No description available.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / A modulação do tecido adiposo marrom (TAM) e do tecido adiposo branco (TAB) está associada à prevenção ou redução do ganho de massa corporal. O óleo de peixe possui diversos efeitos benéficos que podem estar relacionados a esses tecidos. Dessa forma, objetivou-se avaliar os efeitos antiobesogênicos de diferentes dietas hiperlipídicas com óleo de peixe na termogênese do TAM e na lipogênese e beta-oxidação do TAB. Para isso, foram utilizados camundongos machos C57BL/6, com três meses de idade, que foram divididos em quatro grupos experimentais: um que recebeu dieta standard-chow (SC, 10% kcal de lipídios) e outros três que receberam dieta hiperlipídica (HL, 50% kcal de lipídios). Obtivemos os grupos HL com banha de porco (HL-B), HL com banha de porco mais óleo de peixe (HL-B+Px) e HL com óleo de peixe (HL-Px). As dietas foram administradas por um período de oito semanas, sendo que a ingestão alimentar foi avaliada diariamente e a massa corporal, semanalmente. Na última semana de experimento, realizou-se a calorimetria indireta e o teste oral de tolerância à glicose. No sacrifício, a glicemia foi aferida, o sangue foi puncionado para obtenção do plasma e o TAM interescapular e o TAB epididimário foram dissecados e armazenados. A leptina, os triglicerídeos e a insulina foram mensurados no plasma. O índice de adiposidade e o HOMA-IR foram calculados. O TAM e o TAB foram avaliados por microscopia confocal e de luz. Realizou-se RT-qPCR e Western blot para avaliação de marcadores termogênicos, da captação e oxidação de ácidos graxos e glicose e de PPAR no TAM, e para a avaliação da lipogênese e beta-oxidação e de PPAR no TAB. Com relação aos resultados, o grupo HL-B apresentou ganho de massa corporal e elevação da adiposidade, associado com hipertrofia dos adipócitos, hiperleptinemia, hipertrigliceridemia, intolerância à glicose e resistência à insulina, reproduzindo um quadro de obesidade e síndrome metabólica. Por outro lado, a ingestão de óleo de peixe nos dois grupos (HL-B+Px e HL-Px) foi capaz de reduzir o ganho de massa corporal e a adiposidade, sem alterar a ingestão alimentar. Essa ingestão também aumentou o gasto energético dos animais, regularizou a leptina e os triglicerídeos plasmáticos, bem como a tolerância à glicose e a resistência à insulina. Esses efeitos foram associados ao aumento de marcadores termogênicos no TAM, bem como da captação e oxidação de ácidos graxos e glicose e da expressão de PPAR nesse tecido. No TAB, houve redução de marcadores da lipogênese e aumento de marcadores da beta-oxidação, juntamente com elevação na expressão de PPAR. Em conclusão, nossos resultados mostram que a ingestão de óleo de peixe tem efeitos antiobesogênicos em camundongos através da modulação benéfica do TAM e do TAB e pode, portanto, representar uma terapia auxiliar alternativa contra a obesidade e suas comorbidades. / Brown adipose tissue (BAT) and white adipose tissue (WAT) modulation is associated with prevention or reduction of body mass gain. Fish oil has several beneficial effects which can be related to these tissues. Thus, we aimed to evaluate the anti-obesity effects of different high-fat diets with fish oil on BAT thermogenesis and WAT lipogenesis and beta-oxidation. For this, we used 3-mo-old C57BL/6 male mice that were divided into four groups: one that received a standard-chow diet (SC, 10% kcal of lipids) and three that received a high-fat diet (HF, 50% kcal of lipids). We obtained the HF with lard group (HF-L), the HF with lard plus fish oil group (HF-L+FO), and the HF with fish oil group (HF-FO). Diets were administrated for eight weeks, and food intake was evaluated daily and the body mass, weekly. At the end of the experiment, we performed indirect calorimetry and an oral glucose tolerance test. At