Serum osmolarity and haematocrit do not modify the association between the impedance index (Ht2/Z) and total body water in the very old: The Newcastle 85+ Study

Bioelectrical impedance is a non-invasive technique for the assessment of body composition; however, information on its accuracy in the very old (80+ years) is limited. We investigated whether the association between the impedance index and total body water (TBW) was modified by hydration status as assessed by haematocrit and serum osmolarity. This was a cross-sectional analysis of baseline data from the Newcastle 85+ Cohort Study. Anthropometric measurements [weight, height (Ht)] were taken and body mass index (BMI) calculated. Leg-to-leg bioimpedance was used to measure the impedance value (Z) and to estimate fat mass, fat free mass and TBW. The impedance index (Ht2/Z) was calculated. Blood haematocrit, haemoglobin, glucose, sodium, potassium, urea and creatinine concentrations were measured. Serum osmolarity was calculated using a validated prediction equation. 677 men and women aged 85 years were included. The average BMI of the population was 24.3±4.2kg/m2 and the prevalence of overweight and obesity was 32.6% and 9.5%, respectively. The impedance index was significantly associated with TBW in both men (n=274, r=0.76, p<0.001) and women (n=403, r=0.96, p<0.001); in regression models, the impedance index remained associated with TBW after adjustment for height, weight and gender, and further adjustment for serum osmolarity and haematocrit. The impedance index values increased with BMI and the relationship was not modified by hydration status in women (p=0.69) and only marginally in men (p=0.02). The association between the impedance index and TBW was not modified by hydration status, which may support the utilisation of leg-to-leg bioimpedance for the assessment of body composition in the very old

Contribution of abdominal adiposity to age-related differences in insulin sensitivity and plasma lipids in healthy nonobese women

