Whole-body Metabolism Research Articles

High-resolution plasma metabolomics and thiamine status in critically Ill adult patients

IntroductionThiamine (Vitamin B1) is an essential micronutrient and is classically considered a co-factor in energy metabolism. The association between thiamine status and whole-body metabolism in critical illness has not been studied.ObjectivesTo determine association between whole blood thiamine pyrophosphate (TPP) concentrations and plasma metabolites and connected metabolic pathways using high resolution metabolomics (HRM) in critically ill patients.MethodsCross-sectional study performed at Erciyes University Hospital, Kayseri, Turkey and Emory University, Atlanta, GA, USA. Participants were critically ill adults with an expected length of intensive care unit stay longer than 48 h and receiving chronic furosemide therapy. A total of 76 participants were included. Mean age was 69 years (range 33–92 years); 65% were female. Blood for TPP and metabolomics was obtained on the day of ICU admission. Whole blood TPP was measured by HPLC and plasma HRM was performed using liquid chromatography/mass spectrometry. Data was analyzed using regression analysis of TPP levels against all plasma metabolomic features in metabolome-wide association studies (MWAS). MWAS using the highest and lowest TPP concentration tertiles was performed as a secondary analysis.ResultsSpecific metabolic pathways associated with whole blood TPP levels in regression and tertile analysis included pentose phosphate, fructose and mannose, branched chain amino acid, arginine and proline, linoleate, and butanoate pathways.ConclusionsPlasma HRM revealed that thiamine status, determined by whole blood TPP concentrations, was significantly associated with metabolites and metabolic pathways related to metabolism of energy, carbohydrates, amino acids, lipids, and the gut microbiome in adult critically ill patients.

The history context and future directions of lactic acid

Lactic acid, initially considered a neglected metabolic waste product, has gradually shown its irreplaceable value in the human body. Up to now, it has become a hot topic of current research. From its first time its discovery in milk to its becoming a product of cellular respiration and metabolism, lactic acid was viewed to be a useless product in metabolism and therefore resulted in the suspension of related research. Later, with the birth of the concept of lactate shuttle between cells, lactate once again showed a very important function in the energy field of physiological research, including the participation of whole-body energy metabolism and the regulation of the cancer microenvironment. However, after some time, the research on lactic acid seems to have stalled again in the role of lactic acid as a small molecule. Not until 2019, the discovery of acetylation of histone extended a new field of lactate research epigenetic modification. This review summarizes the research on various aspects of lactate and highlights the progress and application of lactate in histone modification.

Commentary: Tracing the fate of metabolic substrates during changes in whole-body energy expenditure in mice

For small mammals, such as mice, cannulation procedures can be quite challenging, limiting research associated with tracing isotopically labelled substrates at the whole-animal level. When cannulation in mice is possible, assessment of substrate use is further limited to when mice are either under anesthesia or are at rest, as there are no studies directly quantifying substrate use during exercise in mice. The use of isotopic tracer techniques has greatly advanced our knowledge in understanding how metabolic substrates (carbohydrates, amino acids, and fatty acids) contribute to whole-body metabolism. However, research regarding tissue-specific fuel use contributions to whole-body energy expenditure in mice at varying metabolic intensities (i.e., exercise) is lacking, despite the popularity of using mice in a variety of metabolic models. In this commentary, we briefly discuss the methodologies, advantages, and disadvantages of using radiolabelled, positron emission, and stable isotopes with a specific focus on fatty acids. We highlight recent mouse studies that have used creative experimental designs employing the use of isotopic tracer techniques and we briefly discuss how these methodologies can be further pursued to deepen our understanding of substrate use during exercise. Lastly, we show findings of a recent study we performed using a radiolabelled fatty acid tracer (14C-bromopalmitic acid) to determine fatty acid uptake in 16 muscles, two brown and two white adipose tissue depots during submaximal exercise in deer mice.

