Phosphocreatine Levels Research Articles

Reduced Hippocampal Volume and Neurochemical Response to Adult Stress Exposure in a Female Mouse Model of Urogenital Hypersensitivity.

Early life stress exposure significantly increases the risk of developing chronic pain syndromes and comorbid mood and metabolic disorders later in life. Structural and functional changes within the hippocampus have been shown to contribute to many early life stress-related outcomes. We have previously reported that adult mice that underwent neonatal maternal separation (NMS) exhibit urogenital hypersensitivity, altered anxiety- and depression-like behaviors, increased adiposity, and decreased gene expression and neurogenesis in the hippocampus. Here, we are using magnetic resonance imaging and spectroscopy (MRI and MRS) to further investigate both NMS- and acute stress-induced changes in the hippocampus of female mice. Volumetric analysis of the whole brain revealed that the left hippocampus of NMS mice was 0.038 mm3 smaller compared to naïve mice. MRS was performed only on the right hippocampus and both total choline (tCho) and total N-acetylaspartate (tNAA) levels were significantly decreased due to NMS, particularly after WAS. Phosphoethanolamine (PE) levels were decreased in naïve mice after WAS, but not in NMS mice, and WAS increased ascorbate levels in both groups. The NMS mice showed a trend toward increased body weight and body fat percentage compared to naïve mice. A significant negative correlation was observed between body weight and phosphocreatine levels post-WAS in NMS mice, as well as a positive correlation between body weight and glutamine for NMS mice and a negative correlation for naïve mice. Together, these data suggest that NMS in mice reduces left hippocampal volume and may result in mitochondrial dysfunction and reduced neuronal integrity of the right hippocampus in adulthood. Hippocampal changes also appear to be related to whole body metabolic outcomes.

Highlights from Recent Cancer Literature

Highlights from Recent Cancer Literature

Schizophrenia: Lower brain Glutamate levels could be linked to antipsychotics; higher could be biomarker for disease severity

A mega‐analysis suggests that lower brain Glutamate (Glu) levels in patients with schizophrenia may be associated with antipsychotic medication exposure, not greater age‐related decline; higher brain Glu levels may act as a biomarker of illness severity in schizophrenia. The study looked at altered brain glutamatergic function via proton magnetic resonance spectroscopy studies. The association of altered glutamatergic function with clinical and demographic factors is unclear, so researchers looked at age, symptom severity, level of functioning, and antipsychotic treatment with brain glutamatergic metabolites. They found a total of 45 studies with useful data, and extracted Glu, Glu plus glutamine (Glx), or total creatine plus phosphocreatine levels, with age, antipsychotic medication dose, symptom severity, and functioning assessed using linear mixed models, with study as a random factor.

Association of Age, Antipsychotic Medication, and Symptom Severity in Schizophrenia With Proton Magnetic Resonance Spectroscopy Brain Glutamate Level