WSTĘP. Autorzy sprawdzili słuszność hipotezy zakładającej, że związany z wiekiem przyrost tkanki tłuszczowej trzewnej odpowiada częściowo za ujemny wpływ na insulinowrażliwość i profil lipidowy u kobiet bez otyłości. MATERIAŁ I METODY. Bezpośrednio oceniono: powierzchnię podskórnej i trzewnej tkanki tłuszczowej (tomografia komputerowa), zużycie glukozy (badanie metodą hiperinsulinowej/euglikemicznej klamry metabolicznej), elementy składowe organizmu (metoda absorpcjometrii promieniami X dwoistej energii), profil lipidowy oraz maksymalne zużycie tlenu (VO2max) u 178 kobiet bez otyłości, zakwalifikowanych do odpowiednich grup wiekowych: grupa 1 - 28 &plusmn; 4 lata (n = 88); grupa 2 - 46 &plusmn; 2 lata (n = 38); grupa 3 - 53 &plusmn; 2 lata (n = 31); grupa 4 - 67 &plusmn; 6 lat (n = 21). WYNIKI. Powierzchnia trzewnej tkanki tłuszczowej zwiększa się wraz z wiekiem (2,36 cm2 rocznie, p < 0,0001). Zanotowano związany z wiekiem wzrost stężenia cholesterolu całkowitego (p < 0,0003), triglicerydów (p < 0,0009), cholesterolu frakcji LDL (p < 0,027) i stosunku stężenia cholesterolu całkowitego do cholesterolu frakcji HDL (p < 0,042). Obserwowane różnice w insulinowrażliwości także wiązały się z wiekiem, jednakże w tym przypadku zależność była odmienna. Insulinowrażliwość, wyrażona jako całkowita lub przeliczona na kilogram beztłuszczowej masy ciała, była najniższa w grupie 4, ale nie różniła się istotnie między grupami 1, 2 i 3. Po analizie statystycznej, uwzględniającej powierzchnię tkanki tłuszczowej trzewnej, niższa insulinowrażliwość utrzymywała się, jednocześnie, relatywnie zmniejszyła się różnica w porównaniu z pozostałymi grupami. Wpływ zawartości trzewnej tkanki tłuszczowej na związane z wiekiem zmiany profilu lipidowego był silniejszy. Różnice w powierzchni trzewnej i głębokiej podskórnej tkanki tłuszczowej znosiły wpływ wieku na stężenie cholesterolu całkowitego, triglicerydów i cholesterolu frakcji LDL. Nie obserwowano natomiast wpływu wartości VO2max lub aktywnego wypoczynku na zależne od wieku zmiany w insulinowrażliwości bądź profilu lipidowym. WNIOSKI. 1) Wraz z wiekiem zwiększa się powierzchnia trzewnej tkanki tłuszczowej, podczas gdy zmniejszenie insulinowrażliwości obserwuje się tylko u kobiet starszych; 2) Związane z wiekiem różnice w trzewnej tkance tłuszczowej tylko w niewielkim stopniu odpowiadają za spadek insulinowrażliwości u kobiet bez otyłości; 3) Niepożądane zmiany profilu lipidowego w dużym stopniu wiążą się z zależnym od wieku przyrostem trzewnej tkanki tłuszczowej.INTRODUCTION. We examined the hypothesis that an age-related increase in the compartments of visceral fat would account, in part, for the deleterious changes in insulin sensitivity and blood lipid profile in nonobese women. MATERIAL AND METHODS. We directly assessed visceral and subcutaneous abdominal adipose tissue areas (computed tomography), glucose disposal (hyperinsulinemic-euglycemic clamp), body composition (dual energy X-ray absorptiometry), blood-lipid profile, and aerobic fitness (VO2max) in 178 nonobese women categorized into four age groups: group 1, 28 &plusmn; 4 years, n = 88; group 2, 46 &plusmn; 2 years, n = 38; group 3, 53 &plusmn; 2 years, n = 31; and group 4, 67 &plusmn; 6 years, n = 21. RESULTS. Visceral abdominal adipose tissue area increased with age (2.36 cm2 per year, P < 0.0001). We noted an age-related increase in total cholesterol (P < 0.0003), triglycerides (P < 0.0009), LDL cholesterol (P < 0.027), and the ratio of total cholesterol to HDL cholesterol (P < 0.042). However, agerelated changes in insulin sensitivity exhibited a different age-related pattern. That is, insulin sensitivity, expressed on an absolute basis or indexed per kilogram of fat-free mass, was lowest in group 4 but was not significantly different among groups 1, 2, and 3. After statistical control for visceral fat, lower insulin sensitivity persisted in group 4, although differences were diminished relative to other groups. However, the effect of visceral fat on agerelated changes in the blood-lipid profile was stronger. That is, differences in visceral and deep subcutaneous adipose tissue area abolished age-related differences in total cholesterol, triglycerides, and LDL cholesterol. No independent effects of VO2max or leisure-time physical activity on age-related changes in insulin sensitivity or on the blood-lipid profile were noted. CONCLUSIONS. We conclude that 1) visceral fat shows an increase with advancing age, whereas a decrease in insulin sensitivity was noted only in older women; 2) age-related differences in visceral fat explain only a modest part of the decline in insulin sensitivity in nonobese women; and 3) unfavorable changes in plasma lipids were strongly associated with the age-related increase in visceral abdominal adipose tissue