A small intestinal bile acid modulates the gut microbiome to improve host metabolic phenotypes following bariatric surgery

Bariatric surgical procedures such as sleeve gastrectomy (SG) provide effective type 2 diabetes (T2D) remission in human patients. Previous work demonstrated that gastrointestinal levels of the bacterial metabolite lithocholic acid (LCA) are decreased after SG in mice and humans. Here, we show that LCA worsens glucose tolerance and impairs whole-body metabolism. We also show that taurodeoxycholic acid (TDCA), which is the only bile acid whose concentration increases in the murine small intestine post-SG, suppresses the bacterial bile acid-inducible (bai) operon and production of LCA both invitro and invivo. Treatment of diet-induced obese mice with TDCA reduces LCA levels and leads to microbiome-dependent improvements in glucose handling. Moreover, TDCA abundance is decreased in small intestinal tissue from T2D patients. This work reveals that TDCA is an endogenous inhibitor of LCA production and suggests that TDCA may contribute to the glucoregulatory effects of bariatric surgery.

High-intensity interval training improves hypothalamic inflammation by suppressing HIF-1α signaling in microglia of male C57BL/6J mice.

Repeated bouts of high-intensity interval training (HIIT) induce an improvement in metabolism via plasticity of melanocortin circuits and attenuated hypothalamic inflammation. HIF-1α, which plays a vital role in hypothalamus-mediated regulation of peripheral metabolism, is enhanced in the hypothalamus by HIIT. This study aimed to investigate the effects of HIIT on hypothalamic HIF-1α expression and peripheral metabolism in obese mice and the underlying molecular mechanisms. By using a high-fat diet (HFD)-induced obesity mouse model, we determined the effect of HIIT on energy balance and the expression of the hypothalamic appetite-regulating neuropeptides, POMC and NPY. Moreover, hypothalamic HIF-1α signaling and its downstream glycolytic enzymes were explored after HIIT intervention. The state of microglia and microglial NF-κB signaling in the hypothalamus were also examined invivo. Invitro by using an adenovirus carrying shRNA-HIF1β, we explored the impact of HIF-1 signaling on glycolysis and NF-κB inflammatory signaling in BV2 cells. Food intake was suppressed and whole-body metabolism was improved in exercised DIO mice, accompanied by changes in the expression of POMC and NPY. Moreover, total and microglial HIF-1α signaling were obviously attenuated in the hypothalamus, consistent with the decreased levels of glycolytic enzymes. Both HFD-induced microglial activation and hypothalamic NF-κB signaling were significantly suppressed following HIIT invivo. In BV2 cells, after HIF-1 complex knockdown, glycolysis and NF-κB inflammatory signaling were significantly attenuated. The data indicate that HIIT improves peripheral metabolism probably via attenuated HFD-induced microglial activation and microglial NF-κB signaling in the hypothalamus, which could be mediated by suppressed microglial HIF-1α signaling.

Differential Mitochondrial Adaptation of the Slow and Fast Skeletal Muscles by Endurance Running Exercise in Streptozotocin-Induced Diabetic Mice.

The skeletal muscle is the main organ responsible for insulin action, and glucose disposal and metabolism. Endurance and/or resistance training raises the number of mitochondria in diabetic muscles. The details of these adaptations, including mitochondrial adaptations of the slow and fast muscles in diabetes, are unclear. This study aimed to determine whether exercise training in streptozotocin (STZ)-induced mice leads to differential adaptations in the slow and fast muscles, and improving glucose clearance. Eight-week-old mice were randomly distributed into normal control (CON), diabetes (DM), and diabetes and exercise (DM+Ex) groups. In the DM and DM+Ex groups, mice received a freshly prepared STZ (100 mg/kg) intraperitoneal injection on two consecutive days. Two weeks after the injection, the mice in the groups ran on a treadmill for 60 min at 20 m/min for a week and subsequently at 25 m/min for 5 weeks (5 days/week). The analyses indicated that running training at low speed (25 m/min) enhanced mitochondrial enzyme activity and expression of lactate and glucose transporters in the plantaris (low-oxidative) muscle that improved whole-body glucose metabolism in STZ-induced diabetic mice. There were no differences in glucose transporter expression levels in the soleus (high-oxidative) muscle. The endurance running exercise at 20-25 m/min was sufficient to induce mitochondrial adaptation in the low-oxidative muscles, but not in the high-oxidative muscles, of diabetic mice. In conclusion, the present study indicated that running training at 25 m/min improved glucose metabolism by increasing the mitochondrial enzyme activity and glucose transporter 4 and monocarboxylate transporter 4 protein contents in the low-oxidative muscles in STZ-induced diabetic mice.

