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OBJECTIVE: Housing temperature is a critical regulator of mouse metabolism and thermoneutral housing can improve human translation. However, the impact of housing temperature on the ability of wheel running to rescue the detrimental effect of diet-induced obese mice is currently not fully understood. METHODS: Lean or obese female mice were housed at standard ambient temperature (22â) or thermoneutrality (30â) with/without access to running wheels. The metabolic phenotype was investigated using glucose tolerance tests, indirect calorimetry, and body composition. Molecular muscle adaptations were measured using immunoblotting, qPCR, and spectrophotometric/fluorescent assays. RESULTS: Obese female mice housed at 22°C showed lower adiposity, lower circulating insulin levels, improved glucose tolerance, and elevated basal metabolic rate compared to 30°C housing. Mice exposed to voluntary wheel running exhibited a larger fat loss and higher metabolic rate at 22°C housing compared to thermoneutrality. In obese female mice, glucose tolerance improved after exercise training independent of housing temperature. Independent of diet and training, 22°C housing increased skeletal muscle sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA) activity. Additionally, 22°C-housing elevated the induction of training-responsive muscle proteins in obese mice. CONCLUSION: Our findings highlight that housing temperature significantly influences adiposity, insulin sensitivity, muscle physiology, and exercise adaptations in diet-induced obese female mice.
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Women typically have less muscle mass and more fat mass than men, while at the same time possessing similar or even greater whole-body insulin sensitivity. Our study aimed to investigate the molecular factors in primarily adipose tissue, but also in skeletal muscle, contributing to this sex difference. In healthy, moderately active premenopausal women and men with normal weight (28 ± 5 and 23 ± 3 years old; BMI 22.2 ± 1.9 and 23.7 ± 1.7) and in healthy, recreationally active women and men with overweight (32.2 ± 6 and 31.0 ± 5 years old; BMI 29.8 ± 4.3 & 30.9 ± 3.7) matched at age, BMI, and fitness level, we assessed insulin sensitivity and glucose tolerance with a hyperinsulinemic-euglycemic clamp or oral glucose tolerance test and studied subcutaneous adipose tissue and skeletal muscle samples with western blotting. Additionally, we traced glucose-stimulated glucose disposal in adipose tissues of female and male C57BL/6J littermate mice aged 16 weeks and measured glucose metabolic proteins. Our findings revealed greater protein expression related to glucose disposal in the subcutaneous adipose tissue (AKT2, insulin receptor, glucose transport 4) and skeletal muscle (hexokinase II, pyruvate dehydrogenase) in women compared to matched men with normal weight and with overweight. This increased protein capacity for glucose uptake extended to white adipose tissues of mice accompanied with ~2-fold greater glucose uptake compared to male mice. Furthermore, even in the obese state, women displayed better glucose tolerance than matched men, despite having 46% body fat and 20 kg less lean mass. In conclusion, our findings suggest that the superior potential for glucose disposal in female subcutaneous adipose tissue and skeletal muscle, driven by greater expression of various glucose metabolic proteins, compensates for their lower muscle mass. This likely explains women's superior glucose tolerance and tissue insulin sensitivity compared to men.