Proton magnetic resonance spectroscopy (1H-MRS) studies indicate that altered brain glutamatergic function may be associated with the pathophysiology of schizophrenia and the response to antipsychotic treatment. However, the association of altered glutamatergic function with clinical and demographic factors is unclear. To assess the associations of age, symptom severity, level of functioning, and antipsychotic treatment with brain glutamatergic metabolites. The MEDLINE database was searched to identify journal articles published between January 1, 1980, and June 3, 2020, using the following search terms: MRS or magnetic resonance spectroscopy and (1) schizophrenia or (2) psychosis or (3) UHR or (4) ARMS or (5) ultra-high risk or (6) clinical high risk or (7) genetic high risk or (8) prodrome* or (9) schizoaffective. Authors of 114 1H-MRS studies measuring glutamate (Glu) levels in patients with schizophrenia were contacted between January 2014 and June 2020 and asked to provide individual participant data. In total, 45 1H-MRS studies contributed data. Associations of Glu, Glu plus glutamine (Glx), or total creatine plus phosphocreatine levels with age, antipsychotic medication dose, symptom severity, and functioning were assessed using linear mixed models, with study as a random factor. Glu, Glx, and Cr values in the medial frontal cortex (MFC) and medial temporal lobe (MTL). In total, 42 studies were included, with data for 1251 patients with schizophrenia (mean [SD] age, 30.3 [10.4] years) and 1197 healthy volunteers (mean [SD] age, 27.5 [8.8] years). The MFC Glu (F1,1211.9 = 4.311, P = .04) and Glx (F1,1079.2 = 5.287, P = .02) levels were lower in patients than in healthy volunteers, and although creatine levels appeared lower in patients, the difference was not significant (F1,1395.9 = 3.622, P = .06). In both patients and volunteers, the MFC Glu level was negatively associated with age (Glu to Cr ratio, F1,1522.4 = 47.533, P < .001; cerebrospinal fluid-corrected Glu, F1,1216.7 = 5.610, P = .02), showing a 0.2-unit reduction per decade. In patients, antipsychotic dose (in chlorpromazine equivalents) was negatively associated with MFC Glu (estimate, 0.10 reduction per 100 mg; SE, 0.03) and MFC Glx (estimate, -0.11; SE, 0.04) levels. The MFC Glu to Cr ratio was positively associated with total symptom severity (estimate, 0.01 per 10 points; SE, 0.005) and positive symptom severity (estimate, 0.04; SE, 0.02) and was negatively associated with level of global functioning (estimate, 0.04; SE, 0.01). In the MTL, the Glx to Cr ratio was positively associated with total symptom severity (estimate, 0.06; SE, 0.03), negative symptoms (estimate, 0.2; SE, 0.07), and worse Clinical Global Impression score (estimate, 0.2 per point; SE, 0.06). The MFC creatine level increased with age (estimate, 0.2; SE, 0.05) but was not associated with either symptom severity or antipsychotic medication dose. Findings from this mega-analysis suggest that lower brain Glu levels in patients with schizophrenia may be associated with antipsychotic medication exposure rather than with greater age-related decline. Higher brain Glu levels may act as a biomarker of illness severity in schizophrenia.

Effects of acute heat stress on salivary metabolites in growing pigs: an analysis using nuclear magnetic resonance-based metabolomics profiling.

Heat stress (HS) causes adverse impacts on pig production and health. A potential biomarker of HS is required to predict its occurrence and thereby better manage pigs under HS. Information about the saliva metabolome in heat-stressed pigs is limited. Therefore, this study was aimed to investigate the effects of acute HS on the saliva metabolome and identify metabolites that could be used as potential biomarkers. Growing pigs (n = 6, 3 boars, and 3 gilts) were raised in a thermal neutral (TN; 25°C) environment for a 5-d adaptation period (CON). After adaptation, the pigs were first exposed to HS (30°C; HS30) and then exposed to higher HS (33°C; HS33) for 24 h. Saliva was collected after adaptation, first HS, and second HS, respectively, for metabolomic analysis using 1H-nuclear magnetic resonance spectroscopy. Four metabolites had significantly variable importance in the projection (VIP > 1; p < 0.05) different levels in TN compared to HS groups from all genders (boars and gilts). However, sex-specific characteristics affected metabolites (glutamate and leucine) by showing the opposite results, indicating that HS was less severe in females than in males. A decrease in creatine levels in males and an increase in creatine phosphate levels in females would have contributed to a protective effect from protein degradation by muscle damage. The results showed that HS led to an alteration in metabolites related to energy and protein. Protection from muscle damage may be attributed to the alteration in protein-related metabolites. However, energy-related metabolites showed opposing results according to sex-specific characteristics, such as sex hormone levels and subcutaneous fat layer. This study had shown that saliva samples could be used as a noninvasive method to evaluate heat-stressed pigs. And the results in this study could be contributed to the development of a diagnostic tool as a noninvasive biomarker for managing heat-stressed pigs.

