iBAT sympathetic innervation is not required for body weight loss induced by central leptin delivery.

We evaluated the contribution of brown adipose tissue (BAT) sympathetic innervation on central leptin-mediated weight loss. In a short- and long-term study, F344BN rats were submitted to either a denervation of interscapular BAT (Denervated) or a sham operation (Sham). Animals from each group received the Ob (Leptin) or green fluorescent protein (GFP; Control) gene through a single injection of recombinant adeno-associated virus delivered centrally. Changes in body weight were recorded for 14 or 35 days, after which adipose tissues and skeletal muscles were weighed. In both studies, hypothalamic phosphorylated STAT3 (P-STAT3) was significantly higher in Sham-Leptin and Denervated-Leptin groups compared with their respective Control groups ( P < 0.01), indicating that leptin signaling was enhanced at the end point. We measured uncoupling protein 1 (UCP1), a marker of BAT thermogenic activity, and found a significant induction in Leptin in Sham animals ( P < 0.001) but not in Denervated animals, demonstrating that BAT UCP1 protein was only induced in Sham rats. Both Sham-Leptin and Denervated-Leptin rats lost ~15% of their initial body weight ( P < 0.001) by day 14 and reached a maximum of 18% body weight loss that stabilized over week 3 of treatment, indicating that sympathetic outflow to BAT is not required for leptin-mediated weight loss. In summary, interscapular BAT (iBAT) denervation did not prevent body weight loss following central leptin gene delivery. The present data show that sympathetic innervation of iBAT is not essential for leptin-induced body weight loss.

Anorexic response to rapamycin does not appear to involve a central mechanism.

The authors have previously demonstrated that a low and intermittent peripheral dose of rapamycin (1 mg/kg three times/week) to rats inhibited mTORC1 signalling, but avoided the hyperlipidemia and diabetes-like syndrome associated with higher doses of rapamycin. The dosing regimen reduced food intake, body weight, adiposity, serum leptin and triglycerides. mTORC1 signalling was inhibited in both liver and hypothalamus, suggesting some of the actions, in particular the decrease in food intake, may be the results of a central mechanism. To test this hypothesis, rapamycin (30 µg/day for 4 weeks) was infused into 23-25-month-old F344xBN rats by intracerebroventricular (icv) mini pumps. Our results demonstrated that central infusion did not alter food intake or body weight, although there was a tendency for a decrease in body weight towards the end of the study. mTORC1 signalling, evidenced by decreased phosphorylation of S6 protein at end of 4 weeks, was not activated in liver, hypothalamus or hindbrain. Fat and lean mass, sum of white adipose tissues, brown adipose tissue, serum glucose, insulin and leptin levels remained unchanged. Thus, these data suggest that the anorexic and body weight responses evident with peripheral rapamycin are not the result of direct central action. The tendency for decreased body weight towards the end of study, suggests that there is either a slow transport of centrally administered rapamycin into the periphery, or that there is delayed action of rapamycin at sites in the brain.

The effects of enalapril and losartan on mechanical ventilation-induced sympathoadrenal activation and oxidative stress in rats.

BACKGROUND: Mechanical ventilation (MV) is a method of maintaining appropriate gas exchange in patients who are unable to sustain adequate alveolar ventilation. While lifesaving in the short-term, prolonged MV leads to altered cardiovascular responses and enhanced lung injury, but the exact mechanism is unknown. Therefore, we investigated the involvement of the sympathoadrenergic and renin-angiotensin system in MV-induced altered cardiovascular responses. METHODS: Sprague-Dawley rats were divided into six groups: (1) spontaneous breathing (SB); (2) SB + enalapril (100 µg/kg intravenous infusion); (3) SB + losartan (100 µg/kg infusion); (4) 12 h of MV; (5) MV + enalapril; and (6) MV + losartan. After the animals were sacrificed, blood and tissue samples were collected. Tyrosine hydroxylase, dopamine beta hydroxylase, and neuropeptide Y were measured in adrenal medulla and hypothalamus, whereas AT1 was measured in lung tissues by Western blot. Norepinephrine enzyme-linked immunosorbent assay and total antioxidant capacity were assayed in plasma. RESULTS: Our findings indicated that MV increases the sympathetic activation markers in adrenal medulla and hypothalamus. Moreover, oxidative stress was increased in lung and brain tissues. Treatment with enalapril or losartan reduced the lipid peroxidation in lung and brain tissues, while preserving the tissue glutathione content and plasma antioxidant capacity. CONCLUSIONS: These data demonstrate that the inhibition of the renin-angiotensin system by enalapril or losartan may reduce the MV-induced increase in sympathetic activity markers and oxidative stress, and thus, may have a beneficial effect as adjuvant therapy.

