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Macrophages but not skeletal muscle cells respond to extracellular succinate via SUCNR1/GPR91.

The maintenance of skeletal muscle plasticity upon changes in the environment, nutrient supply, and activity depends on the crosstalk between metabolic and structural adaptations. Here, we establish a role for the orphan nuclear receptor Nr2f6 in both processes. Nr2f6 overexpression leads to an atrophic state, sharply decreasing muscle mass and myofiber content, which is accompanied by an impairment in force production. These functional phenotypes were followed by the establishment of an inflammatory molecular signature, and a decrease in genes involved in oxidative metabolism and contractility. Conversely, Nr2f6 depletion increased myocytes' oxidative capacity and protected against lipid-induced cell death. In addition, Nr2f6 regulated core components of the cell division machinery, decoupling muscle cell proliferation from differentiation. Collectively, our findings define a novel role for Nr2f6 as a molecular transducer conferring the balance between skeletal muscle structure and oxidative capacity.

The field of bioenergetics is rapidly expanding with new discoveries of mechanisms and potential therapeutic targets. The 2023 Keystone symposium on ‘Bioenergetics in Health and Disease’, which was jointly held with the symposium ‘Adipose Tissue: Energizing Good Fat’, consisted of a powerhouse line-up of researchers who shared their insights.

The circadian clock is a cell-autonomous transcription–translation feedback mechanism that anticipates and adapts physiology and behavior to different phases of the day. A variety of factors including hormones, temperature, food-intake, and exercise can act on tissue-specific peripheral clocks to alter the expression of genes that influence metabolism, all in a time-of-day dependent manner. The aim of this study was to elucidate the effects of exercise timing on adipose tissue metabolism. We performed RNA sequencing on inguinal adipose tissue of mice immediately following maximal exercise or sham treatment at the early rest or early active phase. Only during the early active phase did exercise elicit an immediate increase in serum nonesterified fatty acids. Furthermore, early active phase exercise increased expression of markers of thermogenesis and mitochondrial proliferation in inguinal adipose tissue. In vitro, synchronized 3T3-L1 adipocytes showed a timing-dependent difference in Adrb2 expression, as well as a greater lipolytic activity. Thus, the response of adipose tissue to exercise is time-of-day sensitive and may be partly driven by the circadian clock. To determine the influence of feeding state on the time-of-day response to exercise, we replicated the experiment in 10-h-fasted early rest phase mice to mimic the early active phase metabolic status. A 10-h fast led to a similar lipolytic response as observed after active phase exercise but did not replicate the transcriptomic response, suggesting that the observed changes in gene expression are not driven by feeding status. In conclusion, acute exercise elicits timing-specific effects on adipose tissue to maintain metabolic homeostasis.

Skeletal muscle is an endocrine organ secreting exercise-induced factors (exerkines), which play a pivotal role in interorgan cross talk. Using mass spectrometry (MS)-based proteomics, we characterized the secretome and identified thymosin β4 (TMSB4X) as the most upregulated secreted protein in the media of contracting C2C12 myotubes. TMSB4X was also acutely increased in the plasma of exercising humans irrespective of the insulin resistance condition or exercise mode. Treatment of mice with TMSB4X did not ameliorate the metabolic disruptions associated with diet induced-obesity, nor did it enhance muscle regeneration in vivo. However, TMSB4X increased osteoblast proliferation and neurite outgrowth, consistent with its WADA classification as a prohibited growth factor. Therefore, we report TMSB4X as a human exerkine with a potential role in cellular cross talk.