A Prospective Study: Highlights of Hippocampal Spectroscopy in Cognitive Impairment in Patients with Type 1 and Type 2 Diabetes.

Diabetes mellitus type 1 and 2 is associated with cognitive impairment. Previous studies have reported a relationship between changes in cerebral metabolite levels and the variability of glycemia. However, the specific risk factors that affect the metabolic changes associated with type 1 and type 2 diabetes in cognitive dysfunction remain uncertain. The aim of the study was to evaluate the specificity of hippocampal spectroscopy in type 1 and type 2 diabetes and cognitive dysfunction. Materials and methods: 65 patients with type 1 diabetes with cognitive deficits and 20 patients without, 75 patients with type 2 diabetes with cognitive deficits and 20 patients without have participated in the study. The general clinical analysis and evaluation of risk factors of cognitive impairment were carried out. Neuropsychological testing included the Montreal Scale of Cognitive Dysfunction Assessment (MoCA test). Magnetic resonance spectroscopy (MRS) was performed in the hippocampal area, with the assessment of N-acetylaspartate (NAA), choline (Cho), creatine (Cr), and phosphocreatine (PCr) levels. Statistical processing was performed using the commercially available IBM SPSS software. Results: Changes in the content of NAA, choline Cho, phosphocreatine Cr2 and their ratios were observed in type 1 diabetes. More pronounced changes in hippocampal metabolism were observed in type 2 diabetes for all of the studied metabolites. Primary risk factors of neurometabolic changes in patients with type 1 diabetes were episodes of severe hypoglycemia in the history of the disease, diabetic ketoacidosis (DKA), chronic hyperglycemia, and increased body mass index (BMI). In type 2 diabetes, arterial hypertension (AH), BMI, and patient’s age are of greater importance, while the level of glycated hemoglobin (HbA1c), duration of the disease, level of education and insulin therapy are of lesser importance. Conclusion: Patients with diabetes have altered hippocampal metabolism, which may serve as an early predictive marker. The main modifiable factors have been identified, correction of which may slow down the progression of cognitive dysfunction.

The Relation between Exercise Duration and Intensity on Phosphocreatine (PCr) Level: an Article Review

The Relation between Exercise Duration and Intensity on Phosphocreatine (PCr) Level: an Article Review

The Relation between Exercise Duration and Intensity on Phosphocreatine (PCr) Level: an Article Review

Exercise is a physical activity that planned, structured, and sustainable. Exercise has 4 criteria, that isfrequency, intensity, type, and duration. During exercise, phosphocreatine (PCr) depletion increases, andearly intracellular acidosis has occurred. These changes contribute to a decrease in training capacity interms of training duration. This literature review aimed to determine the relationship between the intensityand duration of exercise with the concentration of PCr and recovery factors. The literature study has carriedout by selecting an Experiment research design. The results of the review showed that PCr was the largestenergy contributor in the first 10 seconds of exercise in the heavy-intensity exercise where phosphocreatinetriggers energy without oxygen or anaerobic. The recovery of PCr influenced by a person’s health conditionand age. The concentration of PCr in children was higher than in adults because of the relatively high rateof oxidative ATP formation. It proved that there was a significant relationship between PCr and the durationand intensity of exercise.

Abstract 14072: Bioenergetic and Metabolic Impairments in Duchenne Muscular Dystrophy (DMD) Patients' Induced Pluripotent Stem Cell-derived Cardiomyocytes (iPSC-CMs)