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Glucose , Músculo Esquelético , Feminino , Humanos , Masculino , Músculo Esquelético/metabolismo , Adulto , Glucose/metabolismo , Animais , Camundongos , Camundongos Endogâmicos C57BL , Tecido Adiposo/metabolismo , Resistência à Insulina/fisiologia , Adulto Jovem , Teste de Tolerância a Glucose , Sobrepeso/metabolismo , Técnica Clamp de GlucoseRESUMO
BACKGROUND: Intrahepatic triacylglycerol (liver TG) content is associated with hepatic insulin resistance and dyslipidemia. Liver TG content can be modulated within days under hypocaloric conditions. OBJECTIVES: We hypothesized that 4 d of eucaloric low-carbohydrate/high-fat (LC) intake would decrease liver TG content, whereas a high-carbohydrate/low-fat (HC) intake would increase liver TG content, and further that alterations in liver TG would be linked to dynamic changes in hepatic glucose and lipid metabolism. METHODS: A randomized crossover trial in males with 4 d + 4 d of LC and HC, respectively, with ≥2 wk of washout. 1H-magnetic resonance spectroscopy (1H-MRS) was used to measure liver TG content, with metabolic testing before and after intake of an LC diet (11E% carbohydrate corresponding to 102 ± 12 {mean ± standard deviation [SD]) g/d, 70E% fat} and an HC diet (65E% carbohydrate corresponding to 537 ± 56 g/d, 16E% fat). Stable [6,6-2H2]-glucose and [1,1,2,3,3-D5]-glycerol tracer infusions combined with hyperinsulinemic-euglycemic clamps and indirect calorimetry were used to measure rates of hepatic glucose production and lipolysis, whole-body insulin sensitivity and substrate oxidation. RESULTS: Eleven normoglycemic males with overweight or obesity (BMI 31.6 ± 3.7 kg/m2) completed both diets. The LC diet reduced liver TG content by 35.3% (95% confidence interval: -46.6, -24.1) from 4.9% [2.4-11.0] (median interquartile range) to 2.9% [1.4-6.9], whereas there was no change after the HC diet. After the LC diet, fasting whole-body fat oxidation and plasma beta-hydroxybutyrate concentration increased, whereas markers of de novo lipogenesis (DNL) diminished. Fasting plasma TG and insulin concentrations were lowered and the hepatic insulin sensitivity index increased after LC. Peripheral glucose disposal was unchanged. CONCLUSIONS: Reduced carbohydrate and increased fat intake for 4 d induced a marked reduction in liver TG content and increased hepatic insulin sensitivity. Increased rates of fat oxidation and ketogenesis combined with lower rates of DNL are suggested to be responsible for lowering liver TG. This trial was registered at clinicaltrials.gov as NCT04581421.
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Estudos Cross-Over , Fígado , Obesidade , Sobrepeso , Triglicerídeos , Humanos , Masculino , Triglicerídeos/metabolismo , Fígado/metabolismo , Adulto , Sobrepeso/metabolismo , Sobrepeso/dietoterapia , Obesidade/metabolismo , Obesidade/dietoterapia , Dieta com Restrição de Carboidratos , Carboidratos da Dieta/administração & dosagem , Carboidratos da Dieta/metabolismo , Adulto Jovem , Pessoa de Meia-Idade , Resistência à InsulinaRESUMO
Arginine methylation is a protein posttranslational modification important for the development of skeletal muscle mass and function. Despite this, our understanding of the regulation of arginine methylation under settings of health and disease remains largely undefined. Here, we investigated the regulation of arginine methylation in skeletal muscles in response to exercise and hypertrophic growth, and in diseases involving metabolic dysfunction and atrophy. We report a limited regulation of arginine methylation under physiological settings that promote muscle health, such as during growth and acute exercise, nor in disease models of insulin resistance. In contrast, we saw a significant remodeling of asymmetric dimethylation in models of atrophy characterized by the loss of innervation, including in muscle biopsies from patients with myotrophic lateral sclerosis (ALS). Mass spectrometry-based quantification of the proteome and asymmetric arginine dimethylome of skeletal muscle from individuals with ALS revealed the largest compendium of protein changes with the identification of 793 regulated proteins, and novel site-specific changes in asymmetric dimethyl arginine (aDMA) of key sarcomeric and cytoskeletal proteins. Finally, we show that in vivo overexpression of PRMT1 and aDMA resulted in increased fatigue resistance and functional recovery in mice. Our study provides evidence for asymmetric dimethylation as a regulator of muscle pathophysiology and presents a valuable proteomics resource and rationale for numerous methylated and nonmethylated proteins, including PRMT1, to be pursued for therapeutic development in ALS.
