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Exercise is fundamental for good health, whereas physical inactivity underpins many chronic diseases of modern society. It is well appreciated that regular exercise improves metabolism and the metabolic phenotype in a number of tissues. The phenotypic alterations observed in skeletal muscle are partly mediated by transcriptional responses that occur following each individual bout of exercise. This adaptive response increases oxidative capacity and influences the function of myokines and extracellular vesicles that signal to other tissues. Our understanding of the epigenetic and transcriptional mechanisms that mediate the skeletal muscle gene expression response to exercise as well as of their upstream signalling pathways has advanced substantially in the past 10 years. With this knowledge also comes the opportunity to design new therapeutic strategies based on the biology of exercise for a variety of chronic conditions where regular exercise might be a challenge. This Review provides an overview of the beneficial adaptive responses to exercise and details the molecular mechanisms involved. The possibility of designing therapeutic interventions based on these molecular mechanisms is addressed, using relevant examples that have exploited this approach.This Review highlights the beneficial adaptive responses to exercise in skeletal muscle and other tissues as well as their molecular mechanisms. In addition, the possibility of exercise-like therapeutic interventions is discussed, providing relevant examples that have used this approach.

It remains unclear as to whether polycystic ovary syndrome (PCOS) is an additional risk factor in the development of left ventricular (LV) hypertrophy in obese women. In the current study, we provide clarity on this issue by rigorously analysing patient LV geometry beyond the basic clinical measures currently used. Importantly, the cohort contained only normotensive patients that would normally be deemed low risk with no further intervention required. The study comprised 24 obese women with PCOS and 29 obese Control women. Transthoracic echocardiography was used to evaluate LV structure/function. Basic clinical and metabolic data were collected for each participant consisting of age, BMI, blood pressure, fasting glucose, LDL-C, HLD-C, cholesterol and triglyceride levels. Exclusion criteria; BMI < 30 g/m2, type 2 diabetes, hypertension. Both groups exhibited concentric remodelling of the LV posterior wall at a prevalence of ~20%, this associated with grade 1 diastolic dysfunction. Estimated LV mass/height2.7 was increased patients with PCOS (45 ± 2.2 vs 37 ± 1.6) with 33% exhibiting LV mass/height2.7 above ASE guidelines, compared to 7% in Controls. Furthermore, 25% of patients with PCOS were characterised with concentric hypertrophy, an alteration in LV geometry that was not observed in the Control group. To our knowledge, this is the first study to assess LV geometric patterns in obese women with PCOS. The results suggest that obese women with PCOS are at greater risk of concentric hypertrophy than obese only women and provide justification for additional cardiovascular risk assessment in normotensive obese/PCOS women.

Development of OA (OA) is multifactorial and is strongly associated with risk factors such as aging, trauma, metabolic disorders, and obesity. Metabolic Syndrome (MetS)-associated OA, collectively coined MetS-OA, is an increasingly recognized entity in which metabolic disorders and low-grade inflammation play a key mechanistic role in the disruption of joint homeostasis and cartilage degradation. Although there have been enormous efforts to discover biomarkers of MetS and OA, studies investigating a pathophysiological link between MetS and OA are relatively limited, and no serum blood marker has proved diagnostic so far. OA biomarkers that are necessary to discriminate and diagnose early disease remain to be elicited, explained in part by limited prospective studies, and therefore limited tools available to utilize in any prognostic capacity. Biomarker validation projects have been established by the Biomarker Consortium to determine biochemical markers demonstrating predictive validity for knee OA. Given that the metabolic constituents of MetS are treatable to varying extents, it stands to reason that treating these, and monitoring such treatment, may help to mitigate deleterious links with OA development. This narrative review will describe the current state of biomarker identification and utility in OA associated with MetS. We discuss the pathophysiological mechanisms of disease according to constituent pathologies of MetS and how identification of biomarkers may guide future investigation of novel targets.

The development of diabetic cardiomyopathy is a key contributor to heart failure and mortality in obesity and type 2 diabetes (T2D). Current therapeutic interventions for T2D have limited impact on the development of diabetic cardiomyopathy. Clearly, new therapies are urgently needed. A potential therapeutic target is protein kinase D (PKD), which is activated by metabolic insults and implicated in the regulation of cardiac metabolism, contractility and hypertrophy. We therefore hypothesised that PKD inhibition would enhance cardiac function in T2D mice. We first validated the obese and T2D db/db mouse as a model of early stage diabetic cardiomyopathy, which was characterised by both diastolic and systolic dysfunction, without overt alterations in left ventricular morphology. These functional characteristics were also associated with increased PKD2 phosphorylation in the fed state and a gene expression signature characteristic of PKD activation. Acute administration of the PKD inhibitor CID755673 to normal mice reduced both PKD1 and 2 phosphorylation in a time and dose-dependent manner. Chronic CID755673 administration to T2D db/db mice for two weeks reduced expression of the gene expression signature of PKD activation, enhanced indices of both diastolic and systolic left ventricular function and was associated with reduced heart weight. These alterations in cardiac function were independent of changes in glucose homeostasis, insulin action and body composition. These findings suggest that PKD inhibition could be an effective strategy to enhance heart function in obese and diabetic patients and provide an impetus for further mechanistic investigations into the role of PKD in diabetic cardiomyopathy.