Psychosocial predictors of visceral adiposity

Psychosocial factors are thought to influence health through primarily direct physiological mechanisms or the alteration of health related behaviors. Three factors hypothesized to negatively impact health include arousal, life stress, and depressive symptomatology. One recent theorist suggests that the interaction between psychological stress and stress hormones on the neuroendocrine system may result in adverse changes to body composition, most notably the increased deposition of visceral adipose tissue (Bjorntorp, 1993). The current study prospectively examined the relationship between self-reported stressful life events, depressive symptoms and trait arousal on the deposition of visceral fat, as measured by computerized tomography (CT). Subjects were obtained from a sample of middle-aged males and females (n = 120). Stress measures included the Weekly Stress Inventory (WSI), a life-events measure of minor stressors, and the Life Events Survey (LES) a measure of major life events. Depression symptoms were measured with the Center for Epidemiological Studies Depression Scale (CES-D). Stress and depression were assessed at baseline, 6 and 12 months, and the CT images of visceral fat were obtained at baseline and 12 months. Trait arousal was measured with the Arousal Predisposition Scale at baseline. Arousal, stress and depression scores over 12 months were then standardized and averaged, and entered into a hierarchical multiple regression model in order to predict changes in visceral adiposity from baseline to 12 months. The model was significant in predicting visceral fat, accounting for 16.9% of the variance. Further examination of the model indicated the presence of a significant 3-way interaction between arousal, stress and depression, such that visceral fat was predicted by the interaction of low arousal, high stress and high depression. When the interaction terms were added to the regression analysis as additional steps, the model continued to be significant, accounting for 20.9% of the variance. Interestingly, these models were significant in predicting visceral adiposity despite the fact that the relationships observed were not all in the expected directions. These findings have implications for both researchers and clinicians, who may wish to incorporate more specific psychosocial measures and interventions in the study and treatment of overweight and obesity

Examination of Genetic Components Affecting Human Obesity-Related Quantitative Traits

Obesity increases the risk for several conditions, including type 2 diabetes mellitus, cardiovascular disease, hypertension, osteoarthirits and certain types of cancer. Twin- and family studies have shown that there is a major genetic component in the determination of body mass. In recent years several technological and scientific advance have been made in obesity research. For instance, novel replicated loci have been revealed by a number of genome wide association studies. This thesis aimed to investigate the association of genetic factors and obesity-related quantitative traits. The first study investigated the role of the lactase gene in anthropometric traits. We genetically defined lactose persistence by genotyping 31 720 individuals of European descent. We found that lactase persistence was significantly correlated with weight and body mass index but not with height. In the second study we performed the largest whole genome linkage scan for body mass index to date. The sample consisted of 4401 twin families and 10 535 individuals from six European countries. We found supporting evidence for two loci (3q29 and 7q36). We observed that the heritability estimate increased substantially when additional family members were removed from the analyses, which suggests reduced environmental variance in the twin sample. In the third study we assessed metabonomic, transcriptomic and genomic variation in a Finnish population cohort of 518 individuals. We formed gene expression networks to portray pathways and showed that a set of highly correlated genes of an inflammatory pathway associated with 80 serum metabolites (of 134 quantified measures). Strong association was found, for example, with several lipoprotein subclasses. We inferred causality by using genetic variation as anchors. The expression of the network genes was found to be dependent on the circulatory metabolite concentrations.Lihavuus on huomattava, lisääntyvä ongelma maailmassa. Lihavuus lisää riskiä sairastua sydän- ja verisuonitautiin, tyypin 2 diabetekseen, nivelrikkoon ja tietyn tyyppisiin syöpiin. Perhe- ja kaksostutkimukset ovat osoittaneet että suuri osa ruumiinpainon vaihtelusta selittyy perinnöllisillä tekijöillä. Tämän työn tarkoituksena oli tutkia lihavuuteen liittyvien jatkuvien muuttujien ja perinnöllisten komponenttien vuorovaikutusta. Ensimmäisessä osatyössä tarkasteltiin laktaasigeenin vaikutusta ruumiin rakenteeseen. Määritimme geneettisesti laktoosi-intoleranssin 31 720 Eurooppalaisessa henkilössä. Havaitsimme, että laktoosiintolerantikoilla oli tilastollisesti merkittävästi pienempi ruumiinpaino, sekä painoindeksi kuin laktoosia sietävillä henkilöillä. Laktoosi-intoleranssin ei havaittu vaikuttavan loppupituuteen. Toisessa osatyössä tutkimme painoindeksiä toistaiseksi suurimmalla kaksosperheistä koostuvalla kytkentätutkimuksella. Tutkimusaineistona oli 10 535 eurooppalaista henkilöä 4 401 perheestä, kuudesta eri maasta. Havaitsimme kromosomeissa 3q29 ja 7q36 aikaisempia tutkimuksia tukevia löydöksiä. Lisäksi havaitsimme että heritabiliteetti kasvoi, kun jätimme analyyseistä pois muut perheenjäsenet, joka viittaisi ympäristöstä johtuvan vaihtelun pienenemiseen kaksosaineistossa. Kolmannessa osatyössä tutkimme aineenvaihdunta-, geeniekspressio- ja geenimerkkidataa suomalaisessa väestöotoksessa joka koostui 518 suomalaisesta henkilöstä. Muodostimme geeniverkkoja keskenään vahvasti korreloivista geeneistä ja havaitsimme että tulehdukseen liittyvä geeniverkko korreloi vahvasti 80 seerumin aineenvaihduntatekijän kanssa 134:stä mitatusta. Erittäin vahvoja korrelaatioita löytyi esimerkiksi lipoproteiinien alaluokista. Arvioimme myös syy-seuraussuhdetta käyttämällä geenimerkkejä suuntaavina pisteinä verkkoanalyysissä. Geeniverkon ilmentymisen eheyden todettiin olevan riippuvainen aineenvaihduntatekijöiden pitoisuudesta veressä