Effects of low temperature on growth and metabolism of larval green sturgeon (Acipenser medirostris) across early ontogeny.

Southern Distinct Population Segment (sDPS) green sturgeon spawn solely in one stretch of the Sacramento River in California. Management of this spawning habitat is complicated by cold water temperature requirements for the conservation of winter-run Chinook salmon. This study assessed whether low incubation and rearing temperatures resulted in carryover effects across embryo to early juvenile life stages on scaling relationships in growth and metabolism in northern DPS green sturgeon used as a proxy for sDPS green sturgeon. Fish were incubated and reared at 11°C and 15°C, with a subset experiencing a reciprocal temperature transfer post-hatch, to assess recovery from cold incubation or to simulate a cold-water dam release which would chillrearing larvae. Growth and metabolic rate of embryos and larvae were measured to 118days post hatch. Reciprocal temperature transfers revealed a greater effect of low temperature exposure during larval rearing rather than during egg incubation. While 11°C eggs hatched at a smaller length, log-transformed length-weight relationships showed that these differences in developmental trajectory dissipated as individuals achieved juvenile morphology. However, considerable size-at-age differences persisted between rearing temperatures, with 15°C fish requiring 60days post-hatch to achieve 1g in mass, whereas 11°C fish required 120days to achieve 1g, resulting in fish of the same age at the completion of the experiment with a ca. 37-fold difference in weight. Consequently, our study suggests that cold rearing temperatures have far more consequential downstream effects than cold embryo incubation temperatures. Growth delays from 11°C rearing temperatures would greatly increase the period of vulnerability to predation in larval green sturgeon. The scaling relationship between log-transformed whole-body metabolism and mass exhibited a steeper slope and thus an increased oxygen requirement with size in 11°C reared fish, potentially indicating an energetically unsustainable situation. Understanding how cold temperatures affect green sturgeon ontogeny is necessary to refine our larval recruitment estimations for this threatened species.

Non-invasive mapping of brown adipose tissue activity with magnetic resonance imaging

Thermogenic brown adipose tissue (BAT) has a positive impact on whole-body metabolism. However, in vivo mapping of BAT activity typically relies on techniques involving ionizing radiation, such as [18F]fluorodeoxyglucose ([18F]FDG) positron emission tomography (PET) and computed tomography (CT). Here we report a noninvasive metabolic magnetic resonance imaging (MRI) approach based on creatine chemical exchange saturation transfer (Cr-CEST) contrast to assess in vivo BAT activity in rodents and humans. In male rats, a single dose of the β3-adrenoceptor agonist (CL 316,243) or norepinephrine, as well as cold exposure, triggered a robust elevation of the Cr-CEST MRI signal, which was consistent with the [18F]FDG PET and CT data and 1H nuclear magnetic resonance measurements of creatine concentration in BAT. We further show that Cr-CEST MRI detects cold-stimulated BAT activation in humans (both males and females) using a 3T clinical scanner, with data-matching results from [18F]FDG PET and CT measurements. This study establishes Cr-CEST MRI as a promising noninvasive and radiation-free approach for in vivo mapping of BAT activity.