Objective Osteoarthritis (OA) is a disease impacting the synovial joint complex, yet transcriptional changes specific to shoulder OA remain underexplored. This study aims to profile transcriptomic changes in periarticular tissues from patients undergoing shoulder replacement for OA. By correlating these profiles with QuickDASH scores—a validated measure of worsening shoulder function—this research seeks to understand the gene expression changes associated with clinical decline. Capsular tissue biopsies from shoulder OA patients were compared with those from a control group undergoing shoulder stabilization for recurrent instability. This investigation forms part of a larger transcriptomic analysis of painful shoulder conditions which will address the current gap in knowledge regarding the molecular and genetic underpinnings of shoulder OA, rotator cuff tears and cuff-tear arthropathy. Results The analysis revealed that genes most strongly associated with increasing QuickDASH scores across tissues were linked to inflammation and stress response. Key pathways involved interleukins, chemokines, complement components, nuclear response factors, and immediate early response genes, reflecting a balance between pro- and anti-inflammatory signalling. Additionally, this study identified unique gene expression patterns in shoulder OA not previously observed in hip and knee OA, along with novel genes implicated in shoulder OA, highlighting areas for future targeted investigation. Trial registration This investigation has been registered with the Australian New Zealand Clinical Trials Registry (ANZCTR), registered on the 26th of March 2018, registration number: 12618000431224, accessible from: https://anzctr.org.au/Trial/Registration/TrialReview.aspx?id=374665&isReview=true

AMP-Activated Protein Kinase Regulates GLUT4 Transcription by Phosphorylating Histone Deacetylase 5 Sean L. McGee 1 2 , Bryce J.W. van Denderen 3 , Kirsten F. Howlett 2 , Janelle Mollica 2 , Jonathan D. Schertzer 1 , Bruce E. Kemp 3 4 and Mark Hargreaves 1 1 Department of Physiology, The University of Melbourne, Melbourne, Australia 2 School of Exercise and Nutrition Sciences, Deakin University, Burwood, Australia 3 St. Vincent’s Institute, Fitzroy, Australia 4 CSIRO Molecular and Health Technologies, Parkville, Australia Address correspondence and reprint requests to Sean McGee, Department of Physiology, The University of Melbourne, 3010, Australia. E-mail: slmcgee{at}unimelb.edu.au Abstract OBJECTIVE— Insulin resistance associated with obesity and diabetes is ameliorated by specific overexpression of GLUT4 in skeletal muscle. The molecular mechanisms regulating skeletal muscle GLUT4 expression remain to be elucidated. The purpose of this study was to examine these mechanisms. RESEARCH DESIGN AND METHODS AND RESULTS— Here, we report that AMP-activated protein kinase (AMPK) regulates GLUT4 transcription through the histone deacetylase (HDAC)5 transcriptional repressor. Overexpression of HDAC5 represses GLUT4 reporter gene expression, and HDAC inhibition in human primary myotubes increases endogenous GLUT4 gene expression. In vitro kinase assays, site-directed mutagenesis, and site-specific phospho-antibodies establish AMPK as an HDAC5 kinase that targets S259 and S498. Constitutively active but not dominant-negative AMPK and 5-aminoimidazole-4-carboxamide-1-β- d -ribonucleoside (AICAR) treatment in human primary myotubes results in HDAC5 phosphorylation at S259 and S498, association with 14-3-3 isoforms, and H3 acetylation. This reduces HDAC5 association with the GLUT4 promoter, as assessed through chromatin immunoprecipitation assays and HDAC5 nuclear export, concomitant with increases in GLUT4 gene expression. Gene reporter assays also confirm that the HDAC5 S259 and S498 sites are required for AICAR induction of GLUT4 transcription. CONCLUSIONS— These data reveal a signal transduction pathway linking cellular energy charge to gene transcription directed at restoring cellular and whole-body energy balance and provide new therapeutic targets for the treatment and management of insulin resistance and type 2 diabetes. AICAR, 5-aminoimidazole-4-carboxamide-1-β-d-ribonucleoside AMPK, AMP-activated protein kinase CaMK, calcium/calmodulin-dependent protein kinases ChIP, chromatin immunoprecipitation GEF, GLUT4 enhancer factor H3, histone 3 H3K9, histone 3 lysine 9 HAT, histone acetyl-transferase HDAC, histone deacetylase MEF, myocyte enhancer factor Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on 9 January 2007. DOI: 10.2337/db07-0843. Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db07-0843 . The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted January 1, 2008. Received June 20, 2007. DIABETES