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Esclerose Lateral Amiotrófica , Arginina , Músculo Esquelético , Proteína-Arginina N-Metiltransferases , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Arginina/metabolismo , Arginina/análogos & derivados , Humanos , Esclerose Lateral Amiotrófica/metabolismo , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/patologia , Animais , Camundongos , Proteína-Arginina N-Metiltransferases/metabolismo , Proteína-Arginina N-Metiltransferases/genética , Masculino , Metilação , Feminino , Processamento de Proteína Pós-Traducional , Camundongos Endogâmicos C57BL , Proteoma/metabolismoRESUMO
Insulin resistance is a risk factor for type 2 diabetes, and exercise can improve insulin sensitivity. However, following exercise, high circulating fatty acid (FA) levels might counteract this. We hypothesized that such inhibition would be reduced by forcibly increasing carbohydrate oxidation through pharmacological activation of the pyruvate dehydrogenase complex (PDC). Insulin-stimulated glucose uptake was examined with a crossover design in healthy young men (n = 8) in a previously exercised and a rested leg during a hyperinsulinemic-euglycemic clamp 5 h after one-legged exercise with 1) infusion of saline, 2) infusion of intralipid imitating circulating FA levels during recovery from whole-body exercise, and 3) infusion of intralipid + oral PDC activator, dichloroacetate (DCA). Intralipid infusion reduced insulin-stimulated glucose uptake by 19% in the previously exercised leg, which was not observed in the contralateral rested leg. Interestingly, this effect of intralipid in the exercised leg was abolished by DCA, which increased muscle PDC activity (130%) and flux (acetylcarnitine 130%) and decreased inhibitory phosphorylation of PDC on Ser293 (â¼40%) and Ser300 (â¼80%). Novel insight is provided into the regulatory interaction between glucose and lipid metabolism during exercise recovery. Coupling exercise and PDC flux activation upregulated the capacity for both glucose transport (exercise) and oxidation (DCA), which seems necessary to fully stimulate insulin-stimulated glucose uptake during recovery.
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Exercício Físico , Insulina , Músculo Esquelético , Complexo Piruvato Desidrogenase , Humanos , Masculino , Exercício Físico/fisiologia , Músculo Esquelético/metabolismo , Músculo Esquelético/efeitos dos fármacos , Insulina/metabolismo , Insulina/sangue , Complexo Piruvato Desidrogenase/metabolismo , Adulto , Adulto Jovem , Técnica Clamp de Glucose , Estudos Cross-Over , Ácido Dicloroacético/farmacologia , Resistência à Insulina/fisiologia , Ácidos Graxos/metabolismo , Glucose/metabolismo , Óleo de Soja/farmacologia , Recuperação após o Exercício , Emulsões , FosfolipídeosRESUMO
AIMS/HYPOTHESIS: Exercise has a profound effect on insulin sensitivity in skeletal muscle. The euglycaemic-hyperinsulinaemic clamp (EHC) is the gold standard for assessment of insulin sensitivity but it does not reflect the hyperglycaemia that occurs after eating a meal. In previous EHC investigations, it has been shown that the interstitial glucose concentration in muscle is decreased to a larger extent in previously exercised muscle than in rested muscle. This suggests that previously exercised muscle may increase its glucose uptake more than rested muscle if glucose supply is increased by hyperglycaemia. Therefore, we hypothesised that the exercise-induced increase in muscle insulin sensitivity would appear greater after eating a meal than previously observed with the EHC. METHODS: Ten recreationally active men performed dynamic one-legged knee extensor exercise for 1 h. Following this, both femoral veins and one femoral artery were cannulated. Subsequently, 4 h after exercise, a solid meal followed by two liquid meals were ingested over 1 h and glucose uptake in the two legs was measured for 3 h. Muscle biopsies from both legs were obtained before the meal test and 90 min after the meal test was initiated. Data obtained in previous studies using the EHC (n=106 participants from 13 EHC studies) were used for comparison with the meal-test data obtained in this study. RESULTS: Plasma glucose and insulin peaked 45 min after initiation of the meal test. Following the meal test, leg glucose uptake and glucose clearance increased twice as much in the exercised leg than in the rested leg; this difference is twice as big as that observed in previous investigations using EHCs. Glucose uptake in the rested leg plateaued after 15 min, alongside elevated muscle glucose 6-phosphate levels, suggestive of compromised muscle glucose metabolism. In contrast, glucose uptake in the exercised leg plateaued 45 min after initiation of the meal test and there were no signs of compromised glucose metabolism. Phosphorylation of the TBC1 domain family member 4 (TBC1D4; p-TBC1D4Ser704) and glycogen synthase activity were greater in the exercised leg compared with the rested leg. Muscle interstitial glucose concentration increased with ingestion of meals, although it was 16% lower in the exercised leg than in the rested leg. CONCLUSIONS/INTERPRETATION: Hyperglycaemia after meal ingestion results in larger differences in muscle glucose uptake between rested and exercised muscle than previously observed during EHCs. These findings indicate that the ability of exercise to increase insulin-stimulated muscle glucose uptake is even greater when evaluated with a meal test than has previously been shown with EHCs.