Introduction: DMD, an X-linked muscle degenerative fatal disease, is caused by mutations in the dystrophin gene. Dilated cardiomyopathy (DCM) is a major cause of morbidity and mortality in DMD patients. Since the DMD DCM treatment is limited, novel therapeutic modalities are urgently needed. Hypothesis: We hypothesized that dystrophin mutations in DMD lead to cardiomyopathy-causing bioenergetic/metabolic impairments, which can be therapeutically targeted for improving cardiac function. Methods: The study included iPSC-CMs from a healthy volunteer and 3 DMD patients (young male, YM; adult male, AM; adult female, AF) and mdx mice. We investigated the bioenergetics, electrophysiology, mitochondrial and metabolic features of iPSC-CMs and heart tissues using the SeaHorse Flux Analyzer, patch clamp, confocal fluorescence microscopy and Liquid Chromatography Mass Spectrometry (LC-MS) technologies, respectively. Results: To test the hypothesis, we measured the iPSC-CM respiration rate using the SeaHorse. Compared to healthy, in both AM and AF DMD, but not in YM DMD cardiomyocytes, ATP production decreased by 75%, and basal respiration decreased by 80% and 45%, respectively. In agreement with impaired oxidative phosphorylation capacity, mitochondrial activity measured by 3D life confocal microscopy was attenuated by 35% in AM, but not in YM. Concurring with the healthy-like bioenergetic status, YM iPSC-CMs fired regularly with no arrhythmias, in contrast to the prominent arrhythmias in AM and AF cardiomyocytes. Further, the LC-MS analysis demonstrated that the levels of 13%, 6% and 7% of the 120 metabolite measured, were lower in AM, AF and YM, while 10%, 18% and 43% were higher, respectively, compared to healthy iPSC-CMs ( p&lt;0.05 ). For example, in AM and AF (but not in YM) the phosphocreatine (PCr) levels were diminished by &gt;80%, compared to healthy iPSC-CMs, indicating a dysfunctional PCr energy system. Finally, the LC-MS analysis of mdx ventricular tissue demonstrated a statistically-significant different metabolic profile in 8 mdx mice vs 8 healthy mice. Conclusion: DMD iPSC-CMs and mdx mice exhibit bioenergetic/metabolic impairments, which constitute novel targets for alleviating the cardiomyopathy in DMD patients.

Elevating the level of hypoxia inducible factor may be a new potential target for the treatment of depression

Hypoxia inducible factor-1 (HIF-1) is a transcriptional factor that regulates gene expressions in response to decreased oxygen levels in the tissue, or hypoxia. HIF-1 exerts protective effects against hypoxia by mediating mitochondrial metabolism and consequently reducing oxidative stress. Recently, increased levels of oxidative stress and abnormal energy metabolism in the brain have been suggested to play essential roles in the pathogenesis of depression. Given that HIF-1 activates creatine metabolism and increases phosphocreatine levels in the intestinal epithelial cells, we assume that HIF-1 may induce similar processes in the brain. Elevated phosphocreatine levels in the brain, as measured by magnetic resonance spectroscopy, were associated with better treatment response to the antidepressants in individuals with depression. In addition, oral creatine supplements, which led to increased phosphocreatine levels in the brain, also enhanced the effects of antidepressants in individuals with depression. As such, we hypothesized that increasing the HIF-1, which potentially facilitates creatine metabolism in the brain, might be a new therapeutic target in depression. With this regard, we suggested that interventions to elevate the HIF-1 levels in the brain, including the intermittent hypoxia conditioning and hyperbaric oxygen therapy, might be considered as new additional treatments for depression.

Analyzing the impact of Mycobacterium tuberculosis infection on primary human macrophages by combined exploratory and targeted metabolomics

The pathogenic success of Mycobacterium tuberculosis (Mtb) is tightly linked to its ability to recalibrate host metabolic processes in infected host macrophages. Since changes in cellular metabolic intermediates or pathways also affect macrophage function in response to pathogens, we sought to analyse specific metabolic alterations induced by Mtb infection. Stimulation of macrophages with Mtb lysate or lipopolysaccharide (LPS) induced a relative increase in glycolysis versus oxidative phosphorylation. Cellular metabolomics revealed that Mtb infection induced a distinct metabolic profile compared to LPS in both M1 and M2 macrophages. Specifically, Mtb infection resulted in elevated intracellular levels of nicotinamide adenine dinucleotide (NAD+), creatine, creatine phosphate and glutathione compared to uninfected control macrophages. Correspondingly, RNA-sequencing datasets showed altered gene expression of key metabolic enzymes involved in NAD+, creatine, glucose and glutamine metabolism (e.g NAMPT, SLC6A8, HK2) in Mtb-infected M2 macrophages. These findings demonstrate clear modulation of host macrophage metabolic pathways by Mtb infection.

