Obesity increases your risk of developing diabetes

There are an estimated 69,000 adults and 1092 children living with diabetes in Northern Ireland in 2010. The number of adults with diabetes in Northern Ireland has increased by 34% since 2004. Many of these cases are preventable and related to obesity. With this in mind, during Diabetes Week (12 - 18 June 2011) the Public Health Agency is encouraging everyone across Northern Ireland to be aware of how diabetes can be prevented and what the signs and symptoms of diabetes are to ensure early diagnosis and good diabetic care.Type 1 diabetes cannot be prevented. It usually occurs in children and young adults. Type 2 diabetes typically occurs after the age of 40, but may occur at a younger age, and can often be prevented - mainly by keeping your weight within the normal range for your height. Dr Brid Farrell, Consultant in Public Health Medicine, PHA, said: "The increase of diabetes occurring in the population can be explained by rising levels of obesity, people living longer and improved detection and diagnosis of diabetes in primary care."The symptoms of diabetes can include increased thirst, passing urine more frequently (bedwetting in children), extreme tiredness, slow healing infections, blurred vision and significant or unexplained weight loss. Symptoms of diabetes can develop quickly over days or weeks, and sometimes with Type 2 diabetes, a person may have no symptoms. Early diagnosis is important. If you think you have diabetes speak to your GP or pharmacist.Dr Farrell continued: "Diabetes is a lifelong condition, but complications can be prevented or delayed by controlling your blood sugar, and treating high blood pressure and high cholesterol. If you have diabetes, a healthy diet and regular exercise is very important."Health Minister Edwin Poots said:"Diabetes is a serious condition, which affects many thousands of people across Northern Ireland. While not all diabetes is preventable, we all have a responsibility to look after our own health. "By making healthier lifestyle choices such as eating a healthy, well-balanced diet and taking regular exercise, we can reduce our risk of developing potentially life threatening conditions such as type 2 diabetes. I would urge everyone to take every possible step to improve their health and avoid developing preventable illnesses."Ends

Prevent type 2 diabetes by preventing obesity

In 2011 nearly 73,000 adults in Northern Ireland are registered as having diabetes. Many cases of diabetes are preventable and are the result of obesity. With this in mind, on World Diabetes Day, 14 November 2011, the Public Health Agency is encouraging everyone across Northern Ireland to be aware of how Type 2 diabetes can be prevented, the dangers it can cause to your health and what the signs and symptoms of diabetes are to ensure early diagnosis.The links between type 2 diabetes and obesity are firmly established. Without the intervention of a healthy diet and appropriate exercise, obesity may develop into diabetes over a relatively short period of time. According to the International Diabetes Federation (IDF), worldwide 80 per cent of people with Type 2 diabetes are overweight or obese at the time of diagnosis.If you are overweight, or obese the key step to preventing or delaying the onset of Type 2 diabetes is to lose a small amount of weight by making healthy food choices and being physically active 30 minutes a day, 5 days a week.Diabetes, if left untreated can cause serious long term health complications such as heart disease, kidney damage, eye problems, which can affect vision, and foot problems leading to amputation.Dr Brid Farrell, Consultant in Public Health Medicine, PHA, said: "The increase of diabetes occurring in the population can be explained by rising levels of obesity, people living longer and improved detection and diagnosis of diabetes in primary care."Having a family history of Type 2 diabetes increases your chances of developing diabetes. Take the first step today toward lowering your risk for Type 2 diabetes and improving your health and the health of future generations." The symptoms of diabetes can include increased thirst, passing urine more, frequently (bedwetting in children), extreme tiredness, slow healing infections, blurred vision and significant or unexplained weight loss. Symptoms of diabetes can develop quickly over days or weeks, and sometimes with Type 2 diabetes, a person may have no symptoms. Early diagnosis is important. If you think you have diabetes speak to your GP or pharmacist.Dr Farrell continued: "Diabetes is a lifelong condition, but complications can be prevented or delayed by controlling your blood sugar, and treating high blood pressure and high cholesterol. If you have diabetes, a healthy diet and regular exercise is very important."Health Minister Edwin Poots said:"Diabetes is a serious condition, which affects many thousands of people across Northern Ireland. While not all diabetes is preventable, we all have a responsibility to look after our own health. "By making healthier lifestyle choices such as eating a healthy, well-balanced diet and taking regular exercise, we can reduce our risk of developing potentially life threatening conditions such as type 2 diabetes. I would urge everyone to take every possible step to improve their health and avoid developing preventable illnesses