Aims/hypothesisIncreased levels of branched-chain amino acids (BCAAs) are associated with type 2 diabetes pathogenesis. However, most metabolomic studies are limited to an analysis of plasma metabolites under fasting conditions, rather than the dynamic shift in response to a metabolic challenge. Moreover, metabolomic profiles of peripheral tissues involved in glucose homeostasis are scarce and the transcriptomic regulation of genes involved in BCAA catabolism is partially unknown. This study aimed to identify differences in circulating and skeletal muscle BCAA levels in response to an OGTT in individuals with normal glucose tolerance (NGT) or type 2 diabetes. Additionally, transcription factors involved in the regulation of the BCAA gene set were identified.MethodsPlasma and vastus lateralis muscle biopsies were obtained from individuals with NGT or type 2 diabetes before and after an OGTT. Plasma and quadriceps muscles were harvested from skeletal muscle-specific PGC-1α knockout and transgenic mice. BCAA-related metabolites and genes were assessed by LC-MS/MS and RT-PCR, respectively. Small interfering RNA and adenovirus-mediated overexpression techniques were used in primary human skeletal muscle cells to study the role of PGC-1A and ESRRA in the expression of the BCAA gene set. Radiolabeled leucine was used to analyze the impact of ERRα knockdown on leucine oxidation.ResultsImpairments in BCAA catabolism in people with type 2 diabetes under fasting conditions were exacerbated after a glucose load. Branched-chain keto acids were reduced 37–56% after an OGTT in the NGT group, whereas no changes were detected in individuals with T2D. These changes were concomitant with a stronger correlation with glucose homeostasis biomarkers and downregulated expression of BCAT2, BCKDH complex subunits and 69% of downstream BCAA-related genes in skeletal muscle. In primary human myotubes overexpressing PGC-1α, 61% of the analyzed BCAA genes were upregulated, while 67% were downregulated in the quadriceps of skeletal muscle-specific PGC-1α knockout mice. ESRRA (encoding estrogen-related receptor α, ERRα) silencing completely abrogated the PGC-1α-induced upregulation of BCAA-related genes in primary human myotubes.Conclusions/interpretationMetabolic inflexibility in type 2 diabetes impacts BCAA homeostasis and attenuates the decrease of circulating and skeletal muscle BCAA-related metabolites after a glucose challenge. Transcriptional regulation of BCAA genes in primary human myotubes via a PGC-1α is ERRα-dependent.Research in contextWhat is already known about this subject?Circulating levels of BCAA are elevated in type 2 diabetes.PGC-1α is involved in the transcription of the BCAA gene set.What is the key question?Does metabolic inflexibility associated with type 2 diabetes encompass BCAA homeostasis and PGC-1α mediated transcription of the BCAA gene set?What are the new findings?BCAA homeostasis is further compromised by a glucose challenge in type 2 diabetes.An OGTT reveals coordinated regulation between BCAA metabolites, blood glucose, and HbA1c levels.ERRα is essential for PGC-1α-mediated BCAA gene expression in primary human myotubes.How might this impact on clinical practice in the foreseeable future?An OGTT can be used to underscore impairments in BCAA metabolism. These findings suggest that interventions targeting the PGC-1α/ ERRα axis may improve BCAA homeostasis.

Obesity and elevated circulating lipids may impair metabolism by disrupting the molecular circadian clock. We tested the hypothesis that lipid overload may interact with the circadian clock and alter the rhythmicity of gene expression through epigenomic mechanisms in skeletal muscle. Palmitate reprogrammed the circadian transcriptome in myotubes without altering the rhythmic mRNA expression of core clock genes. Genes with enhanced cycling in response to palmitate were associated with post-translational modification of histones. The cycling of histone 3 lysine 27 acetylation (H3K27ac), a marker of active gene enhancers, was modified by palmitate treatment. Chromatin immunoprecipitation and sequencing confirmed that palmitate exposure altered the cycling of DNA regions associated with H3K27ac. The overlap between mRNA and DNA regions associated with H3K27ac and the pharmacological inhibition of histone acetyltransferases revealed novel cycling genes associated with lipid exposure of primary human myotubes. Palmitate exposure disrupts transcriptomic rhythmicity and modifies enhancers through changes in histone H3K27 acetylation in a circadian manner. Thus, histone acetylation is responsive to lipid overload and may redirect the circadian chromatin landscape, leading to the reprogramming of circadian genes and pathways involved in lipid biosynthesis in skeletal muscle.