Cardiomyocyte crosstalk with endothelium modulates cardiac structure, function, and ischemia-reperfusion injury susceptibility through erythropoietin.

Erythropoietin (EPO) exerts non-canonical roles beyond erythropoiesis that are developmentally, structurally, and physiologically relevant for the heart as a paracrine factor. The role for paracrine EPO signalling and cellular crosstalk in the adult is uncertain. Here, we provided novel evidence showing cardiomyocyte restricted loss of function in Epo in adult mice induced hyper-compensatory increases in Epo expression by adjacent cardiac endothelial cells via HIF-2α independent mechanisms. These hearts showed concentric cellular hypertrophy, elevated contractility and relaxation, and greater resistance to ischemia-reperfusion injury. Voluntary exercise capacity compared to control hearts was improved independent of any changes to whole-body metabolism or blood O2 content or delivery (i.e., hematocrit). Our findings suggest cardiac EPO had a localized effect within the normoxic heart, which was regulated by cell-specific EPO-reciprocity between cardiomyocytes and endothelium. Within the heart, hyper-compensated endothelial Epo expression was accompanied by elevated Vegfr1 and Vegfb RNA, that upon pharmacological pan-inhibition of VEGF-VEGFR signaling, resulted in a paradoxical upregulation in whole-heart Epo. Thus, we provide the first evidence that a novel EPO-EPOR/VEGF-VEGFR axis exists to carefully mediate cardiac homeostasis via cardiomyocyte-endothelial EPO crosstalk.

Metabolic Effects of Ketogenic Diets: Exploring Whole-Body Metabolism in Connection with Adipose Tissue and Other Metabolic Organs.

The ketogenic diet (KD) is characterized by minimal carbohydrate, moderate protein, and high fat intake, leading to ketosis. It is recognized for its efficiency in weight loss, metabolic health improvement, and various therapeutic interventions. The KD enhances glucose and lipid metabolism, reducing triglycerides and total cholesterol while increasing high-density lipoprotein levels and alleviating dyslipidemia. It significantly influences adipose tissue hormones, key contributors to systemic metabolism. Brown adipose tissue, essential for thermogenesis and lipid combustion, encounters modified UCP1 levels due to dietary factors, including the KD. UCP1 generates heat by uncoupling electron transport during ATP synthesis. Browning of the white adipose tissue elevates UCP1 levels in both white and brown adipose tissues, a phenomenon encouraged by the KD. Ketone oxidation depletes intermediates in the Krebs cycle, requiring anaplerotic substances, including glucose, glycogen, or amino acids, for metabolic efficiency. Methylation is essential in adipogenesis and the body's dietary responses, with DNA methylation of several genes linked to weight loss and ketosis. The KD stimulates FGF21, influencing metabolic stability via the UCP1 pathways. The KD induces a reduction in muscle mass, potentially involving anti-lipolytic effects and attenuating proteolysis in skeletal muscles. Additionally, the KD contributes to neuroprotection, possesses anti-inflammatory properties, and alters epigenetics. This review encapsulates the metabolic effects and signaling induced by the KD in adipose tissue and major metabolic organs.

The ABCA1 gene polymorphisms rs1800977 and rs2230806 are differentially associated with the risk for myocardial infarction in Slovenian subjects with type 2 diabetes mellitus

BackgroundThe adenosine triphosphate-binding cassette transporter A1 (ABCA1) is closely linked to various aspects of the regulation of whole-body cholesterol metabolism and atherosclerosis formation. The object of the study was to investigate the association between rs1800977 and rs2230806 polymorphisms in the ABCA1 gene and myocardial infarction (MI) in Slovenian subjects with type 2 diabetes mellitus (T2DM). Methods1590 T2DM patients (484 subjects with MI and 1106 controls) were included in this retrospective cross-sectional case–control study. After genotyping, Pearson χ2 test was used to compare the distribution of genotypes and alleles among the two groups. Logistic regression analysis adjusted for several risk factors for MI was performed. ResultsGenotype distribution showed significant association with MI in T2DM subjects for both selected polymorphisms in ABCA1 gene (p = 0.009 for rs2230806 and p = 0.042 for rs1800977). After applying corrections for confounding variables like age, waist circumference, diastolic blood pressure, serum high-density lipoprotein levels, gender and smoking several genetic models still showed significant associations with MI (dominant model for rs2230806 and dominant, overdominant and co-dominant for rs1800977). ConclusionOur study showed that presence of the T allele of the rs2230806 ABCA1 gene is associated with higher risk of MI, while the A allele of the rs1800977 conferred protection against MI in Slovenian T2DM subjects.