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Glicemia , Exercício Físico , Técnica Clamp de Glucose , Resistência à Insulina , Insulina , Refeições , Músculo Esquelético , Humanos , Masculino , Exercício Físico/fisiologia , Músculo Esquelético/metabolismo , Resistência à Insulina/fisiologia , Adulto , Glicemia/metabolismo , Insulina/metabolismo , Insulina/sangue , Adulto Jovem , Refeições/fisiologiaRESUMO
Glucose is the universal fuel of most mammalian cells, and it is largely replenished through dietary intake. Glucose availability to tissues is paramount for the maintenance of homeostatic energetics and, hence, supply should match demand by the consuming organs. In its journey through the body, glucose encounters cellular barriers for transit at the levels of the absorbing intestinal epithelial wall, the renal epithelium mediating glucose reabsorption, and the tight capillary endothelia (especially in the brain). Glucose transiting through these cellular barriers must escape degradation to ensure optimal glucose delivery to the bloodstream or tissues. The liver, which stores glycogen and generates glucose de novo, must similarly be able to release it intact to the circulation. We present the most up-to-date knowledge on glucose handling by the gut, liver, brain endothelium, and kidney, and discuss underlying molecular mechanisms and open questions. Diseases associated with defects in glucose delivery and homeostasis are also briefly addressed. We propose that the universal problem of sparing glucose from catabolism in favor of translocation across the barriers posed by epithelia and endothelia is resolved through common mechanisms involving glucose transfer to the endoplasmic reticulum, from where glucose exits the cells via unconventional cellular mechanisms.
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Encéfalo , Glucose , Animais , Humanos , Glucose/metabolismo , Epitélio/metabolismo , Encéfalo/metabolismo , Transporte Biológico , Intestinos , Mamíferos/metabolismoRESUMO
Obesity and type 2 diabetes (T2D) are growing health challenges with unmet treatment needs. Traf2- and NCK-interacting protein kinase (TNIK) is a recently identified obesity- and T2D-associated gene with unknown functions. We show that TNIK governs lipid and glucose homeostasis in Drosophila and mice. Loss of the Drosophila ortholog of TNIK, misshapen, altered the metabolite profiles and impaired de novo lipogenesis in high sugar-fed larvae. Tnik knockout mice exhibited hyperlocomotor activity and were protected against diet-induced fat expansion, insulin resistance, and hepatic steatosis. The improved lipid profile of Tnik knockout mice was accompanied by enhanced skeletal muscle and adipose tissue insulin-stimulated glucose uptake and glucose and lipid handling. Using the T2D Knowledge Portal and the UK Biobank, we observed associations of TNIK variants with blood glucose, HbA1c, body mass index, body fat percentage, and feeding behavior. These results define an untapped paradigm of TNIK-controlled glucose and lipid metabolism.
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Resistência à Insulina , Metabolismo dos Lipídeos , Obesidade , Proteínas Serina-Treonina Quinases , Animais , Camundongos , Diabetes Mellitus Tipo 2/genética , Glucose/metabolismo , Lipídeos , Fígado/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/genética , Obesidade/metabolismo , Proteínas Serina-Treonina Quinases/metabolismoRESUMO
Growth differentiation factor 15 (GDF15) induces weight loss and increases insulin action in obese rodents. Whether and how GDF15 improves insulin action without weight loss is unknown. Obese rats were treated with GDF15 and displayed increased insulin tolerance 5 h later. Lean and obese female and male mice were treated with GDF15 on days 1, 3, and 5 without weight loss and displayed increased insulin sensitivity during a euglycemic hyperinsulinemic clamp on day 6 due to enhanced suppression of endogenous glucose production and increased glucose uptake in WAT and BAT. GDF15 also reduced glucagon levels during clamp independently of the GFRAL receptor. The insulin-sensitizing effect of GDF15 was completely abrogated in GFRAL KO mice and also by treatment with the ß-adrenergic antagonist propranolol and in ß1,ß2-adrenergic receptor KO mice. GDF15 activation of the GFRAL receptor increases ß-adrenergic signaling, in turn, improving insulin action in the liver and white and brown adipose tissue.