Inhibitory control effects in adolescent binge eating and consumption of sugar-sweetened beverages and snacks.

Inhibitory control and sensitivity to reward are relevant to the food choices individuals make frequently. An imbalance of these systems can lead to deficits in decision-making that are relevant to food ingestion. This study evaluated the relationship between dietary behaviors - binge eating and consumption of sweetened beverages and snacks - and behavioral control processes among 198 adolescents, ages 14 to 17. Neurocognitive control processes were assessed with the Iowa Gambling Task (IGT), a generic Go/No-Go task, and a food-specific Go/No-Go task. The food-specific version directly ties the task to food cues that trigger responses, addressing an integral link between cue-habit processes. Diet was assessed with self-administered food frequency and binge eating questionnaires. Latent variable models revealed marked gender differences. Inhibitory problems on the food-specific and generic Go/No-Go tasks were significantly correlated with binge eating only in females, whereas inhibitory problems measured with these tasks were the strongest correlates of sweet snack consumption in males. Higher BMI percentile and sedentary behavior also predicted binge eating in females and sweet snack consumption in males. Inhibitory problems on the generic Go/No-Go, poorer affective decision-making on the IGT, and sedentary behavior were associated with sweetened beverage consumption in males, but not females. The food-specific Go/No-Go was not predictive in models evaluating sweetened beverage consumption, providing some initial discriminant validity for the task, which consisted of sweet/fatty snacks as no-go signals and no sugar-sweetened beverage signals. This work extends research findings, revealing gender differences in inhibitory function relevant to behavioral control. Further, the findings contribute to research implicating the relevance of cues in habitual behaviors and their relationship to snack food consumption in an understudied population of diverse adolescents not receiving treatment for eating disorders.

The Distribution of the Product Explains Normal Theory Mediation Confidence Interval Estimation.

The distribution of the product has several useful applications. One of these applications is its use to form confidence intervals for the indirect effect as the product of 2 regression coefficients. The purpose of this article is to investigate how the moments of the distribution of the product explain normal theory mediation confidence interval coverage and imbalance. Values of the critical ratio for each random variable are used to demonstrate how the moments of the distribution of the product change across values of the critical ratio observed in research studies. Results of the simulation study showed that as skewness in absolute value increases, coverage decreases. And as skewness in absolute value and kurtosis increases, imbalance increases. The difference between testing the significance of the indirect effect using the normal theory versus the asymmetric distribution of the product is further illustrated with a real data example. This article is the first study to show the direct link between the distribution of the product and indirect effect confidence intervals and clarifies the results of previous simulation studies by showing why normal theory confidence intervals for indirect effects are often less accurate than those obtained from the asymmetric distribution of the product or from resampling methods.

Sweetened drink and snacking cues in adolescents: a study using ecological momentary assessment.

The objective of this study was to identify physical, social, and intrapersonal cues that were associated with the consumption of sweetened beverages and sweet and salty snacks among adolescents from lower SES neighborhoods. Students were recruited from high schools with a minimum level of 25% free or reduced cost lunches. Using ecological momentary assessment, participants (N=158) were trained to answer brief questionnaires on handheld PDA devices: (a) each time they ate or drank, (b) when prompted randomly, and (c) once each evening. Data were collected over 7days for each participant. Participants reported their location (e.g., school grounds, home), mood, social environment, activities (e.g., watching TV, texting), cravings, food cues (e.g., saw a snack), and food choices. Results showed that having unhealthy snacks or sweet drinks among adolescents was associated with being at school, being with friends, feeling lonely or bored, craving a drink or snack, and being exposed to food cues. Surprisingly, sweet drink consumption was associated with exercising. Watching TV was associated with consuming sweet snacks but not with salty snacks or sweet drinks. These findings identify important environmental and intrapersonal cues to poor snacking choices that may be applied to interventions designed to disrupt these food-related, cue-behavior linked habits.

