pass Roux en Y) sur les voies regulant le metabolisme du cholesterol. Materiels et Methodes Des souris mâles C57BL6/J de 10 semaines ont recu un regime hyperlipidique pendant 8 a 12 semaines avant la chirurgie. Les souris ont ete randomisees sur le poids et la cholesterolemie et reparties dans 3 groupes experimentaux : un groupe sham (laparotomie), un groupe sham « pair-fed » et un groupe « chirurgie ». Nous avons ensuite mesure les consequences des chirurgies sur le poids, la prise alimentaire et le metabolisme glucidique et lipidique. L'analyse des voies d'excretion du cholesterol a ete determinee par spectrometrie de masse (GC-MS). Resultats Deux semaines apres la chirurgie (J +14), la sleeve et le by-pass induisent une reduction du poids corporel (respectivement − 15,63 % et − 25 %, p Conclusions En conclusion, nous avons mis en place deux modeles de chirurgie bariatrique chez la souris. La sleeve a un effet hypocholesterolemiant modeste principalement lie a des modifications du comportement alimentaire, alors que le by-pass induit une reduction importante du cholesterol sanguin en stimulant son excretion fecale.

Introduction En l'absence de traitement pharmacologique, les chirurgies bariatriques representent une alternative therapeutique de choix chez les patients obeses. Outre la perte de poids, les chirurgies bariatriques reduisent efficacement les complications metaboliques de l'obesite, notamment les dyslipidemies. Toutefois, les mecanismes associes demeurent mal connus. Notre etude vise a mesurer les consequences de la sleeve gastrectomie sur le metabolisme intestinal et hepatobiliaire du cholesterol. Materiels et methodes Des souris mâles C57BL6/J âgees de 10 semaines ont recu un regime hyperlipidique 8 semaines avant la chirurgie. Les souris ont ete ensuite randomisees sur le poids et la cholesterolemie et reparties dans 3 groupes experimentaux: un groupe sham (laparotomie), un groupe sham « pair-fed » et un groupe « sleeve ». Le poids, la prise alimentaire, les parametres lipidiques sanguins, l'excretion biliaire, transintestinale (TICE) et fecale de cholesterol ont ete mesurees avant et apres chirurgie. Resultats La duree operatoire moyenne etait de 49,33±5,09 minutes et la mortalite postchirurgicale etait faible: 7,14 % ( n =39). Deux semaines apres la chirurgie, nous avons note une tendance a la reduction de la prise alimentaire chez les souris « sleeve » (-13 % vs souris sham, p =0,08). Les souris « sleeve » presentaient une reduction significative de leur poids (– 8,3 %, p =0,03) et de leur cholesterolemie (– 20 %, p =0,05) par rapport aux souris sham. En revanche, il n'existe pas de difference entre les souris « sleeve » et les souris sham « pair-fed » suggerant que les effets hypocholesterolemiants sont principalement lies a la restriction alimentaire. Conclusion En conclusion, nous avons mis en place avec succes le modele « sleeve » chez la souris. Des analyses plus approfondies (i.e. mesure du TICE) visant a caracteriser l'effet hypocholesterolemiant de le sleeve sont en cours et permettront de determiner s'ils sont independants de la restriction calorique. Declaration d’interet Les auteurs declarent ne pas avoir d'interet direct ou indirect (financier ou en nature) avec un organisme prive, industriel ou commercial en relation avec le sujet presente.