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Abstract Lipotoxicity, the accumulation of lipids in non-adipose tissues, alters the metabolic transcriptome and mitochondrial metabolism in skeletal muscle. The mechanisms involved remain poorly understood. Here we show that lipotoxicity increased histone deacetylase 4 (HDAC4) and histone deacetylase 5 (HDAC5), which reduced the expression of metabolic genes and oxidative metabolism in skeletal muscle, resulting in increased non-oxidative glucose metabolism. This metabolic reprogramming was also associated with impaired apoptosis and ferroptosis responses, and preserved muscle cell viability in response to lipotoxicity. Mechanistically, increased HDAC4 and 5 decreased acetylation of p53 at K120, a modification required for transcriptional activation of apoptosis. Redox drivers of ferroptosis derived from oxidative metabolism were also reduced. The relevance of this pathway was demonstrated by overexpression of loss-of-function HDAC4 and HDAC5 mutants in skeletal muscle of obese db/db mice, which enhanced oxidative metabolic capacity, increased apoptosis and ferroptosis and reduced muscle mass. This study identifies HDAC4 and HDAC5 as repressors of skeletal muscle oxidative metabolism, which is linked to inhibition of cell death pathways and preservation of muscle integrity in response to lipotoxicity.

Abstract Objective: To determine whether primary school children’s weight status and dietary behaviours vary by remoteness as defined by the Australian Modified Monash Model (MMM). Design: A cross-sectional study design was used to conduct secondary analysis of baseline data from primary school students participating in a community-based childhood obesity trial. Logistic mixed models estimated associations between remoteness, measured weight status and self-reported dietary intake. Setting: Twelve regional and rural Local Government Areas in North-East Victoria, Australia. Participants: Data were collected from 2456 grade 4 (approximately 9–10 years) and grade 6 (approximately 11–12 years) students. Results: The final sample included students living in regional centres (17·4 %), large rural towns (25·6 %), medium rural towns (15·1 %) and small rural towns (41·9 %). Weight status did not vary by remoteness. Compared to children in regional centres, those in small rural towns were more likely to meet fruit consumption guidelines (OR: 1·75, 95 % CI (1·24, 2·47)) and had higher odds of consuming fewer takeaway meals (OR: 1·37, 95 % CI (1·08, 1·74)) and unhealthy snacks (OR = 1·58, 95 % CI (1·15, 2·16)). Conclusions: Living further from regional centres was associated with some healthier self-reported dietary behaviours. This study improves understanding of how dietary behaviours may differ across remoteness levels and highlights that public health initiatives may need to take into account heterogeneity across communities.

Abstract Objective: To report the prevalence of healthy weight and related behaviours among Victorian Aboriginal and non‐Aboriginal children and explore associations between these factors and health‐related quality of life (HRQoL). Methods: Analysis of cross‐sectional data from two cluster randomised controlled trials using logistic and linear mixed models. The sample included Aboriginal (n=303) and non‐Aboriginal (n=3,026) children aged 8–13 years. Results: More than two‐thirds of Aboriginal children met guidelines for fruit (75.9%), sweetened drinks (66.7%), sleep (73.1%), screen time (67.7%) and objectively measured physical activity (83.6%); and 79.1% reported consuming take‐away foods less than once per week. Aboriginal children were more likely to meet vegetable consumption guidelines (OR=1.42, 95%CI: 1.05, 1.93), but less likely to have a healthy weight (OR=0.66, 95%CI: 0.52, 0.85) than non‐Aboriginal children. Mean HRQoL scores were significantly higher among non‐Aboriginal children and both Aboriginal and non‐Aboriginal children meeting health guidelines. Conclusions: Most Aboriginal children in this study met guidelines for fruit, physical activity, screen time and sleep, and those meeting these guidelines had significantly higher HRQoL. Implications for public health: Promoting nutrition, physical activity and sleep is likely to benefit all children. Aboriginal community‐controlled organisations can use these data to design culturally‐specific programs that may improve disparities in healthy weight and HRQoL.