The molecular circadian clock plays a role in metabolic homeostasis. We tested the hypothesis obesity and systemic factors associated with insulin resistance affect skeletal muscle clock gene expression. We determined clock gene expression in skeletal muscle of obese women ( n = 5) and men ( n = 18) before and 6 mo after Roux-en-Y gastric bypass (RYGB) surgery and normal-weight controls (women n = 6, men n = 8). Skeletal muscle clock gene expression was affected by obesity and weight loss. CRY1 mRNA ( P = 0.05) was increased and DBP mRNA ( P < 0.05) was decreased in obese vs. normal weight women and restored to control levels after RYGB-induced weight loss. CLOCK, CRY1, CRY2, and DBP mRNA ( P < 0.05) was decreased in obese men compared with normal weight men. Expression of all other clock genes was unaltered by obesity or weight loss in both cohorts. We correlated clock gene expression with clinical characteristics of the participants. Among the genes studied, DBP and PER3 expression was inversely correlated with plasma lipids in both cohorts. Circadian time-course studies revealed that core clock genes oscillate over time ( P < 0.05), with BMAL1, CIART, CRY2, DBP, PER1, and PER3 expression profiles altered by palmitate treatment. In conclusion, skeletal muscle clock gene expression and function is altered by obesity, coincident with changes in plasma lipid levels. Palmitate exposure disrupts clock gene expression in myotubes, indicating that dyslipidemia directly alters the circadian program. Strategies to reduce lipid overload and prevent elevations in nonesterified fatty acid and cholesterol levels may sustain circadian clock signals in skeletal muscle.

Mechanistic insights into the molecular events by which exercise enhances the skeletal muscle phenotype are lacking, particularly in the context of type 2 diabetes. Here, we unravel a fundamental role for exercise-responsive cytokines (exerkines) on skeletal muscle development and growth in individuals with normal glucose tolerance or type 2 diabetes. Acute exercise triggered an inflammatory response in skeletal muscle, concomitant with an infiltration of immune cells. These exercise effects were potentiated in type 2 diabetes. In response to contraction or hypoxia, cytokines were mainly produced by endothelial cells and macrophages. The chemokine CXCL12 was induced by hypoxia in endothelial cells, as well as by conditioned medium from contracted myotubes in macrophages. We found that CXCL12 was associated with skeletal muscle remodeling after exercise and differentiation of cultured muscle. Collectively, acute aerobic exercise mounts a noncanonical inflammatory response, with an atypical production of exerkines, which is potentiated in type 2 diabetes.

Description, Disturbances in daily rhythms of mitochondrial activity may contribute to skeletal muscle insulin resistance in type 2 diabetes., Circadian rhythms are generated by an autoregulatory feedback loop of transcriptional activators and repressors. Circadian rhythm disruption contributes to type 2 diabetes (T2D) pathogenesis. We elucidated whether altered circadian rhythmicity of clock genes is associated with metabolic dysfunction in T2D. Transcriptional cycling of core-clock genes BMAL1, CLOCK, and PER3 was altered in skeletal muscle from individuals with T2D, and this was coupled with reduced number and amplitude of cycling genes and disturbed circadian oxygen consumption. Inner mitochondria–associated genes were enriched for rhythmic peaks in normal glucose tolerance, but not T2D, and positively correlated with insulin sensitivity. Chromatin immunoprecipitation sequencing identified CLOCK and BMAL1 binding to inner-mitochondrial genes associated with insulin sensitivity, implicating regulation by the core clock. Inner-mitochondria disruption altered core-clock gene expression and free-radical production, phenomena that were restored by resveratrol treatment. We identify bidirectional communication between mitochondrial function and rhythmic gene expression, processes that are disturbed in diabetes.

Skeletal muscle is a highly adaptable tissue and remodels in response to exercise training. Using short RNA sequencing, we determine the miRNA profile of skeletal muscle from healthy male volunteers before and after a 14-day aerobic exercise training regime. Among the exercise training-responsive miRNAs identified, miR-19b-3p was selected for further validation. Overexpression of miR-19b-3p in human skeletal muscle cells increases insulin signaling, glucose uptake, and maximal oxygen consumption, recapitulating the adaptive response to aerobic exercise training. Overexpression of miR-19b-3p in mouse flexor digitorum brevis muscle enhances contraction-induced glucose uptake, indicating that miR-19b-3p exerts control on exercise training-induced adaptations in skeletal muscle. Potential targets of miR-19b-3p that are reduced after aerobic exercise training include KIF13A, MAPK6, RNF11, and VPS37A. Amongst these, RNF11 silencing potentiates glucose uptake in human skeletal muscle cells. Collectively, we identify miR-19b-3p as an aerobic exercise training-induced miRNA that regulates skeletal muscle glucose metabolism., Exercise induces structural and functional adaptations in skeletal muscle that involve transcriptomic remodeling, including of miRNA expression. Here the authors examine the expression of miRNAs in human muscle following exercise training and investigate the functions of miR-19b-3p on glucose metabolism in cells and mouse muscle.