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Resistência à Insulina , Receptores Adrenérgicos beta , Camundongos , Ratos , Masculino , Feminino , Animais , Fator 15 de Diferenciação de Crescimento/farmacologia , Obesidade , Tecido Adiposo , Redução de Peso , Insulina , Tecido Adiposo Marrom , FígadoRESUMO
The molecular events governing skeletal muscle glucose uptake have pharmacological potential for managing insulin resistance in conditions such as obesity, diabetes, and cancer. With no current pharmacological treatments to target skeletal muscle insulin sensitivity, there is an unmet need to identify the molecular mechanisms that control insulin sensitivity in skeletal muscle. Here, the Rho guanine dissociation inhibitor α (RhoGDIα) is identified as a point of control in the regulation of insulin sensitivity. In skeletal muscle cells, RhoGDIα interacted with, and thereby inhibited, the Rho GTPase Rac1. In response to insulin, RhoGDIα was phosphorylated at S101 and Rac1 dissociated from RhoGDIα to facilitate skeletal muscle GLUT4 translocation. Accordingly, siRNA-mediated RhoGDIα depletion increased Rac1 activity and elevated GLUT4 translocation. Consistent with RhoGDIα's inhibitory effect, rAAV-mediated RhoGDIα overexpression in mouse muscle decreased insulin-stimulated glucose uptake and was detrimental to whole-body glucose tolerance. Aligning with RhoGDIα's negative role in insulin sensitivity, RhoGDIα protein content was elevated in skeletal muscle from insulin-resistant patients with type 2 diabetes. These data identify RhoGDIα as a clinically relevant controller of skeletal muscle insulin sensitivity and whole-body glucose homeostasis, mechanistically by modulating Rac1 activity.
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Diabetes Mellitus Tipo 2 , Resistência à Insulina , Inibidor alfa de Dissociação do Nucleotídeo Guanina rho , Animais , Camundongos , Diabetes Mellitus Tipo 2/metabolismo , Glucose/metabolismo , Insulina/metabolismo , Músculo Esquelético/metabolismo , Proteínas rac1 de Ligação ao GTP/metabolismo , Inibidor alfa de Dissociação do Nucleotídeo Guanina rho/metabolismoRESUMO
BACKGROUND: Insulin resistance is a critical cause of metabolic dysfunctions. Metabolic dysfunction is common in patients with cancer and is associated with higher cancer recurrence rates and reduced overall survival. Yet, insulin resistance is rarely considered in the clinic and thus it is uncertain how frequently this condition occurs in patients with cancer. METHODS: To address this knowledge gap, we performed a systematic review and a meta-analysis guided by the Preferred Items for Systematic Review and Meta-Analyses (PRISMA) statement. We included studies assessing insulin resistance in patients with various cancer diagnoses, using the gold-standard hyperinsulinemic-euglycemic clamp method. Studies eligible for inclusion were as follows: (1) included cancer patients older than 18 years of age; (2) included an age-matched control group consisting of individuals without cancer or other types of neoplasms; (3) measured insulin sensitivity using the hyperinsulinemic-euglycemic clamp method. We searched the databases MEDLINE, Embase, and Cochrane Central Register of Controlled Trials for articles published from database inception through March 2023 with no language restriction, supplemented by backward and forward citation searching. Bias was assessed using funnel plot. FINDINGS: Fifteen studies satisfied the criteria. The mean insulin-stimulated rate of glucose disposal (Rd) was 7.5 mg/kg/min in control subjects (n = 154), and 4.7 mg/kg/min in patients with a cancer diagnosis (n = 187). Thus, the Rd mean difference was -2.61 mg/kg/min [95% confidence interval, -3.04; -2.19], p<.01). Heterogeneity among the included studies was insignificant (p=.24). INTERPRETATION: These findings suggest that patients with a cancer diagnosis are markedly insulin resistant. As metabolic dysfunction in patients with cancer associates with increased recurrence and reduced overall survival, future studies should address if ameliorating insulin resistance in this population can improve these outcomes thereby improving patient care.Key pointsMetabolic dysfunction increases cancer recurrence rates and reduces survival for patients with cancer.Insulin resistance is a critical cause of metabolic dysfunctions.To date, no comprehensive compilation of research investigating insulin resistance in cancer patients has been produced.In this meta-analysis, we found that patients with various cancers were markedly insulin-resistant.