Prévention de l'obésité et du diabète de type 2 par les oestrogènes : rôle des fonctions transactivatrices du récepteur des oestrogènes alpha

Les œstrogènes jouent un rôle crucial pour le maintien de l'homéostasie énergétique et glucidique en activant le récepteur nucléaire alpha des œstrogènes (ERa). L'objectif principal de ce travail de thèse a donc été d'étudier le rôle respectif des 2 fonctions de transactivation (ERaAF-1 et ERaAF-2) qui contribuent à moduler la transcription de très nombreux gènes en réponse à l'activation du ERa. Dans ce but, nous avons utilisé des modèles murins déficients en ERa (ERa-/-), en ERß (ERß-/-), ou spécifiquement invalidés pour les fonctions ERaAF-1 (ERaAF-10) ou ERaAF-2 (ERaAF-20), et soumis à un régime obésogène. Après avoir confirmé le rôle du ERa, nous avons montré que les effets bénéfiques des œstrogènes endogènes et de l'administration d'E2 sur la composition corporelle, la sensibilité à l'insuline et l'homéostasie glucidique sont totalement maintenus dans le modèle ERaAF-10, mais abolis chez les souris ERaAF-20. Ainsi, comme précédemment démontré en termes de protection vasculaire et osseuse, l'action bénéfique des œstrogènes sur la composition corporelle, la sensibilité à l'insuline et la tolérance au glucose s'avère indépendante de la fonction AF-1, mais dépendante de la fonction AF-2 du ERa.Estrogens play a crucial role in maintaining energy and glucose homeostasis by activating the nuclear estrogen receptor alpha ( ERa ). However it is essential to better understand the mechanisms of activation. The main objective of this thesis has been to study the roles of two transactivation functions (ERaAF-1 and ERaAF-2) that contribute to modulate the transcription of many genes in response to the activation of ERa. For this purpose, we have developed an experimental approach exclusively in vivo, based on the use of mouse models deficient in ERa (ERa-/-), in ERß (ERß-/-), or specifically invalidated for ERaAF-1 (ERaAF-10) or ERaAF-2 (ERaAF-20) functions, and subjected to an obesogenic diet. After confirming the crucial role of ERa, showing the abolition of the protective effect of oestradiol (E2 ) in ERa-/- mice and not ERa-/-, we showed that the beneficial effects of endogenous estrogen and administration of E2 on body composition, insulin sensitivity and glucose homeostasis are completely retained in the ERaAF-10model, but abolished in ERaAF-20mice. As previously demonstrated in terms of bone and vascular protection, the beneficial actions of estrogen on the body composition, insulin sensitivity and glucose tolerance appears independent function AF-1, but dependent AF -2 of ERa