Nuclear Magnetic Resonance Metabolomics Biomarkers for Identifying High Risk Patients with Extranodal Extension in Oral Squamous Cell Carcinoma.

Extranodal extension (ENE) is an independent adverse prognostic factor in oral squamous cell carcinoma (OSCC), and is difficult to identify preoperatively. We aimed to discover biomarkers for high risk patients with ENE. Tandem tissue, plasma, and urine samples of 110 patients with OSCC were investigated through 600-MHz nuclear magnetic resonance (NMR) metabolomics analysis. We found that the levels of creatine, creatine phosphate, glycine, and tyramine in plasma significantly decreased in stage IV ENE positive OSCC compared with stage IV ENE negative OSCC. To understand the underlying mechanism behind the alteration of plasma metabolites, our tissue analysis revealed that the carnitine level significantly increased in tumors but significantly decreased in the adjacent normal tissue in advanced stage OSCC, in addition to decreased levels of alanine and pyruvate in tumor tissues. The global metabolomics analysis on tumor tissues also showed that stage IV tumors with an ENE positive status demonstrated higher levels of aspartate, butyrate, carnitine, glutamate, glutathione, glycine, glycolate, guanosine, and sucrose but lower levels of alanine, choline, glucose, isoleucine, lactate, leucine, myo-inositol, O-acetylcholine, oxypurinol, phenylalanine, pyruvate, succinate, tyrosine, valine, and xanthine than tumors with an ENE negative status. We concluded that metabolomics alterations in tumor tissues correspond to an increase in the tumor stage and are detectable in plasma samples. Metabolomic alterations of OSCC can serve as potential diagnostic markers and predictors of ENE in patients with stage IV OSCC.

&amp;lt;sup&amp;gt;31&amp;lt;/sup&amp;gt;P MR Spectroscopy with 3D Chemical-Shift Imaging Detects Changes in Levels of Phosphorus Metabolites Due to Saliva Secretion in Human Parotid Glands

.Objectives: To measure phosphorus metabolites in human parotid glands by 31P-MRS using three-dimensional chemical-shift imaging (3D-CSI), and ascertain whether this method can capture changes in adenosine triphosphate (ATP) and phosphocreatine (PCr) levels due to saliva secretion. Study Design: The parotid glands of 20 volunteers were assessed by 31P-MRS using 3D-CSI on 3T MRI. After obtaining a first (baseline) measurement, the participants took vitamin-C tablets and measurements were obtained twice more, in a continuous manner. The peak area ratios of PCr and β-ATP were evaluated. Results: A high proportion of PCr (0.26 ± 0.08) and ATP (α: 0.16 ± 0.06; β: 0.27 ± 0.06; γ: 0.21 ± 0.03) was noted at baseline. A significant decrease in β-ATP was observed between baseline (“pre”; 0.27 ± 0.06) and the first scan after vitamin-C stimulation (“post-1”; 0.19 ± 0.07, p Conclusions: 31P-MRS with 3D-CSI can assess the major phosphorus metabolites in human parotid glands and capture changes in their levels due to saliva secretion. This technique is simple, non-invasive, and provides new information regarding saliva secretion.