Mechanisms of motivational interviewing in health promotion: a Bayesian mediation analysis.

BACKGROUND: Counselor behaviors that mediate the efficacy of motivational interviewing (MI) are not well understood, especially when applied to health behavior promotion. We hypothesized that client change talk mediates the relationship between counselor variables and subsequent client behavior change. METHODS: Purposeful sampling identified individuals from a prospective randomized worksite trial using an MI intervention to promote firefighters' healthy diet and regular exercise that increased dietary intake of fruits and vegetables (n = 21) or did not increase intake of fruits and vegetables (n = 22). MI interactions were coded using the Motivational Interviewing Skill Code (MISC 2.1) to categorize counselor and firefighter verbal utterances. Both Bayesian and frequentist mediation analyses were used to investigate whether client change talk mediated the relationship between counselor skills and behavior change. RESULTS: Counselors' global spirit, empathy, and direction and MI-consistent behavioral counts (e.g., reflections, open questions, affirmations, emphasize control) significantly correlated with firefighters' total client change talk utterances (rs = 0.42, 0.40, 0.30, and 0.61, respectively), which correlated significantly with their fruit and vegetable intake increase (r = 0.33). Both Bayesian and frequentist mediation analyses demonstrated that findings were consistent with hypotheses, such that total client change talk mediated the relationship between counselor's skills--MI-consistent behaviors [Bayesian mediated effect: αß = .06 (.03), 95% CI = .02, .12] and MI spirit [Bayesian mediated effect: αß = .06 (.03), 95% CI = .01, .13]--and increased fruit and vegetable consumption. CONCLUSION: Motivational interviewing is a resource- and time-intensive intervention, and is currently being applied in many arenas. Previous research has identified the importance of counselor behaviors and client change talk in the treatment of substance use disorders. Our results indicate that similar mechanisms may underlie the effects of MI for dietary change. These results inform MI training and application by identifying those processes critical for MI success in health promotion domains.

Parents' Attitudes Toward Domestic Violence as a Risk Factor for Early Childhood Development: Testing an Actor-Partner Interdependence Model Using UNICEF MICS.

Purpose: While the importance of domestic violence has been examined in relation to parenting behaviors and child development, less is known about the link between justifying attitudes toward wife beating and parenting, especially in low- and middle-income countries (LMIC). This study employs an actor-partner interdependence mediation model to examine how parents' justifying attitudes toward violence against women relate to their own (actor effects) and their partners' (partner effects) level of parental involvement, which then influence their preschool children's early development. Method: Using data from mothers, fathers, and children in 16,010 families residing in LMIC that participated in UNICEF's Multiple Indicator Cluster Survey Waves 4-5-6 and a dyadic mediation modeling approach, we have examined the associations between maternal and paternal justification of violence against women, parental involvement, and children's early development. Results: Results revealed that mothers' greater justification of violence against themselves were associated with decreased level of maternal (actor effect) and paternal (partner effect) involvement, while fathers' greater justification of violence against their wives was related to decreased paternal involvement (actor effect). Furthermore, mediation tests indicated that paternal justification of violence was negatively and indirectly associated with early childhood development through paternal involvement. Moreover, maternal justification of violence was negatively and indirectly associated with early childhood development through both maternal and paternal involvement. Conclusion: Mothers' and fathers' justifying attitudes toward domestic violence emerge as a possible risk factor for child development that can be addressed by preventive interventions.

Can school teachers' willingness to teach ASD-inclusion classes be increased via special education training? Uncovering mediating mechanisms.

Changing teacher willingness to teach inclusive classes is critical in achieving optimal outcomes for students with autism spectrum disorder (ASD). The present study investigated the mechanisms underlying the effects of a teacher training in special education strategies for students with ASD on mainstream school teachers' behavioral intentions toward inclusive education. Specifically, the role of attitudes and autism self-efficacy were explored as mediators in this process. The sample comprised 763 mainstream school teachers from eleven cities in Northeastern Turkey who participated in an intensive training that included special education strategies for students with ASD, evidence-based special education applications, and inclusive education practices. Statistical mediation analyses revealed that the training increased teachers' willingness to teach inclusive classes and intention to implement special education techniques in the regular education classroom through increasing their autism self-efficacy. However, though attitudes toward inclusive education was a significant predictor of both willingness to teach inclusive classes and intent to use special education techniques, the training did not improve attitudes. Based on these findings, additional strategies or components to change attitudes toward inclusive education were recommended to be integrated into the teacher training programs on special education strategies for inclusive education.