sacrifice, glycemia was assessed, the blood was punctured to obtain plasma and interscapular BAT and epididymal WAT were dissected and stored. Plasmatic leptin, triglycerides and insulin were analyzed. Adiposity index and HOMA-IR were calculated. BAT and WAT were evaluated through confocal and light microscopy. RT-qPCR and Western blot were performed for analyses of thermogenic markers, fatty acids and glucose uptake and oxidation, and PPAR in BAT, and lipogenesis, beta-oxidation and PPAR in WAT. In relation to the results, the HF-L group presented elevated body mass gain and adiposity, associated with adipocyte hypertrophy, hyperleptinemia, hypertriglyceridemia, glucose intolerance and insulin resistance, displaying a condition that simulates obesity and metabolic syndrome. On the contrary, fish oil intake in both groups (HF-L+FO and HF-FO) was able to reduce body mass gain and adiposity, without affecting food intake. It also increased energy expenditure, normalized plasmatic leptin and triglycerides as well as glucose tolerance and insulin resistance. These effects were associated with increases in thermogenic markers, in uptake and oxidation of fatty acids and glucose and in PPAR expression in BAT. In WAT, lipogenesis was reduced and beta-oxidation and PPAR expression were increased. In conclusion, our results demonstrated that fish oil intake has anti-obesity effects in mice through beneficial modulation of BAT and WAT and can, therefore, represent an auxiliary alternative therapy against obesity and its comorbidities.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / A modulação do tecido adiposo marrom (TAM) e do tecido adiposo branco (TAB) está associada à prevenção ou redução do ganho de massa corporal. O óleo de peixe possui diversos efeitos benéficos que podem estar relacionados a esses tecidos. Dessa forma, objetivou-se avaliar os efeitos antiobesogênicos de diferentes dietas hiperlipídicas com óleo de peixe na termogênese do TAM e na lipogênese e beta-oxidação do TAB. Para isso, foram utilizados camundongos machos C57BL/6, com três meses de idade, que foram divididos em quatro grupos experimentais: um que recebeu dieta standard-chow (SC, 10% kcal de lipídios) e outros três que receberam dieta hiperlipídica (HL, 50% kcal de lipídios). Obtivemos os grupos HL com banha de porco (HL-B), HL com banha de porco mais óleo de peixe (HL-B+Px) e HL com óleo de peixe (HL-Px). As dietas foram administradas por um período de oito semanas, sendo que a ingestão alimentar foi avaliada diariamente e a massa corporal, semanalmente. Na última semana de experimento, realizou-se a calorimetria indireta e o teste oral de tolerância à glicose. No sacrifício, a glicemia foi aferida, o sangue foi puncionado para obtenção do plasma e o TAM interescapular e o TAB epididimário foram dissecados e armazenados. A leptina, os triglicerídeos e a insulina foram mensurados no plasma. O índice de adiposidade e o HOMA-IR foram calculados. O TAM e o TAB foram avaliados por microscopia confocal e de luz. Realizou-se RT-qPCR e Western blot para avaliação de marcadores termogênicos, da captação e oxidação de ácidos graxos e glicose e de PPAR no TAM, e para a avaliação da lipogênese e beta-oxidação e de PPAR no TAB. Com relação aos resultados, o grupo HL-B apresentou ganho de massa corporal e elevação da adiposidade, associado com hipertrofia dos adipócitos, hiperleptinemia, hipertrigliceridemia, intolerância à glicose e resistência à insulina, reproduzindo um quadro de obesidade e síndrome metabólica. Por outro lado, a ingestão de óleo de peixe nos dois grupos (HL-B+Px e HL-Px) foi capaz de reduzir o ganho de massa corporal e a adiposidade, sem alterar a ingestão alimentar. Essa ingestão também aumentou o gasto energético dos animais, regularizou a leptina e os triglicerídeos plasmáticos, bem como a tolerância à glicose