AIMS/HYPOTHESIS: Metabolic effects of exercise may partly depend on the time-of-day when exercise is performed. We tested the hypothesis that exercise timing affects the adaptations in multi-tissue metabolome and skeletal muscle proteome profiles in men with type 2 diabetes.METHODS: Men fitting the inclusion (type 2 diabetes, age 45-68 years and body mass index 23-33 kg/m 2) and exclusion criteria (insulin treatment, smoking, concurrent systemic disease, and regular exercise training) were included in a randomized crossover trial (n = 15). Participants included in this metabolomics and proteomics analysis fully completed all exercise sessions (n = 8). The trial consisted of two weeks of high-intensity interval training (HIT) (three sessions/week) either in the morning (08:00, n = 5) or afternoon (16:45, n = 3), a two-week wash-out period, and an additional two weeks of HIT at the opposing time. Participants and researchers were not blinded to group allocation. Blood, skeletal muscle and subcutaneous adipose tissue were obtained before the first, and after each training period. Broad-spectrum, untargeted proteomic analysis was performed on skeletal muscle, and metabolomic analysis was performed on all biosamples. Differential content was assessed by linear regression and pathway set enrichment analyses were performed. Coordinated metabolic changes across tissues were identified by Spearman correlation analysis. RESULTS: Metabolic and proteomic profiles remained stable after two weeks of HIT, and individual metabolites and proteins were not altered, irrespective of the time of day at which the training was performed. However, coordinated changes in relevant metabolic pathways and protein categories were identified. Morning and afternoon HIT similarly increased plasma diacylglycerols, skeletal muscle acyl-carnitines, and subcutaneous adipose tissue sphingomyelins and lysophospholipids. Acyl-carnitines were central to training-induced metabolic cross-talk across tissues. Plasma carbohydrates, via the penthose phosphate pathway, were increased and skeletal muscle lipids were decreased after morning compared to afternoon HIT. Skeletal muscle lipoproteins were higher, and mitochondrial complex III abundance was lower after morning compared to afternoon HIT.CONCLUSIONS/INTERPRETATION: We provide a comprehensive analysis of a multi-tissue metabolomic and skeletal muscle proteomic responses to training at different times of the day in men with type 2 diabetes. Increased circulating lipids and changes in adipose tissue lipid composition were common between morning and afternoon HIT. However, afternoon HIT increased skeletal muscle lipids and mitochondrial content to a greater degree than morning training. Thus, there is a diurnal component in the metabolomic and proteomic response to exercise in men with type 2 diabetes. The clinical relevance of this response warrants further investigation.

During exercise, skeletal muscles release cytokines, peptides, and metabolites that exert autocrine, paracrine, or endocrine effects on glucose homeostasis. In this study, we investigated the effects of secreted protein acidic and rich in cysteine (SPARC), an exercise-responsive myokine, on glucose metabolism in human and mouse skeletal muscle. SPARC-knockout mice showed impaired systemic metabolism and reduced phosphorylation of AMPK and protein kinase B in skeletal muscle. Treatment of SPARC-knockout mice with recombinant SPARC improved glucose tolerance and concomitantly activated AMPK in skeletal muscle. These effects were dependent on AMPK-γ3 because SPARC treatment enhanced skeletal muscle glucose uptake in wild-type mice but not in AMPK-γ3-knockout mice. SPARC strongly interacted with the voltage-dependent calcium channel, and inhibition of calcium-dependent signaling prevented SPARC-induced AMPK phosphorylation in human and mouse myotubes. Finally, chronic SPARC treatment improved systemic glucose tolerance and AMPK signaling in skeletal muscle of high-fat diet-induced obese mice, highlighting the efficacy of SPARC treatment in the management of metabolic diseases. Thus, our findings suggest that SPARC treatment mimics the effects of exercise on glucose tolerance by enhancing AMPK-dependent glucose uptake in skeletal muscle.-Aoi, W., Hirano, N., Lassiter, D. G., Bjornholm, M., Chibalin, A. V., Sakuma, K., Tanimura, Y., Mizushima, K., Takagi, T., Naito, Y., Zierath, J. R., Krook, A. Secreted protein acidic and rich in cysteine (SPARC) improves glucose tolerance via AMP-activated protein kinase activation.