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Resistência à Insulina , Insulinas , Neoplasias , HumanosRESUMO
Exercise profoundly influences glycemic control by enhancing muscle insulin sensitivity, thus promoting glucometabolic health. While prior glycogen breakdown so far has been deemed integral for muscle insulin sensitivity to be potentiated by exercise, the mechanisms underlying this phenomenon remain enigmatic. We have combined original data from 13 of our studies that investigated insulin action in skeletal muscle either under rested conditions or following a bout of one-legged knee extensor exercise in healthy young male individuals (n = 106). Insulin-stimulated glucose uptake was potentiated and occurred substantially faster in the prior contracted muscles. In this otherwise homogenous group of individuals, a remarkable biological diversity in the glucometabolic responses to insulin is apparent both in skeletal muscle and at the whole-body level. In contrast to the prevailing concept, our analyses reveal that insulin-stimulated muscle glucose uptake and the potentiation thereof by exercise are not associated with muscle glycogen synthase activity, muscle glycogen content, or degree of glycogen utilization during the preceding exercise bout. Our data further suggest that the phenomenon of improved insulin sensitivity in prior contracted muscle is not regulated in a homeostatic feedback manner from glycogen. Instead, we put forward the idea that this phenomenon is regulated by cellular allostatic mechanisms that elevate the muscle glycogen storage set point and enhance insulin sensitivity to promote the uptake of glucose toward faster glycogen resynthesis without development of glucose overload/toxicity or feedback inhibition.
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Resistência à Insulina , Insulina , Humanos , Masculino , Insulina/metabolismo , Glicogênio/metabolismo , Glicogênio Sintase/metabolismo , Resistência à Insulina/fisiologia , Insulina Isófana Humana , Músculo Esquelético/metabolismo , Glucose/metabolismo , Insulina Regular HumanaRESUMO
Exercise induces signaling networks to improve muscle function and confer health benefits. To identify divergent and common signaling networks during and after different exercise modalities, we performed a phosphoproteomic analysis of human skeletal muscle from a cross-over intervention of endurance, sprint, and resistance exercise. This identified 5,486 phosphosites regulated during or after at least one type of exercise modality and only 420 core phosphosites common to all exercise. One of these core phosphosites was S67 on the uncharacterized protein C18ORF25, which we validated as an AMPK substrate. Mice lacking C18ORF25 have reduced skeletal muscle fiber size, exercise capacity, and muscle contractile function, and this was associated with reduced phosphorylation of contractile and Ca2+ handling proteins. Expression of C18ORF25 S66/67D phospho-mimetic reversed the decreased muscle force production. This work defines the divergent and canonical exercise phosphoproteome across different modalities and identifies C18ORF25 as a regulator of exercise signaling and muscle function.
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Proteínas Quinases Ativadas por AMP , Proteínas Adaptadoras de Transdução de Sinal , Exercício Físico , Músculo Esquelético , Proteínas Quinases Ativadas por AMP/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Humanos , Camundongos , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/metabolismo , Fosforilação , Transdução de SinaisRESUMO
Exercise confers protection against obesity, type 2 diabetes and other cardiometabolic diseases1-5. However, the molecular and cellular mechanisms that mediate the metabolic benefits of physical activity remain unclear6. Here we show that exercise stimulates the production of N-lactoyl-phenylalanine (Lac-Phe), a blood-borne signalling metabolite that suppresses feeding and obesity. The biosynthesis of Lac-Phe from lactate and phenylalanine occurs in CNDP2+ cells, including macrophages, monocytes and other immune and epithelial cells localized to diverse organs. In diet-induced obese mice, pharmacological-mediated increases in Lac-Phe reduces food intake without affecting movement or energy expenditure. Chronic administration of Lac-Phe decreases adiposity and body weight and improves glucose homeostasis. Conversely, genetic ablation of Lac-Phe biosynthesis in mice increases food intake and obesity following exercise training. Last, large activity-inducible increases in circulating Lac-Phe are also observed in humans and racehorses, establishing this metabolite as a molecular effector associated with physical activity across multiple activity modalities and mammalian species. These data define a conserved exercise-inducible metabolite that controls food intake and influences systemic energy balance.