Role of enhanced detoxication in a deltamethrin-resistant population of Triatoma infestans (Hemiptera, Reduviidae) from Argentina

Deltamethrin and other pyrethroids have been extensively used in Argentina since 1980, for the chemical control of Triatoma infestans Klug (Hemiptera: Reduviidae). Recently, resistance to deltamethrin was detected in field populations by the survival of bugs exposed by topical application to the diagnostic dose estimated on the CIPEIN susceptible strain. Results of the current study showed low resistant ratios (RRs) to deltamethrin for the resistant populations (RR ranged from 2.0 for San Luis colony to 7.9 for Salta colony). Biochemical studies were made on the most resistant colony (Salta) and the susceptible strain (CIPEIN), in order to establish the importance of degradative mechanisms as a cause of the detected resistance. Esterase activity was measured on 3 days old first instars through phenylthioacetate and a-naphtyl acetate activities. The results showed a significant difference in no cholinesterase esterase activity from susceptible (7.6 ± 0,7 µM S./i.min.) and Salta resistant colony (9.5 ± 0.8 µM S./i.min.). Cytochrome P450 mono-oxygenase (P450) activity was measured on individual insects through ethoxycoumarine deethylase (ECOD) activity using a fluorescence micro plate reader. The dependence of ECOD activity on age and body region of the nymphs, and pH and time of incubation were studied in order to optimize the measurement. As a result, comparative studies were performed on abdomens of 2 days old first instars at pH 7.2 and 4 h incubation time. ECOD activity of first nymphs was significantly lower in the susceptible colony (61.3 ± 9.08 pg ECOD/ insect) than in the resistant one (108.1± 5.7 pg ECOD/ insect). These results suggest that degradative esterases (no-cholinesterase) and mono-oxygenases cytochrome P450, play an important role in the resistance to deltamethrin in Salta colony from Argentina.

Studies of membrane fluidity and heart contractile force in Trypanosoma cruzi infected mice

In Chagas disease serious cardiac dysfunction can appear. We specifically studied the cardiac function by evaluating: ventricle contractile force and norepinephrine response, affinity and density of beta-adrenergic receptors, dynamic properties of myocardial membranes, and electrocardiography. Albino swiss mice (n = 250) were infected with 55 trypomastigotes, Tulahuen strain and studied at 35, 75, and 180 days post-infection, that correspond to the acute, indeterminate, and chronic phase respectively. Cardiac beta-adrenergic receptors' affinity, myocardial contractility, and norepinephrine response progressively decreased from the acute to the chronic phase of the disease (p < 0.01). The density (expressed as fmol/mg.prot) of the receptors was similar to non-infected mice (71.96 ± 0.36) in both the acute (78.24 ± 1.67) and indeterminate phases (77.28 ± 0.91), but lower in the chronic disease (53.32 ± 0.71). Electrocardiographic abnormalities began in the acute phase and were found in 65% of the infected-mice during the indeterminate and chronic phases. Membrane contents of triglycerides, cholesterol, and anisotropy were similar in all groups. A quadratic correlation between the affinity to beta-adrenergic receptors and cardiac contractile force was obtained. In conclusion the changes in cardiac beta-adrenergic receptors suggests a correlation between the modified beta-adrenergic receptors affinity and the cardiac contractile force.

SCAP is required for timely and proper myelin membrane synthesis.