Does learning to code influence cognitive skills of elementary school children? Findings from a randomized experiment.

BACKGROUND: Coding has been added to school curricula in several countries, being one of the necessary competencies of the 21st century. Although it has also been suggested to foster the development of several cognitive skills such as computational thinking and problem-solving, studies on the effects of coding are very limited, provide mixed results, and lack causal evidence. AIM: This study aims to evaluate the impact of a learn-to-code programme on three cognitive skills in children: computational thinking, fluid intelligence, and spatial orientation, using a randomized trial. SAMPLE: One hundred seventy-four (n = 81 girls) 4th-grade children participated in the study. METHODS: Children were randomly assigned to one of the three 10-week learning programmes: learn-to-code (treatment of interest), mathematics (another STEM-related comparison treatment), and reading (control). Children responded to paper-pencil computational thinking, and spatial orientation measurements, and face-to-face matrix reasoning task at pre- and post-tests. RESULTS: Results showed that children's computational thinking scores increased significantly only in the learn-to-code condition. Fluid intelligence significantly increased in all conditions, possibly due to a practice effect. The spatial orientation did not improve in any of the conditions. CONCLUSION: These findings suggested that learning to code can be selectively beneficial for the development of computational thinking skills while not effective for spatial reasoning and fluid intelligence.

Causal Mediation Analysis in the Presence of Post-treatment Confounding Variables: A Monte Carlo Simulation Study.

In many disciplines, mediating processes are usually investigated with randomized experiments and linear regression to determine if the treatment affects the outcome through a mediator. However, randomizing the treatment will not yield accurate causal direct and indirect estimates unless certain assumptions are satisfied since the mediator status is not randomized. This study describes methods to estimate causal direct and indirect effects and reports the results of a large Monte Carlo simulation study on the performance of the ordinary regression and modern causal mediation analysis methods, including a previously untested doubly robust sequential g-estimation method, when there are confounders of the mediator-to-outcome relation. Results show that failing to measure and incorporate potential post-treatment confounders in a mediation model leads to biased estimates, regardless of the analysis method used. Results emphasize the importance of measuring potential confounding variables and conducting sensitivity analysis.

Statistical power for the comparative regression discontinuity design with a nonequivalent comparison group.

In the "sharp" regression discontinuity design (RD), all units scoring on one side of a designated score on an assignment variable receive treatment, whereas those scoring on the other side become controls. Thus the continuous assignment variable and binary treatment indicator are measured on the same scale. Because each must be in the impact model, the resulting multi-collinearity reduces the efficiency of the RD design. However, untreated comparison data can be added along the assignment variable, and a comparative regression discontinuity design (CRD) is then created. When the untreated data come from a non-equivalent comparison group, we call this CRD-CG. Assuming linear functional forms, we show that power in CRD-CG is (a) greater than in basic RD; (b) less sensitive to the location of the cutoff and the distribution of the assignment variable; and that (c) fewer treated units are needed in the basic RD component within the CRD-CG so that savings can result from having fewer treated cases. The theory we develop is used to make numerical predictions about the efficiency of basic RD and CRD-CG relative to each other and to a randomized control trial. Data from the National Head Start Impact study are used to test these predictions. The obtained estimates are closer to the predicted parameters for CRD-CG than for basic RD and are generally quite close to the parameter predictions, supporting the emerging argument that CRD should be the design of choice in many applications for which basic RD is now used. (PsycINFO Database Record

Comparative Regression Discontinuity: A Stress Test With Small Samples.

Compared to the randomized experiment (RE), the regression discontinuity design (RDD) has three main limitations: (1) In expectation, its results are unbiased only at the treatment cutoff and not for the entire study population; (2) it is less efficient than the RE and so requires more cases for the same statistical power; and (3) it requires correctly specifying the functional form that relates the assignment and outcome variables. One way to overcome these limitations might be to add a no-treatment functional form to the basic RDD and including it in the outcome analysis as a comparison function rather than as a covariate to increase power. Doing this creates a comparative regression discontinuity design (CRD). It has three untreated regression lines. Two are in the untreated segment of the RDD-the usual RDD one and the added untreated comparison function-while the third is in the treated RDD segment. Also observed is the treated regression line in the treated segment. Recent studies comparing RE, RDD, and CRD causal estimates have found that CRD reduces imprecision compared to RDD and also produces valid causal estimates at the treatment cutoff and also along all the rest of the assignment variable. The present study seeks to replicate these results, but with considerably smaller sample sizes. The power difference between RDD and CRD is replicated, but not the bias results either at the treatment cutoff or away from it. We conclude that CRD without large samples can be dangerous.