BackgroundIn March 2020, the Australian Government expanded general practitioner (GP) telehealth services in response to the COVID-19 pandemic. ObjectiveThis study sought to assess use patterns of GP telehealth services in response to changing circumstances (before and during the COVID-19 pandemic and with or without a lockdown) in regional Victoria, Australia. MethodsWe conducted a secondary analysis of monthly Medicare claims data from July 2019 to June 2021 from 140 regional GP practices in Western Victoria. The longitudinal patterns of proportion of GP telehealth consultations stratified by type of consultation (ie, videoconference vs telephone) and by geographical, consumer, and consultation characteristics were analyzed. ResultsTelehealth comprised 25.8% (522,932/2,025,615) of GP consultations over the 2-year period. After the introduction of the Australian telehealth expansion policy in March 2020, there was a rapid uptake in GP telehealth services (including telephone and video services), from 0% before COVID-19 to 15% (11,854/80,922) of all consultations in March 2020, peaking at 55% (50,828/92,139) in August 2020. Thereafter, the use of telehealth declined steadily to 31% (23,941/77,344) in January 2021 and tapered off to 28% (29,263/103,798) in June 2021. Telephone services and shorter consultations were the most dominant form, and those aged 15-64 years had higher telehealth use rates than younger or older age groups. The proportion of video consultations was higher during periods with government-imposed lockdowns and higher in the most socioeconomically advantaged areas compared to less socioeconomically advantaged areas. ConclusionsOur findings support the continuation of telehealth use in rural and regional Australia post pandemic. Future policy must identify mechanisms to reduce existing equity gaps in video consultations and consider patient- and system-level implications of the dominant use of short telephone consultations.

Abstract Background Cardiovascular diseases (CVD) are the largest cause of death and disability in Australia. Australian national guidelines for the primary prevention of CVD recommend that all adults without CVD and aged 45 years or more are screened for their absolute risk of CVD every 2 years. Despite the compelling evidence to address CVD risk, treatment gaps remain and evidence suggests that much of the shortcomings are attributed to the performance of primary care practices. To address this issue, a quality improvement initiative is being implemented in a large urban multidisciplinary primary care practice in the South West region of Victoria, Australia. The key outcome of this intervention will be to increase the use and acceptability of CVD risk assessment guidelines. To ensure the intervention is tracking toward its objectives, a robust monitoring and evaluation framework was established. Method/design A novel framework that assimilates key traditional and theory-driven evaluation practices was developed to assess the impact of the intervention. The framework approach is termed the integrated model of evaluation (IMoE). Researchers and stakeholders convened several times to discuss and develop the evaluation protocol and align it with the quality intervention. The main objective here is to explore the feasibility of an integrated approach to evaluating clinical quality improvement interventions. The sub-objectives are to test the alignment of the IMoE to clinical quality improvement projects and its ability to derive findings to the satisfaction of stakeholders. The design and establishment of the evaluation approach is discussed in further detail in this article. Discussion The novel feature of the IMoE is its emphasis on tracking ‘change’ in practices that lead to quality improvement. This emphasis suits the quality improvement theme of this initiative as identification of change elements and explanation behind change is necessary to sustain and promote quality improvement. The other principle behind development of this model, which emphasises practicality in implementation, is to ensure stakeholders gain greatest value from the commissioning of program evaluation. By incorporating practical components and leaving out esoteric concepts, this approach ensures evaluation can be undertaken in realistic timeframes. Ethics approval The quality improvement intervention and evaluation framework received approval from the Deakin University Human Research Ethics Committee (Approval Number: 2017-313).

Abstract Objective: The Australian Capital Territory ‘It's Your Move!’ (ACT‐IYM) was a three‐year (2012–2014) systems intervention to prevent obesity among adolescents. Methods: The ACT‐IYM project involved three intervention schools and three comparison schools and targeted secondary students aged 12–16 years. The intervention consisted of multiple initiatives at individual, community, and school policy level to support healthier nutrition and physical activity. Intervention school‐specific objectives related to increasing active transport, increasing time spent physically active at school, and supporting mental wellbeing. Data were collected in 2012 and 2014 from 656 students. Anthropometric data were objectively measured and behavioural data self‐reported. Results: Proportions of overweight or obesity were similar over time within the intervention (24.5% baseline and 22.8% follow‐up) and comparison groups (31.8% baseline and 30.6% follow‐up). Within schools, two of three the intervention schools showed a significant decrease in the prevalence of overweight and obesity (p

Drugs that recapitulate aspects of the exercise adaptive response have the potential to provide better treatment for diseases associated with physical inactivity. We previously observed reduced skeletal muscle class IIa HDAC (histone deacetylase) transcriptional repressive activity during exercise. Here, we find that exercise-like adaptations are induced by skeletal muscle expression of class IIa HDAC mutants that cannot form a corepressor complex. Adaptations include increased metabolic gene expression, mitochondrial capacity, and lipid oxidation. An existing HDAC inhibitor, Scriptaid, had similar phenotypic effects through disruption of the class IIa HDAC corepressor complex. Acute Scriptaid administration to mice increased the expression of metabolic genes, which required an intact class IIa HDAC corepressor complex. Chronic Scriptaid administration increased exercise capacity, whole-body energy expenditure and lipid oxidation, and reduced fasting blood lipids and glucose. Therefore, compounds that disrupt class IIa HDAC function could be used to enhance metabolic health in chronic diseases driven by physical inactivity.