Myelination requires a massive increase in glial cell membrane synthesis. Here, we demonstrate that the acute phase of myelin lipid synthesis is regulated by sterol regulatory element-binding protein (SREBP) cleavage activation protein (SCAP), an activator of SREBPs. Deletion of SCAP in Schwann cells led to a loss of SREBP-mediated gene expression involving cholesterol and fatty acid synthesis. Schwann cell SCAP mutant mice show congenital hypomyelination and abnormal gait. Interestingly, aging SCAP mutant mice showed partial regain of function; they exhibited improved gait and produced small amounts of myelin indicating a slow SCAP-independent uptake of external lipids. Accordingly, extracellular lipoproteins partially rescued myelination by SCAP mutant Schwann cells. However, SCAP mutant myelin never reached normal thickness and had biophysical abnormalities concordant with abnormal lipid composition. These data demonstrate that SCAP-mediated regulation of glial lipogenesis is key to the proper synthesis of myelin membrane, and provide insight into abnormal Schwann cell function under conditions affecting lipid metabolism.

Benznidazole vs benznidazole in multilamellar liposomes: how different they interact with blood components?

In spite of its widespread use, benznidazole's (BNZ) toxicity and low efficacy remains as major drawbacks that impair successful treatments against Chagas disease. Previously, attempting to increase the selectivity and reduce its toxicity on infected tissues, multilamellar liposomes (MLV) composed of hydrogenated soybean phosphatidylcholine (HSPC): distearoyl-phosphatidylglycerol (DSPG): cholesterol (CHOL) 2:1:2 mol:mol loaded with BNZ (MLV-BNZ) were designed. In this work we compared different properties of MLV-BNZ with those of BNZ. Opposite to other hydrophobic drugs, the results indicated that slight changes of BNZ×s association degree to proteins and lipoproteins should not modify the percentage of unbound drug available to exert pharmacological action. On the other hand, when loaded in MLV, BNZ reduced its association to plasma proteins in 45% and became refractory to the sinking effect of blood, dropping 4.5 folds. Additionally, when loaded in MLV, BNZ had higher volume distribution (160 ± 20 vs 102 ± 15 ml/kg) and total clearance (35.23 ± 2.3 vs 21.9 ± 1.4 ml/h.kg), and lower concentration-time curve (7.23 ± 0.2 vs 9.16 ± 0.5 µg.h/ml) than BNZ. Hence, these studies showed that for MLV-BNZ, the amount of BNZ can be substantially increased, from 25 to 70%, being this formulation more rapidly cleared from circulation than free drug; also due to the lower interaction with blood components, lower side effects can be expected.

Interventions to achieve long-term weight loss in obese older people: A systematic review and meta-analysis

Purpose: the prevalence of obesity is rapidly increasing in older adults. Information is required about what interventions are effective in reducing obesity and influencing health outcomes in this age group. Design: systematic review and meta-analysis. Data sources: thirteen databases were searched, earliest date 1966 to December 2008, including Medline, CINAHL, PsycINFO, the Cochrane database and EMBASE. Study selection: we included studies with participants�۪ mean age 60 years and mean body mass index 30 kg/m2, with outcomes at a minimum of 1 year. Data were independently extracted by two reviewers and differences resolved by consensus. Data extraction: nine eligible trials were included. Study interventions targeted diet, physical activity and mixed approaches. Populations included patients with coronary artery disease, diabetes mellitus and osteoarthritis. Results: meta-analysis (seven studies) demonstrated a modest but significant weight loss of 3.0 kg [95% confidence interval (CI) 5.1���0.9] at 1 year. Total cholesterol (four studies) did not show a significant change: ���0.36 mmol/l (95% CI ���0.75 to 0.04). There was no significant change in high-density lipoprotein, low-density lipoprotein or triglycerides. In one study, recurrence of hypertension or cardiovascular events was significantly reduced (hazard ratio 0.65, 95% CI 0.50���0.85). Six-minute walk test did not significantly change in one study. Health-related quality of life significantly improved in one study but did not improve in a second study. Conclusions: although modest weight reductions were observed, there is a lack of high-quality evidence to support the efficacy of weight loss programmes in older people. ��Keywords: obesity, older, weight loss, meta-analysis, elderly, systematic review