Effect of pregnancy on adipose tissue biology in a mouse model of obesity

Obesity is recognized as a risk factor for adverse pregnancy outcomes. Maternal obesity prevalence has increased in parallel with that in the general population and is associated with an increase in morbidity and mortality for both mother and baby. Obese mothers are more likely to develop gestational diabetes, hypertensive disorders including preeclampsia, thromboembolic complications, miscarriage, and have an increased need for induction of labour. Babies born from obese mothers can be abnormally large (macrosomia) or small for gestational age, and have a higher risk of perinatal death and congenital malformation. Pregnancy induces marked and dynamic changes in energy metabolism, however, the direct effects of pregnancy adipose tissue biology in both normal lean and obese women is still largely unknown. The aim of this thesis was to delineate novel mechanisms by which pregnancy affects adipose tissue biology, and thus infer how obesity might adversely affect pregnancy outcomes. We used an animal model of obesity during pregnancy in which mice were given a high fat diet (HF) to make them obese. We identified that pregnancy was associated with an unexpected curtailment of visceral (mesenteric) adipose tissue mass in HF mice and with an attenuation, rather than worsening of the metabolic impairment expected from the combination of excess dietary fat and insulin resistance/glucose intolerance of pregnancy. To determine the underlying molecular mechanism contributing to this phenotype global gene expression microarray with subsequent pathway analysis and qRT-PCR validation was employed within the visceral adipose tissue. In visceral fat of HF pregnant mice, gene pathways for de novo lipogenesis and lipid storage, inflammation, retinol metabolism, insulin like growth factor and estrogenic signaling showed altered regulation. Given the known role of estrogen on adipose tissue and inflammatory cell function, a hypothesis was generated that altered estrogen receptor (ER)α expression/activation/increased estradiol presence within mesenteric fat formed a unifying molecular mechanism underlying the altered adipose biology and relative amelioration of the metabolic phenotype in HF pregnant mice. To test the ER α hypothesis, a female clonal adipocyte cell line, Chub-S7, and primary visceral and subcutaneous adipocytes from pregnant obese and lean patients were treated with the ERα selective agonist, PPT. PPT downregulated mRNA levels of key genes involved in de novo lipogenesis (ME1, FANS and SCD1 Dgat2), consistent with a direct role for ERα activation in curtailment of fat expansion. Although the primary human study lacked sufficient power to adequately address the hypothesis, PPT significantly suppressed SCD1 mRNA levels in visceral adipocytes of lean women. In parallel with the curtailment of mesenteric fat expansion, HF pregnant mice were found to have increased liver weight and liver triglyceride content. However, this “fatty liver” phenotype was not associated with increased mRNA levels of genes involved in hepatic triglyceride uptake or de novo lipogenesis. This increase in liver triglycerides may be due to an excessive influx of fatty acids from mesenteric fat through the portal vein. In conclusion, pregnancy in obese animals is associated with a beneficial curtailment in mesenteric fat expansion, normalization of metabolic disturbances and reduced adipose inflammation. Increased ERα activation within adipocytes may play a critical role in this phenotype

Differences between the gut microbiota of men and women and their relationship to the prevalence of developing metabolic diseases