There are epidemiological associations between obesity and type 2 diabetes, cardiovascular disease and Alzheimer’s disease. The role of amyloid beta 42 (Aβ 42 ) in these diverse chronic diseases is obscure. Here we show that adipose tissue releases Aβ 42 , which is increased from adipose tissue of male mice with obesity and is associated with higher plasma Aβ 42 . Increasing circulating Aβ 42 levels in male mice without obesity has no effect on systemic glucose homeostasis but has obesity-like effects on the heart, including reduced cardiac glucose clearance and impaired cardiac function. The closely related Aβ 40 isoform does not have these same effects on the heart. Administration of an Aβ-neutralising antibody prevents obesity-induced cardiac dysfunction and hypertrophy. Furthermore, Aβ-neutralising antibody administration in established obesity prevents further deterioration of cardiac function. Multi-contrast transcriptomic analyses reveal that Aβ 42 impacts pathways of mitochondrial metabolism and exposure of cardiomyocytes to Aβ 42 inhibits mitochondrial complex I. These data reveal a role for systemic Aβ 42 in the development of cardiac disease in obesity and suggest that therapeutics designed for Alzheimer’s disease could be effective in combating obesity-induced heart failure. Epidemiological evidence has identified associations among obesity, Alzheimer’s disease, and cardiovascular disease. Here, the authors report that adipose tissue releases amyloid beta 42 (Aβ42) and that antagonizing Aβ42 protects cardiac function in obesity murine models.

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.

Background Increased flux through both glycolytic and oxidative metabolic pathways is a hallmark of breast cancer cells and is critical for their growth and survival. As such, targeting this metabolic reprograming has received much attention as a potential treatment approach. However, the heterogeneity of breast cancer cell metabolism, even within classifications, suggests a necessity for an individualised approach to treatment in breast cancer patients. Methods The metabolic phenotypes of a diverse panel of human breast cancer cell lines representing the major breast cancer classifications were assessed using real-time metabolic flux analysis. Flux linked to ATP production, pathway reserve capacities and specific macromolecule oxidation rates were quantified. Suspected metabolic vulnerabilities were targeted with specific pathway inhibitors, and relative cell viability was assessed using the crystal violet assay. Measures of AMPK and mTORC1 activity were analysed through immunoblotting. Results Breast cancer cells displayed heterogeneous energy requirements and utilisation of non-oxidative and oxidative energy-producing pathways. Quantification of basal glycolytic and oxidative reserve capacities identified cell lines that were highly dependent on individual pathways, while assessment of substrate oxidation relative to total oxidative capacity revealed cell lines that were highly dependent on individual macromolecules. Based on these findings, mild mitochondrial inhibition in ESH-172 cells, including with the anti-diabetic drug metformin, and mild glycolytic inhibition in Hs578T cells reduced relative viability, which did not occur in non-transformed MCF10a cells. The effects on viability were associated with AMPK activation and inhibition of mTORC1 signalling. Hs578T were also found to be highly dependent on glutamine oxidation and inhibition of this process also impacted viability. Conclusions Together, these data highlight that systematic flux analysis in breast cancer cells can identify targetable metabolic vulnerabilities, despite heterogeneity in metabolic profiles between individual cancer cell lines.

Background: The human gastrointestinal tract harbors a complex microbiota that plays a vital role in metabolic health. Dysbiosis of the gut microbiome has been linked to metabolic syndrome (MetS), a growing health concern characterized by obesity, hypertension, and dyslipidemia, all of which are strongly associated with insulin resistance and low-grade inflammation. This study aimed to analyze changes in gut microbiome composition and metabolic parameters in individuals with MetS following a 3-month shared medical appointment program driven by a patient-centered agenda with an emphasis on lifestyle pillars of diet, activity, sleep, and stress management. Methods: Thirty-six individuals with MetS were recruited. Of these, 14 completed a structured metabolic health program with facilitated group appointments, including personalized dietary adjustments, increased physical activity, stress management, and clinical monitoring, while 22 served as an untreated group. Fecal samples were collected for full-length 16S rRNA sequencing. Clinical and biochemical parameters, including body weight, blood pressure, HbA1c, triglycerides, and liver enzymes, were assessed. Microbiome data were analyzed for alpha and beta diversity and differential abundance. Correlations between microbial genera and clinical parameters were evaluated using Spearman correlation. Results: Post-intervention, significant improvements were observed in body weight (p = 0.0061), HbA1c (p = 0.033), triglycerides (p = 0.047), AST (p = 0.016), and systolic blood pressure (p = 0.020). Alpha and beta diversity of the gut microbiome showed no significant changes. However, differential abundance analysis revealed increased levels of butyrate-producing and anti-inflammatory genera including Duncaniella, Megasphaera, Pseudoruminococcus, and Oliverpabstia. Conclusions: A 3-month lifestyle intervention in individuals with MetS was associated with marked improvements in metabolic health and beneficial shifts in gut microbiota composition. These findings suggest that even small lifestyle modifications may be a potential therapeutic target for metabolic syndrome management, highlighting the need for personalized approaches in future research.