e a resistência à insulina. Esses efeitos foram associados ao aumento de marcadores termogênicos no TAM, bem como da captação e oxidação de ácidos graxos e glicose e da expressão de PPAR nesse tecido. No TAB, houve redução de marcadores da lipogênese e aumento de marcadores da beta-oxidação, juntamente com elevação na expressão de PPAR. Em conclusão, nossos resultados mostram que a ingestão de óleo de peixe tem efeitos antiobesogênicos em camundongos através da modulação benéfica do TAM e do TAB e pode, portanto, representar uma terapia auxiliar alternativa contra a obesidade e suas comorbidades. / Brown adipose tissue (BAT) and white adipose tissue (WAT) modulation is associated with prevention or reduction of body mass gain. Fish oil has several beneficial effects which can be related to these tissues. Thus, we aimed to evaluate the anti-obesity effects of different high-fat diets with fish oil on BAT thermogenesis and WAT lipogenesis and beta-oxidation. For this, we used 3-mo-old C57BL/6 male mice that were divided into four groups: one that received a standard-chow diet (SC, 10% kcal of lipids) and three that received a high-fat diet (HF, 50% kcal of lipids). We obtained the HF with lard group (HF-L), the HF with lard plus fish oil group (HF-L+FO), and the HF with fish oil group (HF-FO). Diets were administrated for eight weeks, and food intake was evaluated daily and the body mass, weekly. At the end of the experiment, we performed indirect calorimetry and an oral glucose tolerance test. At sacrifice, glycemia was assessed, the blood was punctured to obtain plasma and interscapular BAT and epididymal WAT were dissected and stored. Plasmatic leptin, triglycerides and insulin were analyzed. Adiposity index and HOMA-IR were calculated. BAT and WAT were evaluated through confocal and light microscopy. RT-qPCR and Western blot were performed for analyses of thermogenic markers, fatty acids and glucose uptake and oxidation, and PPAR in BAT, and lipogenesis, beta-oxidation and PPAR in WAT. In relation to the results, the HF-L group presented elevated body mass gain and adiposity, associated with adipocyte hypertrophy, hyperleptinemia, hypertriglyceridemia, glucose intolerance and insulin resistance, displaying a condition that simulates obesity and metabolic syndrome. On the contrary, fish oil intake in both groups (HF-L+FO and HF-FO) was able to reduce body mass gain and adiposity, without affecting food intake. It also increased energy expenditure, normalized plasmatic leptin and triglycerides as well as glucose tolerance and insulin resistance. These effects were associated with increases in thermogenic markers, in uptake and oxidation of fatty acids and glucose and in PPAR expression in BAT. In WAT, lipogenesis was reduced and beta-oxidation and PPAR expression were increased. In conclusion, our results demonstrated that fish oil intake has anti-obesity effects in mice through beneficial modulation of BAT and WAT and can, therefore, represent an auxiliary alternative therapy against obesity and its comorbidities.

Abstract Obesity is associated with greater risk of several diseases, such as type 2 diabetes and metabolic syndrome. Single nucleotide polymorphisms (SNP) within the fat mass- and obesity-associated gene FTO are robustly associated with increased body mass index (BMI) in several age and ethnic groups. Studies with transgenic mice support a mechanistic role for FTO protein in energy metabolism. Fto-deficient mice are leaner than wild-type and overexpression of Fto leads to obese phenotype; however, the precise mechanism of FTO action in the control of BMI has remained obscure. Fto mRNA is most abundant in the brain while high expression is present also in white and brown adipose tissues (WAT and BAT, respectively). WAT stores the nutritional energy and BAT dissipates it to produce