P.036 The assertive brain: phosphocreatine plus creatine levels from the anterior cingulate correlates with self-directness in healthy adolescents

P.036 The assertive brain: phosphocreatine plus creatine levels from the anterior cingulate correlates with self-directness in healthy adolescents

Abstract 863: Pathological Roles of Senometabolites in Cardiovascular Disorders

Mechanisms contributing for the synchronization of aging are yet to be defined. Here, we define “senometabolite” as circulating metabolites having causal roles for the synchronization and progression of aging. Analyzing metabolomic studies in coronary plaque corrected with directional coronary atherectomy (DCA), we found that hydroxyl-metabolite significantly increased in patients with unstable angina compared with stable angina. We generated murine diet induced obese model and found this metabolite increased in aorta and plasma. Administration of this metabolite into human umbilical vein endothelial cells (HUVECs) induced cellular senescence, and immunofluorescence study showed that putative transhydrogenase increased in patients with atherosclerotic disorders. We did metabolomics studies in aged individuals or patients with heart failure and identified another metabolite, oxidized choline, increased under these conditions compared to respective controls. We generated murine left ventricular (LV) pressure overload model and found that oxidized choline increased both in plasma and failing heart. Administration of oxidized choline deteriorated cardiac function, in contrast, genetic model showed suppression of this metabolite ameliorated systolic dysfunction in LV pressure overload model. Proteomic study showed that oxidized choline reduced the expression of cytochrome c oxidase subunit1, and metabolomics study showed that both ATP and phosphocreatine level significantly reduced in cardiac tissues of wild type mice administrated with this metabolite. Administration of oxidized choline also reduced muscle strength, induced fibrosis in skeletal muscle, and electron microscopy showed an increase in dysfunctional mitochondria both in the heart and skeletal muscle. In aged wild type mice, metabolomic study showed oxidized choline increased in plasma. Aging process is still mysterious and continues to be an interesting topic to be explored. Our findings indicate that circulating senometabolites contribute for the progression of pathologies in age related disorders.

Muscle fibre activation and fatigue with low-load blood flow restricted resistance exercise-An integrative physiology review.

Blood flow-restricted resistance exercise (BFRRE) has been shown to induce increases in muscle size and strength, and continues to generate interest from both clinical and basic research points of view. The low loads employed, typically 20%-50% of the one repetition maximum, make BFRRE an attractive training modality for individuals who may not tolerate high musculoskeletal forces (eg, selected clinical patient groups such as frail old adults and patients recovering from sports injury) and/or for highly trained athletes who have reached a plateau in muscle mass and strength. It has been proposed that achieving a high degree of muscle fibre recruitment is important for inducing muscle hypertrophy with BFRRE, and the available evidence suggest that fatiguing low-load exercise during ischemic conditions can recruit both slow (type I) and fast (type II) muscle fibres. Nevertheless, closer scrutiny reveals that type II fibre activation in BFRRE has to date largely been inferred using indirect methods such as electromyography and magnetic resonance spectroscopy, while only rarely addressed using more direct methods such as measurements of glycogen stores and phosphocreatine levels in muscle fibres. Hence, considerable uncertainity exists about the specific pattern of muscle fibre activation during BFRRE. Therefore, the purpose of this narrative review was (1) to summarize the evidence on muscle fibre recruitment during BFRRE as revealed by various methods employed for determining muscle fibre usage during exercise, and (2) to discuss reported findings in light of the specific advantages and limitations associated with these methods.

Differences in metabolism of triploid and diploidSalmo trutta f. lacustrisunder acclimation conditions and after exposure to stress situations

Differences in metabolism (enzyme activities, metabolites) between diploid and triploid Salmo trutta f. lacustris were investigated under acclimation and stress conditions. Under acclimation conditions enzyme activities differed for 35% of the 27 investigated key regulatory enzymes and temperature optima for 23%. Muscle and liver metabolites related to energy metabolism and diagnostic indices of blood serum were similar, with exception of acetyl-CoA being increased in triploids. Metabolic rate was lower and gill ventilation rate higher in triploids in comparison with diploids. During the tested stress situations (24 hr endurance swimming, 3 hr exposure to hypoxia in water with 32% oxygen saturation) muscle and liver glycogen decreased and serum and muscle lactate increased in both ploidy levels. Specifically, for triploids muscle adenylate energy charge and phosphocreatine levels decreased after endurance swimming and muscle and liver adenylate energy charge after exposure to hypoxia. Acetyl-CoA increased in triploids during both stress situations. In summary, there existed differences in metabolism between the two ploidy levels and the energy metabolism of triploids was less balanced under stress.