La creciente incidencia de las enfermedades metabólicas en la población mundial, particularmente de la obesidad, el síndrome metabólico (SM), y la diabetes de tipo 2 (DT2), ha hecho de ellas un problema sanitario, social, y económico de primer orden. El hecho de que estas patologías muestren un marcado dimorfismo sexual en su desarrollo y prevalencia hace suponer la implicación en ellas de las hormonas sexuales. La obesidad, además de constituir una patología per se, constituye un factor de riesgo para el SM, que a su vez influye en la DT2. Dentro de este marco, se han descrito dos patrones de distribución de la grasa, un patrón periférico, típico de mujeres premenopáusicas, y un patrón central, típico de mujeres posmenopáusicas y hombres. Ambos patrones, sujetos a una base genética regulada por las hormonas sexuales, están relacionados con el desarrollo de las enfermedades metabólicas, mostrando la grasa central (abdominal visceral) un perfil patológico frente a un perfil protector de la grasa periférica (subcutánea). La influencia de las hormonas sexuales en las enfermedades metabólicas está avalada por situaciones en las que sus niveles están alterados. Hombres y mujeres transgénero muestran una redistribución de la grasa corporal tras el tratamiento con esteroides sexuales, al igual que ocurre tras los cambios hormonales de la menopausia. La disminución del nivel de estrógeno, tras la menopausia y tras una ooforectomía, eleva el riesgo de sufrir DT2, mientras que la terapia hormonal con estrógenos en mujeres posmenopáusicas reduce su incidencia. Las mujeres con hiperandrogenismo debido al síndrome del ovario poliquístico (SOP) muestran una mayor adiposidad central y un mayor riesgo de sufrir SM. En los hombres, la terapia de privación de andrógenos aumenta la masa grasa y la prevalencia del SM y la DT2, mientras que el tratamiento con testosterona disminuye la grasa visceral, el SM, y la DT2. En los últimos años, durante el desarrollo de esta tesis, nuestro grupo de investigación, junto con otros grupos de investigación, ha aportado evidencias que apoyan la idea de la existencia de un dimorfismo sexual en la composición de la microbiota intestinal, en el que las hormonas sexuales parecen desempeñar un papel destacado. La alteración o la protección de la mucosa intestinal por parte de la microbiota intestinal es un factor clave en el mantenimiento de la llamada barrera intestinal, que limita el acceso de los microorganismos al torrente sanguíneo y, por tanto, influye en el estado inflamatorio descrito en procesos como la obesidad y el SM. La acción de la microbiota intestinal se extiende al sistema nervioso central a través del eje intestino-cerebro para influir en la ingesta de alimentos, e incluso al hígado a través del eje intestino-hígado para regular el metabolismo de los nutrientes. La interacción entre la microbiota intestinal y su huésped parece influir así en el desarrollo de las enfermedades metabólicas, en donde los cambios en la microbiota podrían conformar, al menos en parte, los mecanismos patogénicos de la obesidad, la resistencia a insulina, y el desarrollo del SM. Además, en ratones se ha constatado la influencia de la microbiota intestinal en el nivel de las hormonas sexuales, pues la colonización por microbios comensales eleva la testosterona en los ratones macho, mientras que la transferencia de la microbiota intestinal de los machos adultos a las hembras inmaduras altera su microbiota y eleva la testosterona. La relación entre la microbiota intestinal, las hormonas sexuales, y el desarrollo de ciertas enfermedades ofrece un nuevo campo de investigación en la prevención de estas enfermedades mediante la manipulación de la microbiota intestinal. En este sentido, los trasplantes fecales han cobrado gran interés como terapia alternativa en el tratamiento de