During the last decade, professional analytical tools and platforms are increasingly more used to analyse and support decision-making regarding urban energy systems. Most of existing urban energy platforms are focused on short-term analysis (present or 2020) and cover specific sectors and/or aspects, without considering the holistic optimisation of the whole energy system. Moreover, usually these platforms can only be operated by users with high technical skills. This article presents the design and development of the innovative SureCity Platform which aims to overcome existing gaps to support cities to achieve their mid-to-long term sustainability targets. The main novelties the SureCity platform are: (i) it is a transparent and user-friendly software which can also be used by non-technical staff, such as politicians; (ii) it allows assessment of urban policies and measures through holistic optimisation of the whole energy system towards low carbon energy systems including air quality, land-use and water use at city level. Furthermore, since it is based on a generic comprehensive model, the SureCity platform can be adjusted and applied to a large number of cities. Because it is generalised, it has been developed using a participatory approach with different city stakeholders, and since it is designed to be used by users with different levels of expertise, it can also improve communication among city actors and benchmarking with other cities.

Paternal preconceptional high-fat diet (HFD) alters whole-body glucose and energy homeostasis over several generations, which may be mediated by altered transcriptomic profiles of metabolic organs. We investigated the effect of paternal HFD on the hepatic transcriptomic and metabolic signatures of female grand-offspring. Paternal HFD strongly impacted the liver transcriptome of the second-generation offspring. Gene set enrichment analysis (GSEA) revealed grandpaternal-HFD altered the TNF-α signaling via NFκB pathway, independent of the grand-offspring's diet. Reduction in the hepatic cytokine levels, including the TNF-α, as well as NFκB content and activity, suggest that the basal inflammatory response in F2 rats is disturbed. GSEA also show altered expression of various genes annotated to the fatty acid metabolism. Grandpaternal-HFD reduced G0/G1 switch gene 2 (G0S2) expression, concomitant with reduced hepatic triglyceride content in F2 rats. In conclusion, the hepatic transcriptome is altered in grand-offspring from HFD-fed grandfathers. Altered TNF-α/NFκB signaling and levels of inflammatory cytokines indicate grandpaternal HFD impacts hepatic immunometabolism. Overall, our findings indicate that paternal exposure to environmental factors transgenerationally reprograms metabolism in a tissue-specific manner, affecting the development and health of future generations.-De Castro Barbosa, T., Alm, P. S., Krook, A., Barres, R., Zierath, J. R. Paternal high-fat diet transgenerationally impacts hepatic immunometabolism.

miRNAs are noncoding RNAs representing an important class of gene expression modulators. Extracellular circulating miRNAs are both candidate biomarkers for disease pathogenesis and mediators of cell-to-cell communication. We examined the miRNA expression profile of total serum and serum-derived exosome-enriched extracellular vesicles in people with normal glucose tolerance or type 2 diabetes. In contrast to total serum miRNA, which did not reveal any differences in miRNA expression, we identified differentially abundant miRNAs in patients with type 2 diabetes using miRNA expression profiles of exosome RNA (exoRNA). To validate the role of these differentially abundant miRNAs on glucose metabolism, we transfected miR-20b-5p, a highly abundant exoRNA in patients with type 2 diabetes, into primary human skeletal muscle cells. miR-20b-5p overexpression increased basal glycogen synthesis in human skeletal muscle cells. We identified AKTIP and STAT3 as miR-20b-5p targets. miR-20b-5p overexpression reduced AKTIP abundance and insulin-stimulated glycogen accumulation. In conclusion, exosome-derived extracellular miR-20b-5p is a circulating biomarker associated with type 2 diabetes that plays an intracellular role in modulating insulin-stimulated glucose metabolism via AKT signaling.