Reversing Pdgfrβ Signaling Restores Metabolically Active Beige Adipocytes by Alleviating ILC2 Suppression in Aged and Obese Mice.

Platelet Derived Growth Factor Receptor Beta (Pdgfrβ) suppresses the formation of cold temperature-induced beige adipocytes in aged mammals. We aimed to determine if deleting Pdgfrβ in aged mice could rejuvenate metabolically active beige adipocytes by activating group 2 innate lymphoid cells (ILC2), and whether this effect could counteract diet-induced obesity-associated beige fat decline. We employed Pdgfrβ gain-of-function and loss-of-function mouse models targeting beige adipocyte progenitor cells (APCs). Our approach included cold exposure, metabolic cage analysis, and age and diet-induced obesity models to examine beige fat development and metabolic function under varied Pdgfrβ activity. Acute cold exposure alone enhanced metabolic benefits in aged mice, irrespective of beige fat generation. However, Pdgfrβ deletion in aged mice reestablished the formation of metabolically functional beige adipocytes, enhancing metabolism. Conversely, constitutive Pdgfrβ activation in young mice stymied beige fat development. Mechanistically, Pdgfrβ deletion upregulated IL-33, promoting ILC2 recruitment and activation, whereas Pdgfrβ activation reduced IL-33 levels and suppressed ILC2 activity. Notably, diet-induced obesity markedly increased Pdgfrβ expression and Stat1 signaling, which inhibited IL-33 induction and ILC2 activation. Genetic deletion of Pdgfrβ restored beige fat formation in obese mice, improving whole-body metabolism. This study reveals that cold temperature exposure alone can trigger metabolic activation in aged mammals. However, reversing Pdgfrβ signaling in aged and obese mice not only restores beige fat formation but also renews metabolic function and enhances the immunological environment of white adipose tissue (WAT). These findings highlight Pdgfrβ as a crucial target for therapeutic strategies aimed at combating age- and obesity-related metabolic decline.

Serum Metabolomic and Lipidomic Profiling Reveals the Signature for Postoperative Obesity among Adult-Onset Craniopharyngioma.

Craniopharyngioma patients often suffer from a diminished quality of life after surgery, which is usually associated with metabolic disorders and hypothalamic obesity. However, the precise etiology of these conditions remains elusive. To identify the metabolic changes after surgery, we conducted a cross-sectional study using metabolomic and lipidomic analysis to profile metabolic alterations in adult-onset craniopharyngioma patients with postoperative obesity. A cohort of 120 craniopharyngioma patients who had undergone surgery were examined. Differential analyses, including clinical characteristics, serum metabolome, and lipidome, were conducted across distinct body mass index (BMI) groups. Our findings indicated no statistically significant differences in age, sex, and fasting blood glucose among postoperative craniopharyngioma patients when stratified by BMI. However, a noteworthy difference was observed in uric acid and blood lipid levels. Further investigation revealed that alterations in metabolites and lipids were evidently correlated with increased BMI, indicating that postoperative obesity of craniopharyngioma patients affected their whole-body metabolism. Additionally, the multi-omics analysis identified specific metabolites and lipids, including uric acid and DG(18:2/20:4), as contributors to the metabolic disorders associated with postoperative obesity of craniopharyngioma patients. This work provides valuable insight into the involvement of metabolites and lipids in metabolic disorders subsequent to craniopharyngioma surgery.