The role of lipids in providing energy and structural cellular components during vertebrate development is poorly understood. To elucidate these roles further, we visualized lipid deposition and examined expression of key lipid-regulating genes during zebrafish embryogenesis. We also conducted a semiquantitative analysis of lipidomic composition using liquid chromatography (LC)-mass spectrometry. Finally, we analyzed processing of boron-dipyrromethene (BODIPY) lipid analogs injected into the yolk using thin layer chromatography. Our data reveal that the most abundant lipids in the embryo are cholesterol, phosphatidylcholine, and triglyceride. Moreover, we demonstrate that lipids are processed within the yolk prior to mobilization to the embryonic body. Our data identify a metabolically active yolk and body resulting in a dynamic lipid composition. This provides a foundation for studying lipid biology during normal or pharmacologically compromised embryogenesis.

The transcriptional coactivators peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) and PGC-1β are positive regulators of skeletal muscle mass and energy metabolism; however, whether they influence muscle growth and metabolic adaptations via increased protein synthesis is not clear. This study revealed PGC-1α or PGC-1β overexpression in C2C12 myotubes increased protein synthesis and myotube diameter under basal conditions and attenuated the loss in protein synthesis following the treatment with the catabolic agent, dexamethasone. To investigate whether PGC-1α or PGC-1β signal through the Akt/mTOR pathway to increase protein synthesis, treatment with the PI3K and mTOR inhibitors, LY294002 and rapamycin, respectively, was undertaken but found unable to block PGC-1α or PGC-1β’s promotion of protein synthesis. Furthermore, PGC-1α and PGC-1β decreased phosphorylation of Akt and the Akt/mTOR substrate, p70S6K. In contrast to Akt/mTOR inhibition, the suppression of ERRα, a major effector of PGC-1α and PGC-1β activity, attenuated the increase in protein synthesis and myotube diameter in the presence of PGC-1α or PGC-1β overexpression. To characterize further the biological processes occurring, gene set enrichment analysis of genes commonly regulated by both PGC-1α and PGC-1β was performed following a microarray screen. Genes were found enriched in metabolic and mitochondrial oxidative processes, in addition to protein translation and muscle development categories. This suggests concurrent responses involving both increased metabolism and myotube protein synthesis. Finally, based on their known function or unbiased identification through statistical selection, two sets of genes were investigated in a human exercise model of stimulated protein synthesis to characterize further the genes influenced by PGC-1α and PGC-1β during physiological adaptive changes in skeletal muscle.

Studies of community-based obesity prevention interventions have hypothesized that stakeholder networks are a critical element of effective implementation. This paper presents a quantitative analysis of the interpersonal network structures within a sub-sample of stakeholders from two past successful childhood obesity prevention interventions.Participants were recruited from the stakeholder groups (steering committees) of two completed community-based intervention studies, Romp & Chomp (R&C), Australia (2004-2008) and Shape Up Somerville (SUS), USA (2003-2005). Both studies demonstrated significant reductions of overweight and obesity among children. Members of the steering committees were asked to complete a retrospective social network questionnaire using a roster of other committee members and free recall. Each participant was asked to recall the people with whom they discussed issues related to childhood obesity throughout the intervention period, along with providing the closeness and level of influence of each relationship.Networks were reported by 13 participants from the SUS steering committee and 8 participants from the R&C steering committee. On average, participants nominated 16 contacts with whom they discussed issues related to childhood obesity through the intervention, with approximately half of the relationships described as 'close' and 30% as 'influential'. The 'discussion' and 'close' networks had high clustering and reciprocity, with ties directed to other steering committee members, and to individuals external to the committee. In contrast, influential ties were more prominently directed internal to the steering committee, with higher network centralization, lower reciprocity and lower clustering.Social network analysis provides a method to evaluate the ties within steering committees of community-based obesity prevention interventions. In this study, the network characteristics between a sub-set of stakeholders appeared to be supportive of diffused communication. Future work should prospectively examine stakeholder network structures in a heterogeneous sample of community-based interventions to identify elements most strongly associated with intervention effectiveness.