heat. Furthermore, these organs participate in a complex endocrine network affecting the whole body metabolism, which is more or less disrupted in obesity. In the browning process, white adipocytes begin to manifest brown characteristics. MicroRNAs (miRNA) are small RNA molecules, which fine-tune post-transcriptionally the expression of genes important in several cellular processes, including WAT and BAT differentiation and browning of WAT. FTO has been shown to participate in these processes as well as miRNA regulation. The current study used a new Fto-deficient mouse model to reveal deeper insights into the role of Fto on genes affecting WAT and BAT differentiation and function, as well as WAT browning. Furthermore, the effects of Fto on the miRNA regulation in WAT browning and BAT were investigated. Our results supported a role for Fto in adipose tissue. Fto-deficient mice were resistant to diet-induced obesity and their WAT and BAT adipocytes did not become hypertrophic similar to wild-type on high-fat diet. Furthermore, the expression of genes affecting adipose tissue differentiation and function was altered in Fto-deficient WAT and BAT, especially after high-fat diet, and the changes may be mediated via altered miRNA expression. Fto-deficient WAT was more susceptible to browning, which in part contributed to the lean phenotype of these mice. Current study supported a role for Fto in whole body metabolism and adaptation of adipose tissue to changes in dietary environment. / Tiivistelmä Lihavuus on toistuvasti yhdistetty useisiin liitännäissairauksiin, kuten tyypin 2 diabetekseen ja metaboliseen oireyhtymään. FTO-geenissä (fat mass- and obesity-associated) esiintyvien yhden nukleotidin muutoksien (single nucleotide polymorphia, SNP) on useissa ikä- ja etnisissä ryhmissä raportoitu liittyvän korkeampaan painoindeksiin ihmisillä. Muuntogeenisillä hiirillä tehdyt tutkimukset tukevat FTO:n mekanistista roolia energia-aineenvaihdunnassa, sillä Fto-poistogeeniset hiiret ovat villityypin hiiriä laihempia ja sen yliekspressio johtaa ylipainoon. FTO:n tarkka rooli painon säätelyssä on kuitenkin vielä epäselvä. Fto:ta tuotetaan eniten aivoissa, mutta myös valkoisessa ja ruskeassa rasvassa. Valkoinen rasva varastoi ravinnosta saatavan energian ja ruskea hajottaa sitä lämmöntuotantoon. Näillä kudoksilla on lisäksi tärkeä rooli energia-aineenvaihdunnan monimutkaisessa verkostossa. Valkoisen rasvakudoksen ruskettumisprosessissa valkoiset rasvasolut alkavat muistuttaa ruskeita rasvasoluja. Mikro-RNA:t (miRNA) ovat pieniä RNA-juosteita, jotka hienosäätävät geenien ekspressiota transkription jälkeen ja vaikuttavat useisiin solun tärkeisiin tapahtumiin, myös valkoisen ja ruskean rasvasolun erilaistumiseen ja ruskettumiseen. FTO osallistuu näihin prosesseihin sekä miRNA-säätelyyn. Tämän tutkimuksen tavoitteena oli selventää Fto:n roolia valkoisen ja ruskean rasvakudoksen erilaistumisessa ja toiminnassa Fto-poistogeenisen hiirimallin avulla. Lisäksi selvitettiin Fto:n vaikutuksia valkoisen rasvan ruskettumiseen ja ruskean rasvan toimintaan osallistuvien miRNA:iden säätelyyn. Tulokset tukivat FTO:n roolia rasvakudoksessa. Fto-poistogeeniset hiiret eivät lihoneet rasvaisella ruokavaliolla eivätkä niiden rasvasolut varastoineet rasvaa yhtä paljon kuin villityypin hiirillä rasvaisen ruokavalion jälkeen. Lisäksi Fto-poistogeenisen rasvakudoksen erilaistumiseen ja toimintaan liittyvien geenien esiintyvyys muuttui erityisesti rasvaisella ruokavaliolla. Nämä muutokset voivat osittain selittyä muuttuneella miRNA-säätelyllä. Tulokset viittasivat siihen, että Fto-poistogeeninen valkoinen rasvakudos oli alttiimpaa ruskettumiselle, mikä osaltaan vaikutti Fto-poistogeenisten hiirten laihuuteen. Tutkimus tuki Fto-geenin roolia energia-aineenvaihdunnan säätelyssä sekä rasvakudoksen mukautumisessa ruokavalion muutoksiin.

