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Activation of AMP-activated kinase (AMPK) in skeletal muscle increases glucose uptake, fatty acid oxidation, and mitochondrial biogenesis by increasing gene expression in these pathways. However, the transcriptional components that are directly targeted by AMPK are still elusive. The peroxisome-proliferator-activated receptor γ coactivator 1α (PGC-1α) has emerged as a master regulator of mitochondrial biogenesis; furthermore, it has been shown that PGC-1α gene expression is induced by exercise and by chemical activation of AMPK in skeletal muscle. Using primary muscle cells and mice deficient in PGC-1α, we found that the effects of AMPK on gene expression of glucose transporter 4, mitochondrial genes, and PGC-1α itself are almost entirely dependent on the function of PGC-1α protein. Furthermore, AMPK phosphorylates PGC-1α directly both in vitro and in cells. These direct phosphorylations of the PGC-1α protein at threonine-177 and serine-538 are required for the PGC-1α-dependent induction of the PGC-1α promoter. These data indicate that AMPK phosphorylation of PGC-1α initiates many of the important gene regulatory functions of AMPK in skeletal muscle.

Age‐related impairment of muscle function severely affects the health of an increasing elderly population. While causality and the underlying mechanisms remain poorly understood, exercise is an efficient intervention to blunt these aging effects. We thus investigated the role of the peroxisome proliferator‐activated receptor γ coactivator 1α (PGC‐1α), a potent regulator of mitochondrial function and exercise adaptation, in skeletal muscle during aging. We demonstrate that PGC‐1α overexpression improves mitochondrial dynamics and calcium buffering in an estrogen‐related receptor α‐dependent manner. Moreover, we show that sarcoplasmic reticulum stress is attenuated by PGC‐1α. As a result, PGC‐1α prevents tubular aggregate formation and cell death pathway activation in old muscle. Similarly, the pro‐apoptotic effects of ceramide and thapsigargin were blunted by PGC‐1α in muscle cells. Accordingly, mice with muscle‐specific gain‐of‐function and loss‐of‐function of PGC‐1α exhibit a delayed and premature aging phenotype, respectively. Together, our data reveal a key protective effect of PGC‐1α on muscle function and overall health span in aging. In old muscle, a dysregulation of mitochondrial and sarcoplasmic calcium handling leads to cellular stress and death. Peroxisome proliferator‐activated receptor γ coactivator 1α, a key regulator of endurance exercise adaptation, can prevent these pathological events and mitigate muscle aging.

ABSTRACTBackgroundObesity is a complex, chronic, stigmatized disease whereby abnormal or excess body fat may impair health or increase the risk of medical complications, and can reduce quality of life and shorten lifespan in children and families. We developed this guideline to provide evidence-based recommendations on options for managing pediatric obesity that support shared decision-making among children living with obesity, their families, and their health care providers. MethodsWe followed the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. We used the Guidelines International Network principles to manage competing interests. Caregivers, health care providers, and people living with obesity participated throughout the guideline development process, which optimized relevance. We surveyed end users (caregivers, health care providers) to prioritize health outcomes, completed 3 scoping reviews (2 on minimal important difference estimates; 1 on clinical assessment), performed 1 systematic review to characterize families’ values and preferences, and conducted 3 systematic reviews and meta-analyses to examine the benefits and harms of behavioural and psychological, pharmacologic, and surgical interventions for managing obesity in children. Guideline panellists developed recommendations focused on an individualized approach to care by using the GRADE evidence-to-decision framework, incorporating values and preferences of children living with obesity and their caregivers. RecommendationsOur guideline includes 10 recommendations and 9 good practice statements for managing obesity in children. Managing pediatric obesity should be guided by a comprehensive child and family assessment based on our good practice statements. Behavioural and psychological interventions, particularly multicomponent interventions (strong recommendation, very low to moderate certainty), should form the foundation of care, with tailored therapy and support using shared decision-making based on the potential benefits, harms, certainty of evidence, and values and preferences of children and families. Pharmacologic and surgical interventions should be considered (conditional recommendation, low to moderate certainty) as therapeutic options based on availability, feasibility, and acceptability, and guided by shared decision-making between health care providers and families. InterpretationThis guideline will support children, families, and health care providers to have informed discussions about the balance of benefits and harms for available obesity management interventions to support value- and preference-sensitive decision-making.