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Ingestão de Alimentos , Comportamento Alimentar , Obesidade , Fenilalanina , Condicionamento Físico Animal , Adiposidade/efeitos dos fármacos , Animais , Peso Corporal/efeitos dos fármacos , Diabetes Mellitus Tipo 2 , Modelos Animais de Doenças , Ingestão de Alimentos/fisiologia , Metabolismo Energético , Comportamento Alimentar/fisiologia , Glucose/metabolismo , Ácido Láctico/metabolismo , Camundongos , Obesidade/metabolismo , Obesidade/prevenção & controle , Fenilalanina/administração & dosagem , Fenilalanina/análogos & derivados , Fenilalanina/metabolismo , Fenilalanina/farmacologia , Condicionamento Físico Animal/fisiologiaRESUMO
Activation of the sympathetic nervous system causes pronounced metabolic changes that are mediated by multiple adrenergic receptor subtypes. Systemic treatment with ß2-adrenergic receptor agonists results in multiple beneficial metabolic effects, including improved glucose homeostasis. To elucidate the underlying cellular and molecular mechanisms, we chronically treated wild-type mice and several newly developed mutant mouse strains with clenbuterol, a selective ß2-adrenergic receptor agonist. Clenbuterol administration caused pronounced improvements in glucose homeostasis and prevented the metabolic deficits in mouse models of ß-cell dysfunction and insulin resistance. Studies with skeletal muscle-specific mutant mice demonstrated that these metabolic improvements required activation of skeletal muscle ß2-adrenergic receptors and the stimulatory G protein, Gs. Unbiased transcriptomic and metabolomic analyses showed that chronic ß2-adrenergic receptor stimulation caused metabolic reprogramming of skeletal muscle characterized by enhanced glucose utilization. These findings strongly suggest that agents targeting skeletal muscle metabolism by modulating ß2-adrenergic receptor-dependent signaling pathways may prove beneficial as antidiabetic drugs.
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Reprogramação Celular/efeitos dos fármacos , Clembuterol/farmacologia , Hipoglicemiantes/farmacologia , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/metabolismo , Animais , Fenômenos Bioquímicos , Clembuterol/metabolismo , Feminino , Glucose/metabolismo , Homeostase , Resistência à Insulina , Masculino , Doenças Metabólicas , Metabolômica , Camundongos , Camundongos Knockout , Receptores Adrenérgicos beta 2/metabolismo , Transdução de SinaisRESUMO
Protein phosphorylation dynamically integrates environmental and cellular information to control biological processes. Identifying functional phosphorylation amongst the thousands of phosphosites regulated by a perturbation at a global scale is a major challenge. Here we introduce 'personalized phosphoproteomics', a combination of experimental and computational analyses to link signaling with biological function by utilizing human phenotypic variance. We measure individual subject phosphoproteome responses to interventions with corresponding phenotypes measured in parallel. Applying this approach to investigate how exercise potentiates insulin signaling in human skeletal muscle, we identify both known and previously unidentified phosphosites on proteins involved in glucose metabolism. This includes a cooperative relationship between mTOR and AMPK whereby the former directly phosphorylates the latter on S377, for which we find a role in metabolic regulation. These results establish personalized phosphoproteomics as a general approach for investigating the signal transduction underlying complex biology.
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Fenômenos Biológicos , Fosfoproteínas , Fosfoproteínas/genética , Fosforilação , Proteômica/métodos , Transdução de Sinais/fisiologiaRESUMO
Growth differentiation factor 15 (GDF15) has recently moved to the forefront of metabolism research. When administered pharmacologically, GDF15 reduces food intake and lowers body weight via the hindbrain-situated receptor GFRAL (glial cell-derived neurotrophic factor family receptor alpha-like). Endogenous GDF15 is a ubiquitous cellular stress signal that can be produced and secreted by a variety of cell types. Circulating levels are elevated in a series of disease states, but also in response to exogenous agents such as metformin, colchicine, AICAR, and cisplatin. Recently, exercise has emerged as a relevant intervention to interrogate GDF15 physiology. Prolonged endurance exercise increases circulating GDF15 to levels otherwise associated with certain pathological states and in response to metformin treatment. The jury is still out on whether GDF15 is a functional "exerkine" mediating organ-to-brain crosstalk or whether it is a coincidental bystander. In this review, we discuss the putative physiological implication of exercise-induced GDF15, focusing on the potential impact on appetite and metabolism.