The mechanisms promoting disturbed white adipocyte function in obesity remain largely unclear. Herein, we integrate white adipose tissue (WAT) metabolomic and transcriptomic data from clinical cohorts and find that the WAT phosphocreatine/creatine ratio is increased and creatine kinase-B expression and activity is decreased in the obese state. In human in vitro and murine in vivo models, we demonstrate that decreased phosphocreatine metabolism in white adipocytes alters adenosine monophosphate-activated protein kinase activity via effects on adenosine triphosphate/adenosine diphosphate levels, independently of WAT beigeing. This disturbance promotes a pro-inflammatory profile characterized, in part, by increased chemokine (C-C motif) ligand 2 (CCL2) production. These data suggest that the phosphocreatine/creatine system links cellular energy shuttling with pro-inflammatory responses in human and murine white adipocytes. Our findings provide unexpected perspectives on the mechanisms driving WAT inflammation in obesity and may present avenues to target adipocyte dysfunction.

SummaryCircadian rhythms are generated by an auto-regulatory feedback loop composed of transcriptional activators and repressors. Disruption of circadian rhythms contributes to Type 2 diabetes (T2D) pathogenesis. We elucidated whether altered circadian rhythmicity of clock genes is associated with metabolic dysfunction in T2D. Transcriptional cycling of core clock genes ARNTL, CLOCK, CRY1 and NR1D1 was altered in skeletal muscle from individuals with T2D and this was coupled with reduced number and amplitude of cycling genes and disturbed circadian oxygen consumption. Mitochondrial associated genes were enriched for differential circadian amplitudes in T2D, and positively correlated with insulin sensitivity. ChIP- sequencing identified CLOCK and BMAL1 binding to circadian mitochondrial genes associated with insulin sensitivity, implicating regulation by the core clock. Mitochondria disruption altered core-clock gene expression and free-radical production, phenomena that were restored by resveratrol treatment. We identify bi-directional communication between mitochondrial function and rhythmic gene expression, processes which are disturbed in diabetes.

Aims/hypothesis: Obesity and elevated circulating lipids may impair metabolism by disrupting the molecular circadian clock. We tested the hypothesis that lipid-overload may interact with the circadian clock and alter the rhythmicity of gene expression through epigenetic mechanisms. Methods: We determined the effect of the saturated fatty acid palmitate on circadian transcriptomics and examined the impact on histone H3 lysine K27 acetylation (H3K27ac) and the regulation of circadian rhythms in primary human skeletal muscle myotubes. Total H3 abundance and histone H3K27ac was assessed in vastus lateralis muscle biopsies from obese and normal weight men. Results: Palmitate disrupted transcriptomic rhythmicity in myotubes. Genes that lost or gained rhythmicity after palmitate treatment were involved in metabolic processes, protein translation and transport, and transcriptional regulation. Histone H3K27ac, a marker of active gene enhancers, was modified by palmitate treatment in myotubes, but not in skeletal muscle from men with obesity. Conclusion/interpretation: Palmitate disrupts transcriptomic rhythmicity and modifies histone H3K27ac in circadian manner, suggesting acute lipid-overload alters the epigenetic state of skeletal muscle. Our results indicate that dietary saturated fatty acids impart post-transcriptional modifications to histone proteins and regulate circadian transcriptomics.

Cities across the globe recognise their role in climate mitigation and are acting to reduce carbon emissions. Knowing whether cities set ambitious climate and energy targets is critical for determining their contribution towards the global 1.5 °C target, partly because it helps to identify areas where further action is necessary. This paper presents a comparative analysis of the mitigation targets of 327 European cities, as declared in their local climate plans. The sample encompasses over 25% of the EU population and includes cities of all sizes across all Member States, plus the UK. The study analyses whether the type of plan, city size, membership of climate networks, and its regional location are associated with different levels of mitigation ambition. Results reveal that 78% of the cities have a GHG emissions reduction target. However, with an average target of 47%, European cities are not on track to reach the Paris Agreement: they need to roughly double their ambitions and efforts. Some cities are ambitious, e.g. 25% of our sample (81) aim to reach carbon neutrality, with the earliest target date being 2020.90% of these cities are members of the Climate Alliance and 75% of the Covenant of Mayors. City size is the strongest predictor for carbon neutrality, whilst climate network(s) membership, combining adaptation and mitigation into a single strategy, and local motivation also play a role. The methods, data, results and analysis of this study can serve as a reference and baseline for tracking climate mitigation ambitions across European and global cities. info:eu-repo/semantics/publishedVersion