KU-55933 is a specific inhibitor of the kinase activity of the protein encoded by Ataxia telangiectasia mutated (ATM), an important tumor suppressor gene with key roles in DNA repair. Unexpectedly for an inhibitor of a tumor suppressor gene, KU-55933 reduces proliferation. In view of prior preliminary evidence suggesting defective mitochondrial function in cells of patients with Ataxia Telangiectasia (AT), we examined energy metabolism of cells treated with KU-55933. The compound increased AMPK activation, glucose uptake and lactate production while reducing mitochondrial membrane potential and coupled respiration. The stimulation of glycolysis by KU-55933 did not fully compensate for the reduction in mitochondrial functions, leading to decreased cellular ATP levels and energy stress. These actions are similar to those previously described for the biguanide metformin, a partial inhibitor of respiratory complex I. Both compounds decreased mitochondrial coupled respiration and reduced cellular concentrations of fumarate, malate, citrate, and alpha-ketogluterate. Succinate levels were increased by KU-55933 levels and decreased by metformin, indicating that the effects of ATM inhibition and metformin are not identical. These observations suggest a role for ATM in mitochondrial function and show that both KU-55933 and metformin perturb the TCA cycle as well as oxidative phosphorylation.

Translation is a basic cellular process and its capacity is adapted to cell function. In particular, secretory cells achieve high protein synthesis levels without triggering the protein stress response. It is unknown how and when translation capacity is increased during differentiation. Here, we show that the transcription factor Creb3l2 is a scaling factor for translation capacity in pituitary secretory cells and that it directly binds ~75% of regulatory and effector genes for translation. In parallel with this cell-autonomous mechanism, implementation of the physiological UPR pathway prevents triggering the protein stress response. Knockout mice for Tpit , a pituitary differentiation factor, show that Creb3l2 expression and its downstream regulatory network are dependent on Tpit . Further, Creb3l2 acts by direct targeting of translation effector genes in parallel with signaling pathways that otherwise regulate protein synthesis. Expression of Creb3l2 may be a useful means to enhance production of therapeutic proteins. Pituitary POMC secreting cells achieve high hormone expression levels after birth but the mechanism for this regulation is unclear. Here, the authors show that this process is driven cell autonomously by the differentiation factor Tpit that activates the bZIP transcription factors Creb3l2 and XBP1 to enhance translation and secretory capacities.

Despite the initial benefits of treating HER2-amplified breast cancer patients with the tyrosine kinase inhibitor lapatinib, resistance inevitably develops. Here we report that lapatinib induces the degradation of the nuclear receptor ERRα, a master regulator of cellular metabolism, and that the expression of ERRα is restored in lapatinib-resistant breast cancer cells through reactivation of mTOR signalling. Re-expression of ERRα in resistant cells triggers metabolic adaptations favouring mitochondrial energy metabolism through increased glutamine metabolism, as well as ROS detoxification required for cell survival under therapeutic stress conditions. An ERRα inverse agonist counteracts these metabolic adaptations and overcomes lapatinib resistance in a HER2-induced mammary tumour mouse model. This work reveals a molecular mechanism by which ERRα-induced metabolic reprogramming promotes survival of lapatinib-resistant cancer cells and demonstrates the potential of ERRα inhibition as an effective adjuvant therapy in poor outcome HER2-positive breast cancer. Despite initial benefits in treating HER2-positive breast cancer patients with lapatinib, resistance is prevalent. Here the authors show that lapatinib resistance can be ascribed to mTOR-mediated re-activation of ERRα and to the consequent induction of a metabolic adaptation.

Type 2 cytokines like IL-4 are hallmarks of helminth infection and activate macrophages to limit immunopathology and mediate helminth clearance. In addition to cytokines, nutrients and metabolites critically influence macrophage polarization. Choline is an essential nutrient known to support normal macrophage responses to lipopolysaccharide; however, its function in macrophages polarized by type 2 cytokines is unknown. Using murine IL-4-polarized macrophages, targeted lipidomics revealed significantly elevated levels of phosphatidylcholine, with select changes to other choline-containing lipid species. These changes were supported by the coordinated up-regulation of choline transport compared to naïve macrophages. Pharmacological inhibition of choline metabolism significantly suppressed several mitochondrial transcripts and dramatically inhibited select IL-4-responsive transcripts, most notably, Retnla . We further confirmed that blocking choline metabolism diminished IL-4-induced RELMα (encoded by Retnla ) protein content and secretion and caused a dramatic reprogramming toward glycolytic metabolism. To better understand the physiological implications of these observations, naïve or mice infected with the intestinal helminth Heligmosomoides polygyrus were treated with the choline kinase α inhibitor, RSM-932A, to limit choline metabolism in vivo . Pharmacological inhibition of choline metabolism lowered RELMα expression across cell-types and tissues and led to the disappearance of peritoneal macrophages and B-1 lymphocytes and an influx of infiltrating monocytes. The impaired macrophage activation was associated with some loss in optimal immunity to H . polygyrus , with increased egg burden. Together, these data demonstrate that choline metabolism is required for macrophage RELMα induction, metabolic programming, and peritoneal immune homeostasis, which could have important implications in the context of other models of infection or cancer immunity.