Interventions to achieve long-term weight loss in obese older people

Purpose: the prevalence of obesity is rapidly increasing in older adults. Information is required about what interventions are effective in reducing obesity and influencing health outcomes in this age group. Design: systematic review and meta-analysis. Data sources: thirteen databases were searched, earliest date 1966 to December 2008, including Medline, CINAHL, PsycINFO, the Cochrane database and EMBASE. Study selection: we included studies with participants�۪ mean age 60 years and mean body mass index 30 kg/m2, with outcomes at a minimum of 1 year. Data were independently extracted by two reviewers and differences resolved by consensus. Data extraction: nine eligible trials were included. Study interventions targeted diet, physical activity and mixed approaches. Populations included patients with coronary artery disease, diabetes mellitus and osteoarthritis. Results: meta-analysis (seven studies) demonstrated a modest but significant weight loss of 3.0 kg [95% confidence interval (CI) 5.1���0.9] at 1 year. Total cholesterol (four studies) did not show a significant change: ���0.36 mmol/l (95% CI ���0.75 to 0.04). There was no significant change in high-density lipoprotein, low-density lipoprotein or triglycerides. In one study, recurrence of hypertension or cardiovascular events was significantly reduced (hazard ratio 0.65, 95% CI 0.50���0.85). Six-minute walk test did not significantly change in one study. Health-related quality of life significantly improved in one study but did not improve in a second study. Conclusions: although modest weight reductions were observed, there is a lack of high-quality evidence to support the efficacy of weight loss programmes in older people. ��Keywords: obesity, older, weight loss, meta-analysis, elderly, systematic review��

Cardiovascular disease, chronic kidney disease, and diabetes mortality burden of cardiometabolic risk factors from 1980 to 2010: a comparative risk assessment.

BACKGROUND: High blood pressure, blood glucose, serum cholesterol, and BMI are risk factors for cardiovascular diseases and some of these factors also increase the risk of chronic kidney disease and diabetes. We estimated mortality from cardiovascular diseases, chronic kidney disease, and diabetes that was attributable to these four cardiometabolic risk factors for all countries and regions from 1980 to 2010. METHODS: We used data for exposure to risk factors by country, age group, and sex from pooled analyses of population-based health surveys. We obtained relative risks for the effects of risk factors on cause-specific mortality from meta-analyses of large prospective studies. We calculated the population attributable fractions for each risk factor alone, and for the combination of all risk factors, accounting for multicausality and for mediation of the effects of BMI by the other three risks. We calculated attributable deaths by multiplying the cause-specific population attributable fractions by the number of disease-specific deaths. We obtained cause-specific mortality from the Global Burden of Diseases, Injuries, and Risk Factors 2010 Study. We propagated the uncertainties of all the inputs to the final estimates. FINDINGS: In 2010, high blood pressure was the leading risk factor for deaths due to cardiovascular diseases, chronic kidney disease, and diabetes in every region, causing more than 40% of worldwide deaths from these diseases; high BMI and glucose were each responsible for about 15% of deaths, and high cholesterol for more than 10%. After accounting for multicausality, 63% (10·8 million deaths, 95% CI 10·1-11·5) of deaths from these diseases in 2010 were attributable to the combined effect of these four metabolic risk factors, compared with 67% (7·1 million deaths, 6·6-7·6) in 1980. The mortality burden of high BMI and glucose nearly doubled from 1980 to 2010. At the country level, age-standardised death rates from these diseases attributable to the combined effects of these four risk factors surpassed 925 deaths per 100 000 for men in Belarus, Kazakhstan, and Mongolia, but were less than 130 deaths per 100 000 for women and less than 200 for men in some high-income countries including Australia, Canada, France, Japan, the Netherlands, Singapore, South Korea, and Spain. INTERPRETATION: The salient features of the cardiometabolic disease and risk factor epidemic at the beginning of the 21st century are high blood pressure and an increasing effect of obesity and diabetes. The mortality burden of cardiometabolic risk factors has shifted from high-income to low-income and middle-income countries. Lowering cardiometabolic risks through dietary, behavioural, and pharmacological interventions should be a part of the global response to non-communicable diseases. FUNDING: UK Medical Research Council, US National Institutes of Health.

Binary classification of dyslipidemia from the waist-to-hip ratio and body mass index: a comparison of linear, logistic, and CART models.