Background & Aims. The physiological regulation and contribution of the multiple phosphorylation sites of insulin receptor substrate 1 (IRS1) to the pathogenesis of insulin resistance is unknown. Our aims were to map the phosphorylated motifs of IRS1 in skeletal muscle from people with normal glucose tolerance (NGT; n = 11) or type 2 diabetes mellitus (T2DM; n = 11). Methods Skeletal muscle biopsies were obtained under fasted conditions or during a euglycemic clamp and IRS1 phosphorylation sites were identified by mass spectrometry. Results We identified 33 phosphorylation sites in biopsies from fasted individuals, including 2 previously unreported sites ([Ser393] and [Thr1017]). In men with NGT and T2DM, insulin increased phosphorylation of 5 peptides covering 10 serine or threonine sites and decreased phosphorylation of 6 peptides covering 9 serine, threonine or tyrosine sites. Insulin-stimulation increased phosphorylation of 2 peptides, and decreased phosphorylation of 2 peptides only in men with NGT. Insulin increased phosphorylation of 2 peptides only in men with T2DM. Conclusions Despite severe skeletal muscle insulin resistance, the pattern of IRS1 phosphorylation was not uniformly altered in T2DM. Our results contribute to the evolving understanding of the physiological regulation of insulin signaling and complement the comprehensive map of IRS1 phosphorylation in T2DM.

Many cities around the world have adopted climate neutrality targets, and, to reduce their greenhouse gas emissions, they need climate action plans. Energy system optimization models (ESOMs) can be used as tools to support their energy transitions. ESOMs have been in use at the national level for several years and also have recently been used at the city level. Even though several researchers have focused on how city ESOMs can be developed, the literature lacks a discussion of the challenges that are faced in data collection during model development. In this paper, we share the challenges encountered in the model development, as well as in the scenario development and recommend practical solutions for overcoming these challenges. The following three challenges were identified and discussed in the model development process: (a) data availability and quality; (b) communication; and (c) knowledge and background of civil servants and researchers. The main challenges in the scenario development were: (a) parameter selection and (b) complexity. It was found that explanation of the terminology used in ESOMs, presentation of the model structure and preliminary base-year results were crucial actions for overcoming challenges during model development. During the scenario development, collaboration between modelers and civil servants when reviewing parameter combinations and working with preliminary scenario results were decisive strategies for improving the civil servants’ understanding of ESOMs. Complementarily, it was found that continuous communication between the researcher and the civil servant and good comprehension of the model on the municipality's side helped improve the usefulness of ESOMs in cities’ energy transitions.

We aimed to determine whether interrupting prolonged sitting improves glycemic control and the metabolic profile of free-living adults with obesity. Sixteen sedentary individuals {10 women/6 men; median [interquartile range (IQR)] age 50 (44–53) yr, body mass index (BMI) 32 (32–35.8) kg/m2} were fitted with continuous glucose and activity monitors for 4 wk. After a 1-wk baseline period, participants were randomized into habitual lifestyle (Control) or frequent activity breaks from sitting (FABS) intervention groups. Each day, between 0800 and 1800 h, FABS received smartwatch notifications to break sitting with 3 min of low-to-moderate-intensity physical activity every 30 min. Glycemic control was assessed by oral glucose tolerance test (OGTT) and continuous glucose monitoring. Blood samples and vastus lateralis biopsies were taken for assessment of clinical chemistry and the skeletal muscle lipidome, respectively. Compared with baseline, FABS increased median steps by 744 [IQR (483–951)] and walking time by 10.4 [IQR (2.2–24.6)] min/day. Other indices of activity/sedentary behavior were unchanged. Glucose tolerance and average 24-h glucose curves were also unaffected. However, mean (±SD) fasting glucose levels [−0.34 (±0.37) mmol/L] and daily glucose variation [%CV; −2% (±2.2%)] reduced in FABS, suggesting a modest benefit for glycemic control that was most robust at higher volumes of daily activity. Clinical chemistry and the skeletal muscle lipidome were largely unperturbed, although two long-chain triglycerides increased 1.25-fold in FABS, postintervention. All parameters remained stable in control. Under free-living conditions, FABS lowered fasting glucose and glucose variability. Larger volumes of activity breaks from sitting may be required to promote greater health benefits. NEW & NOTEWORTHY Under free-living conditions, breaking sitting modestly increased activity behavior. Breaking sitting was insufficient to modulate glucose tolerance or the skeletal muscle lipidome. Activity breaks reduced fasting blood glucose levels and daily glucose variation compared with baseline, with a tendency to also decrease fasting LDLc. This intervention may represent the minimal dose for breaking sedentary behavior, with larger volumes of activity possibly required to promote greater health benefits.