Le rat Lou/C, issu de la souche Wistar, reste maigre tout au long de sa vie. Le but de ce travail était de caractériser la balance énergétique du rat Lou/C et d’établir quel(s) étai(en)t le(s) tissu(s) thermogène(s) impliqué(s) dans la dissipation de l’énergie alimentaire ingérée en excès. Si la quantité d’énergie ingérée, rapportée par unité de masse corporelle, n’était pas différente entre les deux souches de rats, la dépense énergétique du Lou/C était supérieure au repos, suite à un repas et lors de l’exercice physique. Le rat Lou/C montrait également une hyperactivité locomotrice spontanée volontaire bien supérieure à celle du Wistar. De façon inattendue, le tissu adipeux brun (BAT) des Lou/C était peu actif, comme l'ont montré des approches fonctionnelles in vivo, biochimiques in vitro ou moléculaires. L'absence d'activation du BAT du rat Lou/C n’était pas liée à une déficience du tissu puisqu’il était aisément activable par une exposition prolongée au froid. La forte activité physique spontanée du Lou/C ne s’accompagnait pas de l’activation de processus thermogènes particuliers des mitochondries isolées de BAT ou de muscle squelettique. En revanche, nous avons mis en évidence un mécanisme potentiel de découplage des oxydations phosphorylantes mitochondriales dans le foie des Lou/C. Contre toute attente, le rat Lou/C disposait de capacités de synthèse des acides gras équivalentes à celles du Wistar dans le foie et supérieures dans le tissu adipeux blanc avec de fortes capacités d’oxydation de ces substrats dans ces tissus, suggérant un possible cycle futile entre la synthèse des acides gras et leur oxydation dans le foie et le tissu adipeux blanc. Le rat Lou/C représente donc un modèle original de régulation de la balance énergétique qui n’est pas basé sur l’activité thermogène du BAT. Le muscle squelettique, le foie et le tissu adipeux blanc du Lou/C pourraient participer à un métabolisme actif des lipides et contribuer à la dissipation accrue de l’énergie ingérée en excès. / Lou/C rat, an inbred strain of Wistar origin, remains lean throughout life. Our study aimed to characterize the energy balance of Lou/C rats and determine the tissue(s) that could be implicated in the dissipation of excess energy intake. Food intake, expressed per unit body mass, was not different between the two strains of rats but resting metabolic rate, diet-induced thermogenesis and exercise-associated energy expenditure were higher in the Lou/C strain. Moreover, the spontaneous activity of Lou/C rats was amazingly higher than that of Wistar rats. Unexpectedly, the thermogenic brown adipose tissue (BAT) of Lou/C rats was not over-stimulated as demonstrated by functional in vivo, biochemical in vitro or molecular approaches. Nevertheless, Lou/C BAT was not deficient as it could easily be stimulated by prolonged cold exposure. The high spontaneous activity of Lou/C rats was not correlated with an activation of specific thermogenic processes in isolated mitochondria of BAT or skeletal muscle. However, oxidation and phosphorylation were partly uncoupled in liver mitochondria of Lou/C rats. Unexpectedly, Lou/C rats displayed similar capacities for fatty acid synthesis in liver but higher capacities in white adipose tissue than Wistar rats, in association with high capacities for oxidation of these substrates in these tissues. These results suggested a possible mechanism of futile cycling between fatty acid synthesis and oxidation in liver and white adipose tissue. Lou/C rats therefore represent an original model of regulation of energy balance that is not based on the thermogenic activity of BAT. Skeletal muscle, liver and white adipose tissue of Lou/C rats could contribute to a higher lipid metabolism and the dissipation of excess energy intake.

Pheochromocytoma and functional paraganglioma (PPGL) are rare neuroendocrine tumors characterized by catecholamines overproduction, which give a rise to disorders of glucose, lipid, and energy metabolism. The role of adipose tissue in these processes remains unclear. Our aim was to determine the gene expression profile in subcutaneous and visceral adipose tissue of patients with PPGL focusing on endocrine functions of adipose tissue, occurrence of brown (BAT) and beige adipose tissue (BeAT), all in connection with other measured metabolic and energy parameters and levels of circulating adipokines. We demonstrate signs of UCP1-dependent norepinephrine induced thermogenesis connected with overexpression of DIO2 in retroperitoneal VAT of PPGL and higher expression of key transcriptional factors of brown/beige adipogenesis, namely PPARGC1α, CEBPB and PRDM16. However, classic murine BAT or BeAT gene signature in VAT of PPGL was not detected. In subcutaneous adipose tissue (SAT) of PPGL we found signs of possible BeAT transformation, however without simultaneously undergoing UCP1-dependent thermogenesis. We also demonstrate that patients with PPGL have higher serum levels of FGF21 compared to healthy controls and these levels do not differ from obese patients. Furthermore, successful tumor removal...