Adaptive gene expression of alternative splicing variants of PGC-1α regulates whole-body energy metabolism

The transcriptional coactivator PGC-1α has been implicated in the regulation of multiple metabolic processes. However, the previously reported metabolic phenotypes of mice deficient in PGC-1α have been inconsistent. PGC-1α exists as multiple isoforms, including variants transcribed from an alternative first exon. We show here that alternative PGC-1α variants are the main entity that increases PGC-1α during exercise. These variants, unlike the canonical isoform of PGC-1α, are robustly upregulated in human skeletal muscle after exercise. Furthermore, the extent of this upregulation correlates with oxygen consumption. Mice lacking these variants manifest impaired energy expenditure during exercise, leading to the development of obesity and hyperinsulinemia. The alternative variants are also upregulated in brown adipose tissue in response to cold exposure, and mice lacking these variants are intolerant of a cold environment. Our findings thus indicate that an increase in PGC-1α expression, attributable mostly to upregulation of alternative variants, is pivotal for adaptive enhancement of energy expenditure and heat production and thereby essential for the regulation of whole-body energy metabolism.

A spatial portrait of the human sebaceous gland transcriptional program

Sebaceous glands (SG) and their oily secretion (sebum) are indispensable for maintaining skin structure and function, and their deregulation causes skin disorders including but not limited to acne. Recent studies also indicate that sebum may have important immunomodulatory activities and may influence whole-body energy metabolism. However, the progressive transcriptional changes of sebocytes that lead to sebum production have never been characterized in detail. Here, we exploited the high cellular resolution provided by sebaceous hyperplasia and integrated spatial transcriptomics, pseudotime analysis, RNA velocity, and functional enrichment to map the landscape of sebaceous differentiation by employing spatial transcriptomics. Our results were validated by comparison with published SG transcriptome data and further corroborated by assessing the protein expression pattern of a subset of the transcripts in the public repository Human Protein Atlas. Departing from four sebocyte differentiation stages generated by unsupervised clustering, we demonstrate consecutive modulation of cellular functions associable with specific gene sets, from cell proliferation and oxidative phosphorylation via lipid synthesis to cell death. Both validation methods confirmed the biological significance of our results. Our report is complemented by a freely available and browsable online tool. Our data provide the first high-resolution spatial portrait of the SG transcriptional landscape and deliver starting points for experimentally assessing novel candidate molecules for regulating SG homeostasis in health and disease.

Metabolic Profile and Lipid Metabolism Phenotype in Mice with Conditional Deletion of Hepatic BMAL1.

The disruption of circadian rhythms (CRs) has been linked to metabolic disorders, yet the role of hepatic BMAL1, a key circadian regulator, in the whole-body metabolism and the associated lipid metabolic phenotype in the liver remains unclear. Bmal1 floxed (Bmal1f/f) and hepatocyte-specific Bmal1 knockout (Bmal1hep-/-) C57BL/6J mice underwent a regular feeding regimen. Hepatic CR, lipid content, mitochondrial function, and systemic metabolism were assessed at zeitgeber time (ZT) 0 and ZT12. Relevant molecules were examined to elucidate the metabolic phenotype. Hepatocyte-specific knockout of Bmal1 disrupted the expression of rhythmic genes in the liver. Bmal1hep-/- mice exhibited decreased hepatic TG content at ZT0, primarily due to enhanced lipolysis, reduced lipogenesis, and diminished lipid uptake. The β-oxidation function of liver mitochondria decreased at both ZT0 and ZT12. Our findings on the metabolic profile and associated hepatic lipid metabolism in the absence of Bmal1 in hepatocytes provides new insights into metabolic syndromes from the perspective of liver CR disturbances.