BACKGROUND: We sought to improve upon previously published statistical modeling strategies for binary classification of dyslipidemia for general population screening purposes based on the waist-to-hip circumference ratio and body mass index anthropometric measurements. METHODS: Study subjects were participants in WHO-MONICA population-based surveys conducted in two Swiss regions. Outcome variables were based on the total serum cholesterol to high density lipoprotein cholesterol ratio. The other potential predictor variables were gender, age, current cigarette smoking, and hypertension. The models investigated were: (i) linear regression; (ii) logistic classification; (iii) regression trees; (iv) classification trees (iii and iv are collectively known as "CART"). Binary classification performance of the region-specific models was externally validated by classifying the subjects from the other region. RESULTS: Waist-to-hip circumference ratio and body mass index remained modest predictors of dyslipidemia. Correct classification rates for all models were 60-80%, with marked gender differences. Gender-specific models provided only small gains in classification. The external validations provided assurance about the stability of the models. CONCLUSIONS: There were no striking differences between either the algebraic (i, ii) vs. non-algebraic (iii, iv), or the regression (i, iii) vs. classification (ii, iv) modeling approaches. Anticipated advantages of the CART vs. simple additive linear and logistic models were less than expected in this particular application with a relatively small set of predictor variables. CART models may be more useful when considering main effects and interactions between larger sets of predictor variables.

Linking epigenetics to lipid metabolism: focus on histone deacetylases.

A number of recent studies revealed that epigenetic modifications play a central role in the regulation of lipid and of other metabolic pathways such as cholesterol homeostasis, bile acid synthesis, glucose and energy metabolism. Epigenetics refers to aspects of genome functions regulated in a DNA sequence-independent fashion. Chromatin structure is controlled by epigenetic mechanisms through DNA methylation and histone modifications. The main modifications are histone acetylation and deacetylation on specific lysine residues operated by two different classes of enzymes: Histone acetyltransferases (HATs) and histone deacetylases (HDACs), respectively. The interaction between these enzymes and histones can activate or repress gene transcription: Histone acetylation opens and activates chromatin, while deacetylation of histones and DNA methylation compact chromatin making it transcriptionally silent. The new evidences on the importance of HDACs in the regulation of lipid and other metabolic pathways will open new perspectives in the comprehension of the pathophysiology of metabolic disorders.

Smoking offsets the metabolic benefits of parental longevity in women: the CoLaus study.

OBJECTIVE: We evaluated whether subjects with long-lived parents show lower levels of cardiovascular risk factors, including the metabolic syndrome. METHODS: We analyzed data from a Swiss population-based sample (1163 men and 1398 women) aged 55-75 years from Lausanne. Participants were stratified by number of parents (0, 1, 2) who survived to 85 years or more. The associations of parental longevity with cardiovascular risk factors and related metabolic variables were analyzed using multiple linear regressions. RESULTS: Age-adjusted metabolic syndrome prevalence varied from 24.8%, 20.5% to 13.8% in women (P<0.05) and from 28.8%, 32.1% to 27.6% in men (not significant) with 0, 1 and 2 long-lived parents. The association between parental longevity and metabolic syndrome prevalence was particularly strong in women who had never smoked. In this group, women with 2 long-lived parents had lower Body Mass Index and smaller waist circumference. In never-smokers of both genders, mean (95% CI) adjusted High Density Lipoprotein-cholesterol levels were 1.64(1.61-1.67), 1.67(1.65-1.70) and 1.71(1.65-1.76) mmol/L for 0, 1 and 2 long-lived parents (P<0.01), respectively. The trend was not significant in former and current smokers. CONCLUSIONS: In women, not in men, parental longevity is associated with a better metabolic profile. The metabolic benefits of having long-lived parents are offset by smoking.