enfermedades como el SM, en donde la transferencia de la microbiota fecal de donantes sanos a pacientes con esta patología mejora la sensibilidad a la insulina. En la misma línea, han surgido terapias basadas en la modificación de la microbiota mediante intervención dietética y el uso de prebióticos y probióticos.The increasing incidence of metabolic diseases in the world population, particularly obesity, metabolic syndrome (MetS), and type 2 diabetes (T2D), has made them a major health, social and economic problem. The fact that these pathologies show a marked sexual dimorphism in their development and prevalence suggests that sex hormones are involved. Obesity, in addition to being a pathology per se, is a risk factor for MetS, which in turn influences T2D. Within this framework, two patterns of fat distribution have been described, a central pattern, typical of postmenopausal women and men, and a peripheral pattern, typical of premenopausal women. Both patterns, subject to a genetic basis regulated by sex hormones, are related to the development of metabolic diseases, with central (visceral abdominal) fat showing a pathological profile versus a protective profile of peripheral (subcutaneous) fat. The influence of sex hormones on metabolic diseases is supported by situations in which their levels are altered. Transgender men and women show a redistribution of body fat after sex steroid treatment, as occurs after the hormonal changes of menopause. Decreased estrogen levels after menopause and after oophorectomy increase the risk of T2D, whereas estrogen hormone therapy in postmenopausal women reduces its incidence. Women with hyperandrogenism due to polycystic ovary syndrome (PCOS) show increased central adiposity and increased risk of MetS. In men, androgen deprivation therapy increases fat mass and the prevalence of MetS and T2D, while testosterone treatment decreases visceral fat, T2D and MetS In recent years, during the development of this thesis, our research group, together with other research groups, has provided evidence supporting the idea of the existence of a sexual dimorphism in the composition of the gut microbiota, in which sex hormones seem to play a prominent role. The alteration or protection of the gut mucosa by the gut microbiota is a key factor in the maintenance of the so-called gut barrier, which limits the access of microorganisms to the bloodstream and thus influences the inflammatory state described in processes such as obesity and MetS. The action of the gut microbiota extends to the central nervous system via the gut-brain axis to influence food intake, and even to the liver via the gut-liver axis to regulate nutrient metabolism. The interaction between the gut microbiota and its host thus appears to influence the development of metabolic diseases, where changes in the microbiota could shape, at least in part, the pathogenic mechanisms of obesity, insulin resistance, and the development of MetS. In addition, the influence of gut microbiota on sex hormone levels has been demonstrated in mice, where colonisation by commensal microbes raises testosterone in male mice, while transfer of gut microbiota from adult males to immature females alters their microbiota and raises testosterone. The relationship between gut microbiota, sex hormones, and disease development offers a new field of research in disease prevention through manipulation of the gut microbiota. In this regard, faecal transplants have become of great interest as an alternative therapy in the treatment of diseases such as MetS, where the transfer of faecal microbiota from healthy donors to patients with MetS improves insulin sensitivity. In the same vein, therapies based on modification of the microbiota through dietary intervention, as well as the use of prebiotics and probiotics, have emerged