Role of polymeric immunoglobulin receptor in glucose metabolism

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Fundación La Caixa 2022 HR22-0253. Comunidad de Madrid P2022/BMD-7333 INMUNOVAR-CM Background Type 2 diabetes and obesity are leading causes of death and disability worldwide, being both risk factors for cardiovascular disease. Intestinal immune system is being shown to have a key role in insulin resistance (IR). Polymeric immunoglobulin receptor (PIGR) is a transmembrane protein which facilitates the transcytosis of the soluble polymeric isoforms of immunoglobulin A (IgA) and is widely expressed in mucosal epithelial cells. IgA levels are reduced in obesity and the loss of IgA in mice worsens insulin resistance and increases inflammation in adipose tissue. However, the specific role of PIGR in IR has not been fully elucidated. Aim To analyze the role of PIGR in systemic glucose metabolism. Methods To determine the impact of global silencing of Pigr on whole-body glucose metabolism, we metabolically characterized the Pigr-/- female mouse 60% fat diet (HFD). We performed glucose and insulin tolerance tests. In vivo and ex vivo adiposity was measured by dual x-ray absorptiometry (DXA) and adipose tissue depots weight, fasting glucose and insulin plasma levels were determined at endpoint. Circulating IgA levels were measured by ELISA and IgA deposition in liver and adipose tissue of control and Pigr-/- mice was determined by western blot and immunohistochemistry. Results As previously described, we show that IgA serum levels were highly increased in Pigr -/- mice. Besides, we demonstrate that IgA deposition in liver and adipose tissue was increased in these mice. We demonstrate that global deletion of Pigr results in whole-body glucose intolerance and IR mice fed HFD. Fasting glucose levels (169.24±24.49 mg/dl in Pigr -/- mice vs 142±27mg/dl in control mice) and fasting insulin levels (1.27±0.42 ng/ml in Pigr -/- mice vs 0.92±0.37 ng/ml in control mice) were significantly increased in Pigr -/- mice fed HFD for 17 weeks. No differences were found in lipid profile levels (triglycerides, HDL-c, VLDL+LDL-c and NEFA). Interestingly, Pigr-/- mice show significant increased adiposity (46±4.11 % adiposity vs 50.6±4.9 in control) measured by DXA, which results in a significant increase in body weight (BW), compared to control (BW gain over 20 weeks on HFD: 21.85± 3.06 gr in Pigr -/- mice vs 17.93±2.1 gr). mRNA expression of the β isoform of carbohydrate responsive-element binding protein (ChREBPβ) is significantly reduced (0.5 folds vs control group) in Pigr -/- adipose tissue, which might link the whole-body metabolic phenotype to ChREBP-dependent glucose sensing by adipose tissue. Conclusion Global Pigr deletion results in whole-body glucose intolerance and IR in female mice fed HFD. Our results suggest cell-intrinsic mechanisms of Pigr deletion as well as extracellular components (increased IgA serum levels and deposition in tissues) as potential triggers of systemic glucose metabolism disruption. Management of PIGR levels might be key for glucose-metabolism-related pathologies.

Adipose tissue as a linchpin of organismal ageing.

Ageing is a conserved biological process, modulated by intrinsic and extrinsic factors, that leads to changes in life expectancy. In humans, ageing is characterized by greatly increased prevalence of cardiometabolic disease, type 2 diabetes and disorders associated with impaired immune surveillance. Adipose tissue displays species-conserved, temporal changes with ageing, including redistribution from peripheral to central depots, loss of thermogenic capacity and expansion within the bone marrow. Adipose tissue is localized to discrete depots, and also diffusely distributed within multiple organs and tissues in direct proximity to specialized cells. Thus, through their potent endocrine properties, adipocytes are capable of modulating tissue and organ function throughout the body. In addition to adipocytes, multipotent progenitor/stem cells in adipose tissue play a crucial role in maintenance and repair of tissues throughout the lifetime. Adipose tissue may therefore be a central driver for organismal ageing and age-associated diseases. Here we review the features of adipose tissue during ageing, and discuss potential mechanisms by which these changes affect whole-body metabolism, immunity and longevity. We also explore the potential of adipose tissue-targeted therapies to ameliorate age-associated disease burdens.