Recent studies suggest adipose tissue plays a critical role in regulating whole body energy homeostasis in both animals and humans. In particular, activating brown adipose tissue (BAT) activity is now appreciated as a potential therapeutic strategy against obesity and metabolic disease. However, the signaling circuits that coordinate nutrient uptake and BAT function are poorly understood. Here, I investigated the role of the nutrient-sensing mTOR signaling pathway in BAT by conditionally deleting Rictor, which encodes an essential component of mTOR Complex 2 (mTORC2) either in brown adipocyte precursors or mature brown adipocytes. In general, inhibiting BAT mTORC2 reduces glucose uptake and de novo lipogenesis pathways while increases lipid uptake and oxidation pathways indicating a switch in fuel utilization. Moreover, several key thermogenic factors (Ucp1, Pgc1α, and Irf4) are elevated in Rictor-deficient BAT, resulting in enhanced thermogenesis. Accordingly, mice with mTORC2 loss in BAT are protected from HFD-induced obesity and metabolic disease at thermoneutrality. In vitro culture experiments further suggest that mTORC2 cell-autonomously regulates the BAT thermogenic program, especially Ucp1 expression, which depends on FoxO1 activity. Mechanistically, mTORC2 appears to inhibit FoxO1 by facilitating its lysine-acetylation but not through the canonical AKT-mediated phosphorylation pathway. Finally, I also provide evidence that β-adrenergic signaling which normally triggers thermogenesis also induces FoxO1 deacetylation in BAT. Based on these data, I propose a model in which mTORC2 functions in BAT as a critical signaling hub for coordinating nutrient uptake, fuel utilization, and thermogenic gene expression. These data provide a foundation for future studies into the mTORC2-FoxO1 signaling axis in different metabolic tissues and physiological conditions.

No description available.

No description available.

Le cycle glycérolipides/acides gras libres (GL/FFA) est une voie métabolique clé qui relie le métabolisme du glucose et des acides gras et il est composé de deux processus métaboliques appelés lipogenèse et lipolyse. Le cycle GL/FFA, en particulier la lipolyse des triglycérides, génère diverses molécules de signalisation pour réguler la sécrétion d'insuline dans les cellules bêta pancréatiques et la thermogenèse non-frissonnante dans les adipocytes. Actuellement, les lipides provenant spécifiquement de la lipolyse impliqués dans ce processus sont mal connus. L’hydrolyse des triglycérides dans les cellules β est réalisée par les actions successives de la triglycéride lipase adipocytaire pour produire le diacylglycérol, ensuite par la lipase hormono-sensible pour produire le monoacylglycérol (MAG) et enfin par la MAG lipase (MAGL) qui relâche du glycerol et des acides gras. Dans les cellules bêta, la MAGL classique est très peu exprimée et cette étude a démontré que l’hydrolyse de MAG dans les cellules β est principalement réalisée par l'α/β-Hydrolase Domain-6 (ABHD6) nouvellement identifiée. L’inhibition d’ABHD6 par son inhibiteur spécifique WWL70, conduit à une accumulation des 1-MAG à longues chaines saturées à l'intérieur des cellules, accompagnée d’une augmentation de la sécrétion d'insuline stimulée par le glucose (GSIS). Baisser les niveaux de MAG en surexprimant ABHD6 dans la lignée cellulaire bêta INS832/13 réduit la GSIS, tandis qu’une augmentation des niveaux de MAG par le « knockdown » d’ABHD6 améliore la GSIS. L'exposition aiguë des monoacylglycérols exogènes stimule la sécrétion d'insuline de manière dose-dépendante et restaure la GSIS supprimée par un inhibiteur de lipases appelé orlistat. En outre, les souris avec une inactivation du gène ABHD6 dans tous les tissus (ABHD6-KO) et celles avec une inactivation du gène ABHD6 spécifiquement dans la cellule β présentent une GSIS stimulée, et leurs îlots montrent une augmentation de la production de monoacylglycérol