The Antiepileptic Ketogenic Diet Alters Hippocampal Transporter Levels and Reduces Adiposity in Aged Rats.

Nutritional ketosis is induced by high fat/low carbohydrate dietary regimens, which produce high levels of circulating ketone bodies, shifting metabolism away from glucose utilization. While ketogenic diets (KD) were initially introduced to suppress seizures, they are garnering attention for their potential to treat a myriad of neurodegenerative and metabolic disorders that are associated with advanced age. The feasibility and physiological impact of implementing a long-term KD in old animals, however, has not been systematically examined. In this study, young and aged rats consumed a calorically- and nutritionally-matched KD or control diet for 12 weeks. All KD-fed rats maintained higher levels of BHB and lower levels of glucose relative to controls. However, it took the aged rats longer to reach asymptotic levels of BHB compared to young animals. Moreover, KD-fed rats had significantly less visceral white and brown adipose tissue than controls without a loss of lean mass. Interestingly, the KD led to significant alterations in protein levels of hippocampal transporters for monocarboxylates, glucose, and vesicular glutamate and gamma-aminobutyric acid. Most notably, the age-related decline in vesicular glutamate transporter expression was reversed by the KD. These data demonstrate the feasibility and potential benefits of KDs for treating age-associated neural dysfunction.

ACE2 activator diminazene aceturate reduces adiposity but preserves lean mass in young and old rats.

The obesity epidemic is multi-generational and is particularly debilitating in the aging population, necessitating the use of pharmaceutical interventions. Recent evidence suggests that increasing the activity of the angiotensin converting enzyme-2 [ACE2]/angiotensin-(1-7)[Ang-(1-7)]/Mas receptor (MasR) axis in obese animal models leads to significant reductions in body weight. It was hypothesized that activation of ACE2 via diminazene aceturate (DIZE) will significantly reduce body weight of rats fed a high fat diet. Young and old (4 and 23 months, respectively) male Fisher 344 × Brown Norway rats were fed 60% high fat diet for one week, and subsequently given either 15 mg/kg/day DIZE s.c. or vehicle for three weeks. DIZE treatment resulted in a significant reduction of food intake and body weight in both young and old animals. However, that decrease was so dramatic in the older animals that they all nearly stopped eating. Interestingly, the TD-NMR assessments revealed that the weight-loss was primarily a result of decreased body fat percentage, with a relative preservation of lean mass. Tissue weights confirm the significant loss of white adipose tissue (WAT), with no change in muscle weights. Gene expression and serum ACE2 activity analyses implied that increased activation of the ACE2/Ang-(1-7)/MasR axis plays a role in reducing fat mass. Collectively, our results suggest that DIZE may be a useful tool in the study of obesity; however, caution is recommended when using this compound in older animals due to severe anorectic effects, although there is a mechanism by which muscle is preserved.

Overpressure blast injury-induced oxidative stress and neuroinflammation response in rat frontal cortex and cerebellum.

BACKGROUND & AIM: Overpressure blast-wave induced brain injury (OBI) and its long-term neurological outcome pose significant concerns for military personnel. Our aim is to investigate the mechanism of injury due to OBI. METHODS: Rats were divided into 3 groups: (1) Control, (2) OBI (exposed 30psi peak pressure, 2-2.5ms), (3) Repeated OBI (r-OBI) (three exposures over one-week period). Lung and brain (cortex and cerebellum) tissues were collected at 24h post injury. RESULTS: The neurological examination score was worse in OBI and r-OBI (4.2±0.6 and 3.7±0.5, respectively) versus controls (0.7±0.2). A significant positive correlation between lung and brain edema was found. Malondialdehyde (index for lipid peroxidation), significantly increased in OBI and r-OBI groups in cortex (p<0.05) and cerebellum (p<0.01-0.001). The glutathione (endogenous antioxidant) level decreased in cortex (p<0.01) and cerebellum (p<0.05) of r-OBI group when compared with the controls. Myeloperoxidase activity indicating neutrophil infiltration, was significantly (p<0.01-0.05) elevated in r-OBI. Additionally, tissue thromboplastin activity, a coagulation marker, was elevated, indicating a tendency to bleed. NGF and NF-κB proteins along with Iba-1 and GFAP immunoreactivity significantly augmented in the frontal cortex demonstrating microglial activation. Serum biomarkers of injury, NSE, TNF-alpha and leptin, were also elevated. CONCLUSION: OBI triggers both inflammation and oxidative injury in the brain. This data in conjunction with our previous observations suggests that OBI triggers a cascade of events beginning with impaired cerebral vascular function leading to ischemia and chronic neurological consequences.

