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In the context of obesity, senescent cells accumulate in white adipose tissue (WAT). The cellular underpinnings of WAT senescence leading to insulin resistance are not fully elucidated. The objective of the current study was to evaluate the presence of WAT senescence early after initiation of high‐fat diet (HFD, 1–10 weeks) in 5‐month‐old male C57BL/6J mice and the potential role of energy metabolism. We first showed that WAT senescence occurred 2 weeks after HFD as evidenced in whole WAT by increased senescence‐associated ß‐galactosidase activity and cyclin‐dependent kinase inhibitor 1A and 2A expression. WAT senescence affected various WAT cell populations, including preadipocytes, adipose tissue progenitors, and immune cells, together with adipocytes. WAT senescence was associated with higher glycolytic and mitochondrial activity leading to enhanced ATP content in HFD‐derived preadipocytes, as compared with chow diet‐derived preadipocytes. One‐month daily exercise, introduced 5 weeks after HFD, was an effective senostatic strategy, since it reversed WAT cellular senescence, while reducing glycolysis and production of ATP. Interestingly, the beneficial effect of exercise was independent of body weight and fat mass loss. We demonstrated that WAT cellular senescence is one of the earliest events occurring after HFD initiation and is intimately linked to the metabolic state of the cells. Our data uncover a critical role for HFD‐induced elevated ATP as a local danger signal inducing WAT senescence. Exercise exerts beneficial effects on adipose tissue bioenergetics in obesity, reversing cellular senescence, and metabolic abnormalities., High‐fat diet (HFD) induced senescence of various white adipose tissue (WAT) cell types as one of the earliest events preceding mitochondrial dysfunction, inflammation, and fibrosis. In WAT of HFD‐fed mice and preadipocytes derived from HFD‐fed mice, ATP levels were increased. The anti‐senescence effects of exercise were partially dependent on purine catabolism as blocking xanthine oxidase activity increased ATP levels and inhibited exercise's rescue effects in subcutaneous WAT.