et de la sécrétion d'insuline en réponse au glucose. L’inhibition d’ABHD6 chez les souris diabétiques (modèle induit par de faibles doses de streptozotocine) restaure la GSIS et améliore la tolérance au glucose. De plus, les résultats montrent que les MAGs non seulement améliorent la GSIS, mais potentialisent également la sécrétion d’insuline induite par les acides gras libres ainsi que la sécrétion d’insuline induite par divers agents et hormones, sans altération de l'oxydation et l'utilisation du glucose ainsi que l'oxydation des acides gras. Nous avons démontré que le MAG se lie à la protéine d’amorçage des vésicules appelée Munc13-1 et l’active, induisant ainsi l’exocytose de l'insuline. Sur la base de ces observations, nous proposons que le 1-MAG à chaines saturées agit comme facteur de couplage métabolique pour réguler la sécrétion d'insuline et que ABHD6 est un modulateur négatif de la sécrétion d'insuline. En plus de son rôle dans les cellules bêta, ABHD6 est également fortement exprimé dans les adipocytes et son niveau est augmenté avec l'obésité. Les souris dépourvues globalement d’ABHD6 et nourris avec une diète riche en gras (HFD) montrent une faible diminution de la prise alimentaire, une diminution du gain de poids corporel et de la glycémie à jeun et une amélioration de la tolérance au glucose et de la sensibilité à l'insuline et ont une activité locomotrice accrue. En outre, les souris ABHD6-KO affichent une augmentation de la dépense énergétique et de la thermogenèse induite par le froid. En conformité avec ceci, ces souris présentent des niveaux élevés d’UCP1 dans les adipocytes blancs et bruns, indiquant le brunissement des adipocytes blancs. Le phénotype de brunissement est reproduit dans les souris soit en les traitant de manière chronique avec WWL70 (inhibiteur d’ABHD6) ou des oligonucléotides anti-sense ciblant l’ABHD6. Les tissus adipeux blanc et brun isolés de souris ABHD6-KO montrent des niveaux très élevés de 1-MAG, mais pas de 2-MAG. L'augmentation des niveaux de MAG soit par administration exogène in vitro de 1-MAG ou par inhibition ou délétion génétique d’ABHD6 provoque le brunissement des adipocytes blancs. Une autre évidence indique que les 1-MAGs sont capables de transactiver PPARα et PPARγ et que l'effet de brunissement induit par WWL70 ou le MAG exogène est aboli par les antagonistes de PPARα et PPARγ. L’administration in vivo de l’antagoniste de PPARα GW6471 à des souris ABHD6-KO inverse partiellement les effets causés par l’inactivation du gène ABHD6 sur le gain de poids corporel, et abolit l’augmentation de la thermogenèse, le brunissement du tissu adipeux blanc et l'oxydation des acides gras dans le tissu adipeux brun. L’ensemble de ces observations indique que ABHD6 régule non seulement l’homéostasie de l'insuline et du glucose, mais aussi l'homéostasie énergétique et la fonction des tissus adipeux. Ainsi, 1-MAG agit non seulement comme un facteur de couplage métabolique pour réguler la sécrétion d'insuline en activant Munc13-1 dans les cellules bêta, mais régule aussi le brunissement des adipocytes blancs et améliore la fonction de la graisse brune par l'activation de PPARα et PPARγ. Ces résultats indiquent que ABHD6 est une cible prometteuse pour le développement de thérapies contre l'obésité, le diabète de type 2 et le syndrome métabolique. / The glycerolipid/ free fatty acid (GL/FFA) cycle is a key metabolic pathway that links glucose and fatty acid metabolism and it consists of lipogenesis and lipolysis. GL/FFA cycling, especially in its lipolysis arm, generates various lipid signaling molecules to regulate insulin secretion in pancreatic ß-cells and non-shivering thermogenesis in adipocytes. Currently, the lipolysis-derived lipid signals involved in this process are uncertain. Triglyceride hydrolysis in mammalian cells is accomplished by the sequential actions of adipose triglyceride lipase to produce diacylglycerol, by hormone sensitive