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Apetite/fisiologia , Ingestão de Alimentos/fisiologia , Exercício Físico/fisiologia , Comportamento Alimentar/fisiologia , Fator 15 de Diferenciação de Crescimento/metabolismo , Músculo Esquelético/metabolismo , Animais , Humanos , Condicionamento Físico Animal/fisiologia , Transdução de Sinais/fisiologiaRESUMO
In mice, exercise is suggested to activate the mechanistic target of rapamycin complex 2 (mTORC2) in skeletal muscle, and mTORC2 is required for normal muscle glucose uptake during exercise. Whether this translates to human skeletal muscle and what signaling pathways facilitate the exercise-induced mTORC2 activation is unknown. We herein tested the hypothesis that exercise increases mTORC2 activity in human skeletal muscle and investigated if ß2-adrenergic receptor (AR) activation mediates exercise-induced mTORC2 activation. We examined several mTORC2 activity readouts (p-NDRG1 Thr346, p-Akt Ser473, p-mTOR S2481, and p-Akt Thr450) in human skeletal muscle biopsies after uphill walking or cycling exercise. In mouse muscles, we assessed mTORC2 activity readouts following acute activation of muscle ß2-adrenergic or GS signaling and during in vivo and ex vivo muscle contractions. Exercise increased phosphorylation of NDRG1 Thr346 in human soleus, gastrocnemius, and vastus lateralis muscle, without changing p-Akt Ser473, p-Akt Thr450, and p-mTOR Ser2481. In mouse muscle, stimulation of ß2-adrenergic or GS signaling and ex vivo contractions failed to increase p-NDRG1 Thr346, whereas in vivo contractions were sufficient to induce p-NDRG1 Thr346. In conclusion, the mTORC2 activity readout p-NDRG1 Thr346 is a novel exercise-responsive signaling protein in human skeletal muscle. Notably, contraction-induced p-NDRG1 Thr346 appears to require a systemic factor. Unlike exercise, and in contrast to published data obtained in cultured muscles cells, stimulation of ß2-adrenergic signaling is not sufficient to trigger NDRG1 phosphorylation in mature mouse skeletal muscle.NEW & NOTEWORTHY The mTORC2 readout p-NDRG Thr346 is a novel exercise-responsive protein in human skeletal muscle. ß2-AR and GS signaling are not sufficient to induce mTORC2 signaling in adult muscle. In vivo, but not ex vivo, contraction induced p-NDRG Thr346, which indicates requirement of a systemic factor for exercise-induced mTORC2 activation.
Assuntos
Proteínas de Ciclo Celular/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Alvo Mecanístico do Complexo 2 de Rapamicina/metabolismo , Músculo Esquelético/metabolismo , Transdução de Sinais/fisiologia , Caminhada/fisiologia , Adulto , Animais , Células Cultivadas , Feminino , Fibroblastos/metabolismo , Voluntários Saudáveis , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Contração Muscular/fisiologia , Fosforilação/fisiologia , Receptores Adrenérgicos beta 2/metabolismo , Adulto JovemRESUMO
The interaction between insulin and exercise is an example of balancing and modifying the effects of two opposing metabolic regulatory forces under varying conditions. While insulin is secreted after food intake and is the primary hormone increasing glucose storage as glycogen and fatty acid storage as triglycerides, exercise is a condition where fuel stores need to be mobilized and oxidized. Thus, during physical activity the fuel storage effects of insulin need to be suppressed. This is done primarily by inhibiting insulin secretion during exercise as well as activating local and systemic fuel mobilizing processes. In contrast, following exercise there is a need for refilling the fuel depots mobilized during exercise, particularly the glycogen stores in muscle. This process is facilitated by an increase in insulin sensitivity of the muscles previously engaged in physical activity which directs glucose to glycogen resynthesis. In physically trained individuals, insulin sensitivity is also higher than in untrained individuals due to adaptations in the vasculature, skeletal muscle and adipose tissue. In this paper, we review the interactions between insulin and exercise during and after exercise, as well as the effects of regular exercise training on insulin action.