Neuroprotective effects of creatine treatment on the differentiation of E14 rat cortical stem cells and expression of GABA-ergic neurons.

Along with the promotion of muscle growth and recovery, it has been observed that the supplement, creatine, also contains neuroprotective properties that aid in the developmental process of neuronal cells by increasing developmental competency in early differentiation. In clinical research, addiction treatments are beginning to introduce dietary supplements such as Creatine for patients in early recovery to improve recovery abstinence. Research has shown that supplemental Creatine induces higher cerebral phosphocreatine levels which could help with improved neuron connectivity. In order to examine the neuroprotective effects of Creatine, E14 rat cortical stem cells were differentiated and treated with different dosages of alcohol and creatine. Alcohol was used as a negative control in order to compare the differentiation and expression of GABAergic neurons associated with alcohol exposure and neuronal protection from Creative. We anticipate that Creatine acts as a neuroprotective agent in GABAergic neurons treated with alcohol

NEUROPROTECTIVE EFFECTS OF CREATINE TREATMENT ON THE DIFFERENTIATION OF E14 RAT CORTISOL STEM CELLS AND EXPRESSION OF GABA-ERGIC NEURONS

Along with the promotion of muscle growth and recovery, it has been observed that the supplement, Creatine, also contains neuroprotective properties that aid in the developmental process of neuronal cells by increasing developmental competency in early differentiation. In clinical research, addiction treatments are beginning to introduce dietary supplements such as Creatine for patients in early recovery to improve recovery abstinence. Research has shown that supplemental Creatine induces higher cerebral phosphocreatine levels which could help with improved neuron connectivity. In order to examine the neuroprotective effects of Creatine, E14 rat cortical stem cells were differentiated and treated with different dosages of alcohol and creatine. Alcohol was used as a negative control in order to compare the differentiation and expression of GABAergic neurons associated with alcohol exposure and neuronal protection from Creative. We anticipate that Creatine acts as a neuroprotective agent in GABAergic neurons treated with alcohol.

Ablation of adipocyte creatine transport impairs thermogenesis and causes diet-induced obesity.

Depleting creatine levels in thermogenic adipocytes by inhibiting creatine biosynthesis reduces thermogenesis and causes obesity. However, whether creatine import from the circulation affects adipocyte thermogenesis is unknown. Here we show that deletion of the cell-surface creatine transporter (CrT) selectively in fat (AdCrTKO) substantially reduces adipocyte creatine and phosphocreatine levels, and reduces whole-body energy expenditure in mice. AdCrTKO mice are cold intolerant and become more obese than wild-type animals when fed a high-fat diet. Loss of adipocyte creatine transport blunts diet- and β3-adrenergic-induced thermogenesis, whereas creatine supplementation during high-fat feeding increases whole-body energy expenditure in response to β3-adrenergic agonism. In humans, CRT expression in purified subcutaneous adipocytes correlates with lower body mass index and increased insulin sensitivity. Our data indicate that adipocyte creatine abundance depends on creatine sequestration from the circulation. Given that it affects whole-body energy expenditure, enhancing creatine uptake into adipocytes may offer an opportunity to combat obesity and obesity-associated metabolic dysfunction. Creatine can be used for thermogenesis in adipocytes. Here Kazak et al. show that creatine uptake is required to sustain this thermogenic pathway. Knockdown of the creatine transporter, CrT, in adipocytes decreases thermogenesis and energy expenditure, whereas creatine supplementation increases energy expenditure in mice fed a high-fat diet.