Impact de la citrulline sur le métabolisme du tissu adipeux

Obesity is frequently associated with type 2 diabetes and cardiovascular diseases, related to metabolic and endocrine dysregulation of white adipose tissue (WAT). During aging, the loss of muscle mass may be associated with obesity and defines the concept of sarcopenic obesity. Treatments implemented to counteract these conditions showed a very partial success. It is therefore appropriate to develop original alternative strategies that could lead to targeted therapies. Our team studies the metabolic regulation of WAT, the major source of energy storage in the body. Non-esterified fatty acids (NEFA) and glycerol are released in the blood from stored triglycerides through lipolysis and used as a source of energy for other tissues. In addition to their β-oxidation, NEFA are re-esterified in part, a process that limits their release in the blood. Glyceroneogenesis is the pathway necessary to NEFA re-esterification in the fasting state. Previous studies showed that administration of citrulline (CIT) for three months to aging rats induced a decrease of approximately 40% of the visceral WAT mass. This non-protein amino acid is given as a dietary supplement during aging or sports to increase muscle mass. We studied the effects of CIT on explant cultures of rat WAT. In the first part of this work, we show that CIT exerts a direct lipolytic and anti-glyceroneogenic effect on explants from rats whether young or old. However, the release of NEFA from the explants of young rats is limited by an increase in the oxidative capacity of the tissue. During aging, WAT mass augments in parallel to the increase in a pro-inflammatory state. To understand the influence of these two parameters regardless of age, we studied in the second part of this work, the effects of CIT on WAT explants from young rats fed a control (CD) or high fat (HFD) diet. We show an CIT-induced increase in lipolysis and beta-oxidative capacity of WAT from rats whatever the diet, while glyceroneogenesis is reduced. However, NEFA are selectively released from WAT of HFD rats, in connection with a drastic reduction of their re-esterification. NO is a mediator of these effects. In the third part of this work, we show that CIT acts directly on WAT from CD and HFD rats to induce the expression of uncoupling protein, UCP1, in line with the potential "browning" of WAT by this amino acid. These effects were not observed in explants from old rats. Altogether our results establish the basis for future investigations aimed at elucidating the mechanisms by which CIT reduces body fat and open new therapeutic perspectives to fight overweight and sarcopenic obesity.L’obésité s’accompagne de pathologies comme le diabète de type 2 et les maladies cardiovasculaires, liées à des dérégulations métaboliques et endocriniennes du tissu adipeux blanc (TAB). Au cours du vieillissement, la perte de masse musculaire peut être associée à l’obésité et définit le concept d’obésité sarcopénique. Les traitements mis en œuvre pour contrecarrer ces pathologies n’ont qu’un succès très partiel. Il est donc opportun de développer des stratégies alternatives originales qui pourraient aboutir à des thérapeutiques ciblées. Notre équipe étudie les régulations métaboliques du TAB, source majeure de stockage de l’énergie de l’organisme. Les triglycérides stockés sont libérés à jeun grâce à la lipolyse qui libère les acides gras non-estérifiés (AGNE) et le glycérol dans le sang, comme source d’énergie des autres tissus. En plus de la β-oxydation des AGNE, leur ré-estérification partielle intervient pour limiter leur libération lors de la lipolyse. La glycéronéogenèse est nécessaire à la ré-estérification en situation de jeûne. Des études préalables ont montré que l'administration de citrulline (CIT) pendant trois mois à des rats vieillissants induit une diminution d’environ 40% de la masse viscérale du TAB. Cet acide aminé non protéique est un complément alimentaire donné au cours du vieillissement ou à des sportifs pour augmenter la masse musculaire. Nous avons étudié les effets de la CIT sur des cultures d’explants de TAB de rats. Dans la première partie de ce travail, nous montrons que la CIT a un effet direct lipolytique et anti-glycéronéogénique sur les explants des rats qu’ils soient jeunes ou âgés. Cependant, la libération des AGNE du TAB des rats jeunes est limitée par une augmentation de la capacité oxydative du tissu. Avec l’âge, la masse du TAB augmente en parallèle à l’augmentation d’un état pro-inflammatoire. Afin de comprendre l’influence de ces deux paramètres indépendamment de l’âge, nous avons étudié dans la deuxième partie de ce travail, les effets de la CIT sur les explants de TAB de rats jeunes soumis à un régime contrôle (CD) ou hyperlipidique (HFD). Nous observons une augmentation, induite par la CIT, de la lipolyse et de la capacité ß-oxydative du TAB des rats quel que soit le régime, alors que la glycéronéogenèse est diminuée. Toutefois, les AGNE sont sélectivement libérés par le TAB de rats HFD, en relation avec une réduction drastique de leur ré-estérification. Le NO est un médiateur de ces effets. Dans une troisième partie, nous démontrons que la CIT agit directement sur le TAB de rats CD et HFD pour induire l'expression de la protéine découplante, UCP1, en lien avec le « brunissement » potentiel du TAB par cet acide aminé. Ces effets ne sont pas observés au sein du TAB des rats âgés. L’ensemble de nos résultats établit les bases pour de futures investigations visant à élucider les mécanismes par lesquels la CIT réduit la masse adipeuse et ouvre de nouvelles perspectives thérapeutiques pour lutter contre le surpoids et l’obésité sarcopénique

Glucose Tolerance

The progression from normal glucose tolerance (NGT) to type 2 diabetes involves intermediate stages of impaired fasting glucose (IFG) and impaired glucose tolerance (IGT), also known as prediabetes. The pathophysiology underlying the development of these glucose metabolic alterations is multifactorial, leading to an alteration in the balance between insulin sensitivity and insulin secretion. Our knowledge of the molecular basis of the signaling pathways mediating the various physiologic effects of insulin is steadily advancing. New substrates and signaling molecules have been identified and potential mechanisms involved in the pathophysiology of type 2 diabetes have been revealed. This book summarises the current state of knowledge on the pathophysiology underlying the progression from normal glucose tolerance to type 2 diabetes and therapeutic advances in the improvement of glycaemic control in prediabetic and diabetic states