Electronic monitoring of compliance to lipid-lowering therapy in clinical practice

Nonadherence to treatment is a common problem in the clinical management of hypercholesterolemic patients. This study was carried out with the aim of monitoring the daily compliance to a 6-month course of lipid-lowering therapy, using a microelectronic device, the Medication Event Monitoring System (MEMS), versus pill count. Forty men with primary hypercholesterolemia were prescribed fluvastatin 1 x 40 mg daily, provided in a MEMS package to record the date and time of each opening of the pillbox. Thirty-nine of 40 patients (98%) completed the study. Total cholesterol and LDL cholesterol levels decreased significantly (18% and 25%, p < 0.001) during the 6-month therapy period. A high mean rate of compliance was achieved by MEMS using the following three indexes--compliance to total prescribed dose (88.8% +/- 13.5%), compliance to prescribed days (82.4% +/- 19.5%), and compliance to prescribed time of day (81.86% +/- 19.5%)--and by pill count (93.4% +/- 9.5%). In addition, the MEMS provided some patterns of nonadherence to medication, undetectable by pill count alone, such as a drug holiday in 38% of cases, a drug omission for more than 7 consecutive days in 9% of cases, and, conversely, use of more than the one prescribed daily dose in 47% of cases. A significant correlation between the rate of compliance and the decrease in LDL cholesterol was observed only when the compliance was assessed by MEMS. The results indicate that MEMS is a useful tool for monitoring compliance in clinical practice and may possibly increase adherence to long-term lipid-lowering therapy.

Binding of d-methadone, l-methadone, and dl-methadone to proteins in plasma of healthy volunteers: role of the variants of alpha 1-acid glycoprotein.

The plasma concentrations of alpha 1-acid glycoprotein (AAG), albumin, triglycerides, cholesterol, and total proteins, as well as the plasma binding of racemic, d-methadone, and l-methadone were measured in 45 healthy subjects. The AAG phenotypes and the concentrations of AAG variants were also determined. The measured free fractions for racemic, d-methadone, and l-methadone were, respectively, 12.7% +/- 3.3%, 10.0% +/- 2.9%, and 14.2% +/- 3.2% (mean +/- SD). A significant correlation was obtained between the binding ratio (B/F) for dl-methadone and the total AAG concentration (r = 0.724; p less than 0.001). A multiple stepwise regression analysis showed that AAG was the main explanatory variable for the binding of the racemate. When concentrations of AAG variants were considered, a significant correlation was obtained between the binding ratio of dl-methadone and orosomucoid2 A concentration (r = 0.715; p less than 0.001), a weak correlation between dl-methadone and orosomucoid1 S concentration (r = 0.494; p less than 0.001), and no correlation between dl-methadone and orosomucoid1 F1 concentration (r = 0.049; not significant). Similar findings were obtained with the enantiomers. This study shows the importance of considering not only total AAG but also concentrations of AAG variants when measuring the binding of methadone and possibly of other drugs in plasma.