lipase to produce monoacylglycerol (MAG) and by MAG lipase (MAGL) that releases free fatty acid and glycerol. Our work shows that in pancreatic ß-cell, the classical MAGL is poorly expressed and that MAG hydrolysis is mainly conducted by the newly identified α/β-Hydrolase Domain-6 (ABHD6). Inhibition of ABHD6 by its specific inhibitor WWL70, leads to long-chain saturated 1-MAG accumulation inside the cells, accompanied by enhanced glucose-stimulated insulin secretion (GSIS). Decreasing the MAG levels by overexpression of ABHD6 in the ß-cell line INS832/13 reduces GSIS, while increasing MAG levels by ABHD6 knockdown enhances GSIS. Acute exposure of INS832/13 cells to various MAG species dose-dependently stimulates insulin secretion and restores GSIS suppressed by the pan-lipase inhibitor orlistat. Also, various biochemical and pharmacological experiments show that saturated 1-MAG levels species rather than unsaturated or 2-MAG species best correlate with insulin secretion. Furthermore, whole-body and β-cell-specific ABHD6-KO mice exhibit enhanced GSIS in vivo, and their isolated islets show elevated MAG production and GSIS. Inhibition of ABHD6 in low dose streptozotocin diabetic mice restores GSIS and improves glucose tolerance. Results further show that ABHD6-accessible MAGs not only enhance GSIS, but also potentiate fatty acid and non-fuel-induced insulin secretion without alteration in glucose oxidation and utilization as well as fatty acid oxidation. We have identified that MAG binds and activates the vesicle priming protein Munc13-1, thereby inducing insulin exocytosis. Based on all these observations, we propose that lipolysis-derived saturated 1-MAG acts as a metabolic coupling factor to regulate insulin secretion and ABHD6 is a negative modulator of insulin secretion. Besides its role in ß-cells, ABHD6 is also highly expressed in adipocytes and its level is increased with obesity. Mice globally lacking ABHD6 on high fat diet (HFD) show modestly reduced food intake, decreased body weight gain, insulinemia and fasting glycemia and improved glucose tolerance and insulin sensitivity and enhanced locomotor activity. In addition, ABHD6-KO mice display increased energy expenditure and cold-induced thermogenesis. In accordance with this, these mice show elevated UCP1 level in white and brown adipocytes, indicating browning of white adipocytes. The browning phenotype is reproduced in the mice either chronically treated with the ABHD6 inhibitor WWL70 or an antisense oligonucleotides targeting ABHD6. White and brown adipose tissues isolated from whole body ABHD6 KO mice show greatly elevated levels of 1-MAG, but not 2-MAG. Increasing MAG levels by either exogenous administration of 1-MAG or ABHD6 inhibition or genetic deletion induces browning of white adipocytes in a cell-autonomous manner. Further evidence indicates that 1-MAGs can transactivate PPARα and PPARγ and the browning effect induced by WWL70 or exogenous MAG is abolished by PPARα and PPARγ antagonists. In vivo administration of the PPARα antagonist GW6471 to ABHD6 KO mice partially reversed the ABHD6-KO effects on body weight gain, and abolishes the enhanced thermogenesis, white adipose browning and fatty acid oxidation in brown adipose tissue. All these observations indicate that ABHD6 regulates not only insulin and glucose homeostasis but also energy homeostasis and adipose tissue function. Thus, ABHD6-accessible 1-MAG not only acts as a metabolic coupling factor to regulate fuel and non-fuel induced insulin secretion by activating Munc13-1 in beta cells, but also regulates glucose, insulin and energy homeostasis. The latter effects are mediated at least in part via browning of white adipocytes and enhanced brown fat function through the activation of PPARα and PPARγ. Collectively these findings suggest that ABHD6 is a promising target for developing therapeutics against obesity, type 2 diabetes and metabolic syndrome.