Dysregulation of skeletal muscle metabolism influences whole-body insulin sensitivity and glucose homeostasis. We hypothesized that type 2 diabetes-associated alterations in the plasma metabolome directly contribute to skeletal muscle immunometabolism and the subsequent development of insulin resistance. To this end, we analyzed the plasma and skeletal muscle metabolite profile and identified glutamine as a key amino acid that correlates inversely with BMI and insulin resistance index (HOMA-IR) in men with normal glucose tolerance or type 2 diabetes. Using an in vitro model of human myotubes and an in vivo model of diet-induced obesity and insulin resistance in male mice, we provide evidence that glutamine levels directly influence the inflammatory response of skeletal muscle and regulate the expression of the adaptor protein GRB10, an inhibitor of insulin signaling. Moreover, we demonstrate that a systemic increase in glutamine levels in a mouse model of obesity improves insulin sensitivity and restores glucose homeostasis. We conclude that glutamine supplementation may represent a potential therapeutic strategy to prevent or delay the onset of insulin resistance in obesity by reducing inflammatory markers and promoting skeletal muscle insulin sensitivity.

International audience; Despite similarities in their current energy mixes, France and Sweden's pathways have been very different since the 1970s, when both systems were highly dependent on fossil fuels. After the oil crisis, both countries chose to reduce their oil consumption by developing nuclear power. However, Sweden pursued a more diversified energy policy that has subsequently allowed it to reduce its CO 2 emissions. Today, both countries have committed to a carbon neutrality goal: by 2045 for Sweden and 2050 for France. In order to understand the key factors that can drive energy transition toward a carbon neutrality goal, we propose to compare the past energy transitions in France and Sweden, two countries that have significantly reduced their CO 2 emissions and fossil fuel dependency. To assess the impacts of the current energy system and its regulations on the feasibility of meeting carbon neutrality, we use TIMES bottom-up energy system optimization models. The results show that France faces more challenges in transforming its energy system than Sweden i.e. an increase in power production, a decrease in gas consumption, the replacement of heating systems in buildings, and the electrification of industry, thus confirming that its energy policy has to be driven with a long-run perspective.

Diurnal oscillations in energy metabolism are linked to the activity of biological clocks and contribute to whole-body glucose homeostasis. Postprandially, skeletal muscle takes up approximately 80% of circulatory glucose and hence is a key organ in maintenance of glucose homeostasis. Dysregulation of molecular clock components in skeletal muscle disrupts whole-body glucose homeostasis. Next to light-dark cycles, nonphotic cues such as nutrient intake and physical activity are also potent cues to (re)set (dys)regulated clocks. Physical exercise is one of the most potent ways to improve myocellular insulin sensitivity. Given the role of the biological clock in glucose homeostasis and the power of exercise to improve insulin sensitivity, one can hypothesize that there might be an optimal time for exercise to maximally improve insulin sensitivity and glucose homeostasis. In this review, we aim to summarize the available information related to the interaction of diurnal rhythm, glucose homeostasis, and physical exercise as a nonphotic cue to correct dysregulation of human glucose metabolism.

Context Autonomic nervous system activation mediates the increase in whole-body glucose uptake in response to electroacupuncture but the mechanisms are largely unknown. Objective To identify the molecular mechanisms underlying electroacupuncture-induced glucose uptake in skeletal muscle in insulin-resistant overweight/obese women with and without polycystic ovary syndrome (PCOS). Design/Participants In a case-control study, skeletal muscle biopsies were collected from 15 women with PCOS and 14 controls before and after electroacupuncture. Gene expression and methylation was analyzed using Illumina BeadChips arrays. Results A single bout of electroacupuncture restores metabolic and transcriptional alterations and induces epigenetic changes in skeletal muscle. Transcriptomic analysis revealed 180 unique genes (q Conclusion Our findings provide evidence that electroacupuncture normalizes gene expression in skeletal muscle in a manner similar to acute exercise. Electroacupuncture might therefore be a useful way of assisting those who have difficulties performing exercise.