Bias, Type I Error Rates, and Statistical Power of a Latent Mediation Model in the Presence of Violations of Invariance.

When testing a statistical mediation model, it is assumed that factorial measurement invariance holds for the mediating construct across levels of the independent variable X. The consequences of failing to address the violations of measurement invariance in mediation models are largely unknown. The purpose of the present study was to systematically examine the impact of mediator noninvariance on the Type I error rates, statistical power, and relative bias in parameter estimates of the mediated effect in the single mediator model. The results of a large simulation study indicated that, in general, the mediated effect was robust to violations of invariance in loadings. In contrast, most conditions with violations of intercept invariance exhibited severely positively biased mediated effects, Type I error rates above acceptable levels, and statistical power larger than in the invariant conditions. The implications of these results are discussed and recommendations are offered.

A Proteomic Evaluation of Sympathetic Activity Biomarkers of the Hypothalamus-Pituitary-Adrenal Axis by Western Blotting Technique Following Experimental Traumatic Brain Injury.

Endocrine disorders and autonomic dysfunction are common paradigms following traumatic brain injury (TBI). Alterations in the hypothalamus-pituitary-adrenal (HPA) axis following TBI may result in impaired vasopressor response, energy imbalance, fatigue, depression, or neurological disorders. Autonomic dysfunction is a common disorder following TBI. The sympathetic activity markers on HPA axis can be measured by Western blot protein analysis. Tyrosine hydroxylase, dopamine beta hydroxylase are the key enzymes for the synthesis of norepinephrine; and neuropeptide Y (NPY) is the peptide that is co-stored and co-released with norepinephrine. Thus, the present chapter reviews the experimental protocols for Western blot protein analysis for the measurement of biomarkers that indicate sympathetic activity in brain regions (hypothalamus, pituitary, cerebral cortex, and cerebellum) following TBI.

Intracerebroventricular tempol administration in older rats reduces oxidative stress in the hypothalamus but does not change STAT3 signalling or SIRT1/AMPK pathway.

Hypothalamic inflammation and increased oxidative stress are believed to be mechanisms that contribute to obesity. 4-Hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl (tempol), a free radical scavenger, has been shown to reduce inflammation and oxidative stress. We hypothesized that brain infusion of tempol would reduce oxidative stress, and thus would reduce food intake and body weight and improve body composition in rats with age-related obesity and known elevated oxidative stress. Furthermore, we predicted an associated increase in markers of leptin signalling, including the silent mating type information regulator 2 homolog 1 (SIRT1)/5'AMP-activated protein kinase (AMPK) pathway and the signal transducer and activator of transcription 3 (STAT3) pathway. For this purpose, osmotic minipumps were placed in the intracerebroventricular region of young (3 months) and aged (23 months) male Fischer 344 x Brown Norway rats for the continuous infusion of tempol or vehicle for 2 weeks. Tempol significantly decreased (p < 0.01) nicotinamide adenine dinucleotide phosphate oxidase activity in the hypothalamus but failed to reduce food intake or weight gain and did not alter body composition. SIRT1 activity and Acetyl p53 were decreased and phosphorylation of AMPK was increased with age, but they were unchanged with tempol. Basal phosphorylation of STAT3 was unchanged with age or tempol. These results indicate that tempol decreases oxidative stress but fails to alter feeding behaviour, body weight, or body composition. Moreover, tempol does not modulate the SIRT1/AMPK/p53 pathway and does not change leptin signalling. Thus, a reduction in hypothalamic oxidative stress is not sufficient to reverse age-related obesity.