Chemotherapy resistance is a critical barrier in cancer treatment. Metabolic adaptations have been shown to fuel therapy resistance; however, little is known regarding the generality of these changes and whether specific therapies elicit unique metabolic alterations. Using a combination of metabolomics, transcriptomics, and functional genomics, we show that two anthracyclines, doxorubicin and epirubicin, elicit distinct primary metabolic vulnerabilities in human breast cancer cells. Doxorubicin-resistant cells rely on glutamine to drive oxidative phosphorylation and de novo glutathione synthesis, while epirubicin-resistant cells display markedly increased bioenergetic capacity and mitochondrial ATP production. The dependence on these distinct metabolic adaptations is revealed by the increased sensitivity of doxorubicin-resistant cells and tumor xenografts to buthionine sulfoximine (BSO), a drug that interferes with glutathione synthesis, compared with epirubicin-resistant counterparts that are more sensitive to the biguanide phenformin. Overall, our work reveals that metabolic adaptations can vary with therapeutics and that these metabolic dependencies can be exploited as a targeted approach to treat chemotherapy-resistant breast cancer.

Metabolic programming of the innate immune cells known as dendritic cells (DCs) changes in response to different stimuli, influencing their function. While the mechanisms behind increased glycolytic metabolism in response to inflammatory stimuli are well-studied, less is known about the programming of mitochondrial metabolism in DCs. We used lipopolysaccharide (LPS) and interferon-β (IFN-β), which differentially stimulate the use of glycolysis and oxidative phosphorylation (OXPHOS), respectively, to identify factors important for mitochondrial metabolism. We found that the expression of peroxisome proliferator-activated receptor gamma co-activator 1β (PGC-1β), a transcriptional co-activator and known regulator of mitochondrial metabolism, decreases when DCs are activated with LPS, when OXPHOS is diminished, but not with IFN-β, when OXPHOS is maintained. We examined the role of PGC-1β in bioenergetic metabolism of DCs and found that PGC-1β deficiency indeed impairs their mitochondrial respiration. PGC-1β-deficient DCs are more glycolytic compared to controls, likely to compensate for reduced OXPHOS. PGC-1β deficiency also causes decreased capacity for ATP production at steady state and in response to IFN-β treatment. Loss of PGC-1β in DCs leads to increased expression of genes in inflammatory pathways, and reduced expression of genes encoding proteins important for mitochondrial metabolism and function. Collectively, these results demonstrate that PGC-1β is a key regulator of mitochondrial metabolism and negative regulator of inflammatory gene expression in DCs.

Purpose The purpose of this work was to detail our center's experience in transitioning from a Co‐60 treatment technique to an intensity modulated radiation therapy (IMRT) based lateral‐field extended source‐to‐axis distance (e‐SAD) technique for total body irradiation (TBI). Materials and Methods An existing beam model in RayStation v.10A was validated for the use of e‐SAD TBI treatments. Data were acquired with an Elekta Synergy linear accelerator (LINAC) at an extended source‐to‐surface distance of 365 cm with an 18 MV beam. Beam model validation measurements included percentage depth dose (PDD), profile data, surface dose, build‐up region and transmission measurements. End‐to‐end testing was carried out using an anthropomorphic phantom. Treatments were performed in a supine position in a whole‐body Vac‐Lok at an e‐SAD of 400 cm with a beam spoiler 10 cm from the couch. Planning was achieved using IMRT, where multi‐leaf collimators were used to modulate the beam and shield the organs at risk. Beam's eye view projection images were used for in‐room patient positioning and in‐vivo dosimetry was performed for every treatment. Results The percent difference between the measured and calculated PDD and profiles was less than 2% at all locations. Surface dose was 83.8% of the maximum dose with the beam spoiler at a 10 cm distance from the phantom. The largest percent difference between the treatment planning system (TPS) and measured data within the anthropomorphic phantom was approximately 2%. In‐vivo dosimetry measurements yielded results within the 5% institutional threshold. Conclusion In 2022, 17 patients were successfully treated using the new IMRT‐based lateral‐field e‐SAD TBI technique. The resulting clinical plans respected the institutional standard. The commissioning process, as well as the treatment planning and delivery aspects were described in this work with the intention of supporting other clinics in implementing this treatment method.