Obesity is associated with metabolic dysregulation characterized by insulin resistance and glucose intolerance. Nuclear factor E2-related factor (Nrf2) is a critical regulator of the stress response and Nrf2-deficient mice (Nrf2−/−) are protected against high fat diet (HFD)-induced metabolic derangement. We searched for factors that could underline this favorable phenotype and found that Nrf2−/− mice exhibit higher circulating levels of sirtuin 1 (Sirt1), a key player in cellular homeostasis and energy metabolism, compared to wild-type mice. Increased Sirt1 levels in Nrf2−/− mice were found not only in animals under standard diet but also following HFD. Interestingly, we report here that the visceral adipose tissue (eWAT) is the sole source of increased Sirt1 protein in plasma. eWAT and other fat depots displayed enhanced adipocytes lipolysis, increased fatty acid oxidation and glycolysis, suggesting autocrine and endocrine actions of Sirt1 in this model. We further demonstrate that removal of eWAT completely abolishes the increase in circulating Sirt1 and that this procedure suppresses the beneficial effect of Nrf2 deficiency on glucose tolerance, but not insulin sensitivity, following a HFD regime. Thus, in contrast to many other stressful conditions where Nrf2 deficiency exacerbates damage, our study indicates that up-regulation of Sirt1 levels specifically in the visceral adipose tissue of Nrf2−/− mice is a key adaptive mechanism that mitigates glucose intolerance induced by nutritional stress., Graphical abstract Image 1, Highlights • Nrf2−/− mice are protected against weight gain and metabolic dysfunction under high fat diet (HFD). • Nrf2−/− mice display increased production of sirtuin 1 exclusively in visceral white adipose tissue (eWAT). • Removal of eWAT prior to HFD abolishes the increase in sirtuin 1 and impairs glucose tolerance. • A strong link exists between Nrf2 deficiency, SIRT1 in eWAT and regulation of glucose homeostasis.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in industrializedcountries because being strongly associated with the development of metabolic syndrome and relateddyslipidemia. To date, the mechanisms of pathology remain poorly defined and available therapeutic meanshave moderate efficacy. Epidemiological studies have reported a beneficial effect of tea consumption in thefight against liver disorders and cardiovascular risk factors such as dyslipidemia. However, the mechanismsby which a blend of green tea, oolong tea and Pu-erh tea, Hao Ling tea, reduces fatty liver and dyslipidemiaremain unknown. Therefore, the objective of this thesis was to evaluate the effects and mechanisms of actionof Hao Ling tea on NAFLD and dyslipidemia, through two approaches, one on cellular model and the other onanimal model. Our results show that Hao Ling tea reduces the hepatic lipogenesis in vitro and in vivo and thusattenuates steatosis induced by a high fat-high sucrose diet in a rat model. We observed that this tea improvesthe blood lipid profile by increasing plasma HDL levels. We were also able to highlight that tea ownsantioxidant and hepato-protective properties to counteract an inducer of oxidative stress in vitro and todecrease lipid peroxidation in vivo. Finally, we have shown that the oxidative stress per se resulted in anaccumulation of intracellular lipid in isolated hepatocytes and that the tea, due to its antioxidant properties,prevented this phenomenon. The Hao Ling tea is a good nutritional approach in preventing NAFLD and tomaintain LDL/HDL ratio., La stéatose hépatique non-alcoolique (NAFLD) est l’affection hépatique chronique la plus fréquente à l’heure actuelle dans le monde industrialisé car fortement liée au développement du syndrome métabolique et des dyslipidémies associées. À ce jour, les mécanismes de la pathologie restent mal définis et les moyens thérapeutiques disponibles ont une efficacité modérée. Des études épidémiologiques ont rapporté un effet bénéfique de la consommation de thé pour lutter contre les désordres hépatiques et les facteurs de risque cardiovasculaires tel que la dyslipidémie. Cependant, les mécanismes par lesquels le thé atténue la stéatose hépatique et la dyslipidémie restent méconnus. Par conséquent, l’objectif de ce travail de thèse était d’évaluer les effets et les mécanismes d’action d’un mélange de thés vert, oolong et Pu-erh, le thé Hao Ling, sur la NAFLD et la dyslipidémie, à travers deux approches, l’une sur modèle cellulaire et l’autre sur modèle animal.Les résultats ont permis de mettre en évidence que le thé Hao Ling permettait de diminuer la lipogenèse hépatique in vitro et in vivo et ainsi d’atténuer la stéatose induite par un régime hyperlipidique et riche en saccharose chez le rat Wistar. Nous avons observé que ce thé permettait d’améliorer le profil lipidique sanguin en augmentant le taux de HDL plasmatique. Nous avons également pu mettre en évidence que le thé possédait des propriétés antioxydantes et hépato-protectrices permettant de lutter contre un inducteur de stress oxydant in vitro et de diminuer la peroxydation lipidique in vivo. Enfin, nous avons démontré que le stress oxydant "per se" entraînait une accumulation de lipides intracellulaires sur hépatocytes isolés et que le thé, grâce à ses propriétés antioxydantes, prévenait ce phénomène. Le thé Hao Ling constitue une bonne approche nutritionnelle dans la prévention de la NAFLD et dans le maintien du rapport LDL-Cholestérol/HDLCholestérol.

International audience

International audience; Tea is an interesting source of antioxidants capable of counteracting the oxidative stress implicated in liver diseases. We investigated the impact of antioxidant molecules provided by a mixture of teas' leaves (green, oolong, pu-erh) after different infusion durations in the prevention of oxidative stress in isolated rat hepatocytes, by comparison with pure epigallocatechin-3-gallate (EGCG), the main representative of tea catechins. Dried aqueous tea extracts (ATE) obtained after 5, 15 and 30 min infusion time were characterized for total polyphenols (gallic acid equivalent), catechins, gallic acid and caffeine (HPLC-DAD/ESI-MS) contents, and for scavenging ability against 2,2-diphenyl-1-picrylhydrazyl free radical. Hepatoprotection was evaluated through hepatocyte viability tests using tert-butyl hydroperoxide as a stress inducer, (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, neutral red uptake, real-time cellular impedance) and mitochondrial function tests. We showed that a 5-min incubation time is sufficient for an optimal bioaccessibility of tea compounds with the highest antioxidative ability, which decreases for longer durations. A 4-h pretreatment of cells with ATE significantly prevented cell death by regulating reactive oxygen species production and maintaining mitochondrial integrity. Pure EGCG, at doses similar in ATE (5-12 µM), was inefficient, suggesting a plausible synergy of several water-soluble tea compounds to explain the ATE beneficial effects.