PPAR beta a player in astrocyte metabolism and morphology

AbstractPPARP is a nuclear receptor responding in vivo to several free fatty acids, and implicated in cell metabolism, differentiation and survival. PPARp is ubiquitously expressed but shows high expression in the developing and adult brain. PPARp is expressed in different cell types such as neurons and astrocytes, where it might play a role in metabolism. To study this nuclear receptor the laboratory engineered a PPARP -/- mouse model. The aim of my PhD was to dissect the role of PPARP in astrocytes.Experiments in primary culture revealed that cortical astrocytes from PPARP -/- mouse have an impaired energetic metabolism. Unstimulated PPARP -/- astrocytes exhibit a 30% diminution in glucose uptake, correlating to a 30% decrease in lactate release and intracellular glucose. After acute stimulation by D- aspartate mimicking glutamate exposure, both WT and -/- astrocytes up-regulate their metabolism to respond to the increasing energy needed (ATP) for glutamate uptake. According to the Astrocyte Neuron Lactate Shuttle Hypothesis (ANLSH), the ratio between glucose uptake/ lactate release is 1. However, stimulated PPARp -/- astrocytes display a higher increase in lactate release than glucose uptake which remains lower than in WT. The extra glucose equivalents could come from the degradation of intra cellular glycogen stores, which indeed decrease in PPARP -/- cells upon stimulation. Lower glucose metabolism correlates with a decreased acute glutamate uptake in PPARP -/- astrocytes. Reciprocally, we also observed an increase of glutamate uptake and ATP production after treatment of WT astrocytes with a PPARp agonist. Glutamate transporter protein expression is not affected. However, their trafficking and localization might be altered as PPARp -/- astrocytes have higher cholesterol levels, which may also affect proper transporter structure in the membrane.Metabolism, transporter localization and cholesterol levels are respectively linked to cell mobility, cell cytoskeleton and cellular membrane composition. All three functions are important in astrocytes to in vivo acquire star shaped morphology, in a process known as stellation. PPARP -/- astrocytes showed an impaired acquired stellation in presence of neurons or chemical stimuli, as well as more actin stress fibers and cell adhesion structures. While non stellation of astrocytes is mainly an in vitro phenomenon, it reveals PPARp -/- primary astrocytes inability to respond to different exterior stimuli. These morphological phenotypes correlate with a slower migration in cell culture wound healing assays.This thesis work demonstrates that PPARp is implicated in cortical astrocyte glucose metabolism. PPARp absence leads to an unusual intracellular glycogen use. Added to the effect on acute glutamate uptake and astrocyte migration, PPARp could be an interesting target for neuroprotection therapies.RésuméPPARP est un récepteur nucléaire qui a pour ligands naturels certains acides gras libres. Il est impliqué dans le métabolisme, la différentiation et la survie des cellules. PPARP est ubiquitaire, et a une expression élevée dans le cerveau en développement ainsi qu'adulte. PPARp est exprimé dans différents types cellulaires tels que les neurones et les astrocytes, où il régule potentiellement leurs métabolismes. Pour étudier ce récepteur nucléaire, le laboratoire a créé un modèle de souris PPARp -/-. L'objectif de ma thèse est de comprendre le rôle de PPARp dans les astrocytes.Les expériences montrent un défaut du métabolisme énergétique dans les astrocytes corticaux primaires tirés de souris PPARp -/-. Sans stimulation, l'entrée du glucose dans les astrocytes PPARP -/- est diminuée de 30% ce qui correspond à une diminution de 30% du relargage du lactate. Après stimulation par du D-Aspartate qui mime une exposition au glutamate, les astrocytes WT et -/- augmentent leur métabolisme en réponse à la demande accrue en énergie (ATP) due à l'entrée du glutamate. D'après l'Astrocyte Neuron Lactate Shuttle Hypothesis (ANLSH), le ratio entre le glucose entrant et le lactate sortant est de 1. Cependant le relargage du lactate dans les astrocytes PPARP-/- est plus élevé que l'entrée du glucose. L'apport supplémentaire de glucose transformé en lactate pourrait provenir de la dégradation des stocks de glycogène intracellulaire, qui sont partiellement diminués après stimulation dans les cellules PPARP -/-. Un métabolisme plus faible du glucose corrèle avec une réduction de l'import du glutamate dans les astrocytes PPARp -/-. Réciproquement, nous observons une augmentation de l'import du glutamate et de la production d'ATP après traitement avec l'agoniste pour PPARp. Bien que l'expression des transporteurs de glutamate ne soit pas affectée, nous ne pouvons pas exclure que leur localisation et leur structure soient altérées du fait du niveau élevé de cholestérol dans les astrocytes PPARp -/-.Le métabolisme, la localisation des transporteurs et le niveau de cholestérol sont tous liés au cytosquelette, à la mobilité, et à la composition des membranes cellulaires. Toutes ces fonctions sont importantes pour les astrocytes pour acquérir leur morphologie in vivo. Les astrocytes PPARP -/- présentent un défaut de stellation, aussi bien en présence de neurones que de stimuli chimiques, ainsi qu'un plus grand nombre de fibres de stress (actine) et de structures d'adhésion cellulaire. Bien que les astrocytes non stellaires soient principalement observés in vitro, le défaut de stellation des astrocytes primaires PPARp -/- indique une incapacité à répondre aux différents stimuli extérieurs. Ces phénotypes morphologiques corrèlent avec une migration plus lente en cas de lésion de la culture.Ce travail de thèse a permis de démontrer l'implication de PPARP dans le métabolisme du glucose des astrocytes corticaux. L'absence de ce récepteur nucléaire amène à l'utilisation du glucose intracellulaire, auquel s'ajoutent les effets sur l'import du glutamate et la migration des astrocytes. PPARp aurait des effets neuroprotecteurs, et de ce fait pourrait être utilisé à des fins thérapeutiques.