The novel adrenergic agonist ATR-127 targets skeletal muscle and brown adipose tissue to tackle diabesity and steatohepatitis

ObjectiveSimultaneous activation of β2- and β3-adrenoceptors (ARs) improves whole-body metabolism via beneficial effects in skeletal muscle and brown adipose tissue (BAT). Nevertheless, high-efficacy agonists simultaneously targeting these receptors whilst limiting activation of β1-ARs – and thus inducing cardiovascular complications – are currently non-existent. Therefore, we here developed and evaluated the therapeutic potential of a novel β2-and β3-AR, named ATR-127, for the treatment of obesity and its associated metabolic perturbations in preclinical models. MethodsIn the developmental phase, we assessed the impact of ATR-127's on cAMP accumulation in relation to the non-selective β-AR agonist isoprenaline across various rodent β-AR subtypes, including neonatal rat cardiomyocytes. Following these experiments, L6 muscle cells were stimulated with ATR-127 to assess the impact on GLUT4-mediated glucose uptake and intramyocellular cAMP accumulation. Additionally, in vitro, and in vivo assessments are conducted to measure ATR-127's effects on BAT glucose uptake and thermogenesis. Finally, diet-induced obese mice were treated with 5 mg/kg ATR-127 for 21 days to investigate the effects on glucose homeostasis, body weight, fat mass, skeletal muscle glucose uptake, BAT thermogenesis and hepatic steatosis. ResultsExposure of L6 muscle cells to ATR-127 robustly enhanced GLUT4-mediated glucose uptake despite low intramyocellular cAMP accumulation. Similarly, ATR-127 markedly increased BAT glucose uptake and thermogenesis both in vitro and in vivo. Prolonged treatment of diet-induced obese mice with ATR-127 dramatically improved glucose homeostasis, an effect accompanied by decreases in body weight and fat mass. These effects were paralleled by an enhanced skeletal muscle glucose uptake, BAT thermogenesis, and improvements in hepatic steatosis. ConclusionsOur results demonstrate that ATR-127 is a highly effective, novel β2- and β3-ARs agonist holding great therapeutic promise for the treatment of obesity and its comorbidities, whilst potentially limiting cardiovascular complications. As such, the therapeutic effects of ATR-127 should be investigated in more detail in clinical studies.

Quantification and interpretation of postprandial whole-body protein metabolism using stable isotope methodology: a narrative review.

Stable isotopes are routinely applied to determine the impact of factors such as aging, disease, exercise, and feeding on whole-body protein metabolism. The most common approaches to quantify whole-body protein synthesis, breakdown, and oxidation rates and net protein balance are based on the quantification of plasma amino acid kinetics. In the postabsorptive state, plasma amino acid kinetics can easily be assessed using a constant infusion of one or more stable isotope labeled amino acid tracers. In the postprandial state, there is an exogenous, dietary protein-derived amino acid flux that needs to be accounted for. To accurately quantify both endogenous as well as exogenous (protein-derived) amino acid release in the circulation, the continuous tracer infusion method should be accompanied by the ingestion of intrinsically labeled protein. However, the production of labeled protein is too expensive and labor intensive for use in more routine research studies. Alternative approaches have either assumed that 100% of exogenous amino acids are released in the circulation or applied an estimated percentage based on protein digestibility. However, such estimations can introduce large artifacts in the assessment of whole-body protein metabolism. The preferred estimation approach is based on the extrapolation of intrinsically labeled protein-derived plasma bioavailability data obtained in a similar experimental design setting. Here, we provide reference data on exogenous plasma amino acid release that can be applied to allow a more accurate routine assessment of postprandial protein metabolism. More work in this area is needed to provide a more extensive reference data set.