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It has been hypothesized that insulin resistance is mediated by a deficiency of mitochondria in skeletal muscle. In keeping with this hypothesis, high-fat diets that cause insulin resistance have been reported to result in a decrease in muscle mitochondria. In contrast, we found that feeding rats high-fat diets that cause muscle insulin resistance results in a concomitant gradual increase in muscle mitochondria. This adaptation appears to be mediated by activation of peroxisome proliferator-activated receptor (PPAR)δ by fatty acids, which results in a gradual, posttranscriptionally regulated increase in PPAR γ coactivator 1α (PGC-1α) protein expression. Similarly, overexpression of PPARδ results in a large increase in PGC-1α protein in the absence of any increase in PGC-1α mRNA. We interpret our findings as evidence that raising free fatty acids results in an increase in mitochondria by activating PPARδ, which mediates a posttranscriptional increase in PGC-1α. Our findings argue against the concept that insulin resistance is mediated by a deficiency of muscle mitochondria.

Insulin resistance is a significant contributor to the development of type 2 diabetes (T2D) and is associated with obesity, physical inactivity, and low maximal oxygen uptake. While intense and prolonged exercise may have negative effects, physical activity can have a positive influence on cellular metabolism and the immune system. Moderate exercise has been shown to reduce oxidative stress and improve antioxidant status, whereas intense exercise can increase oxidative stress in the short term. The impact of exercise on pro‐inflammatory cytokine production is complex and varies depending on intensity and duration. Exercise can also counteract the harmful effects of ageing and inflamm‐ageing. This review aims to examine the molecular pathways altered by exercise in non‐obese individuals at higher risk of developing T2D, including glucose utilization, lipid metabolism, mitochondrial function, inflammation and oxidative stress, with the potential to improve insulin sensitivity. The focus is on understanding the potential benefits of exercise for improving insulin sensitivity and providing insights for future targeted interventions before onset of disease.

Summary Identification of mechanisms underlying physical function will be important for addressing the growing challenge that health care will face with physical disablement in the expanding aging population. Therefore, the goals of the current study were to use metabolic profiling to provide insight into biologic mechanisms that may underlie physical function by examining the association between baseline and the 6‐month change in serum mass spectrometry‐obtained amino acids, fatty acids, and acylcarnitines with baseline and the 6‐month change in muscle strength (leg press one repetition maximum divided by total lean mass, LP/Lean), lower extremity function [short physical performance battery (SPPB)], and mobility (400 m gait speed, 400‐m), in response to 6 months of a combined resistance exercise and nutritional supplementation (whey protein or placebo) intervention in functionally‐limited older adults (SPPB ≤ 10; 70–85 years, N = 73). Metabolites related to gut bacterial metabolism (cinnamoylglycine, phenol sulfate, p‐cresol sulfate, 3‐indoxyl sulfate, serotonin, N‐methylproline, hydrocinnamate, dimethylglycine, trans‐urocanate, valerate) that are altered in response to peroxisome proliferator‐activated receptor‐alpha (PPAR‐α) activation (α‐hydroxyisocaproate, α‐hydroxyisovalerate, 2‐hydroxy‐3‐methylvalerate, indolelactate, serotonin, 2‐hydroxypalmitate, glutarylcarnitine, isobutyrylcarnitine, cinnamoylglycine) and that are related to insulin sensitivity (monounsaturated fatty acids: 5‐dodecenoate, myristoleate, palmitoleate; γ‐glutamylamino acids: γ‐glutamylglutamine, γ‐glutamylalanine, γ‐glutamylmethionine, γ‐glutamyltyrosine; branched‐chain amino acids: leucine, isoleucine, valine) were associated with function at baseline, with the 6‐month change in function or were identified in backward elimination regression predictive models. Collectively, these data suggest that gut microbial metabolism, PPAR‐α activation, and insulin sensitivity may be involved in mechanisms that underlie physical function in functionally‐limited older adults.

Sepsis‐associated acute kidney injury (AKI) is a significant problem in critically ill children and adults resulting in increased morbidity and mortality. Fundamental mechanisms contributing to sepsis‐associated AKI are poorly understood. Previous research has demonstrated that peroxisome proliferator‐activated receptor α (PPARα) expression is associated with reduced organ system failure in sepsis. Using an experimental model of polymicrobial sepsis, we demonstrate that mice deficient in PPARα have worse kidney function, which is likely related to reduced fatty acid oxidation and increased inflammation. Ultrastructural evaluation with electron microscopy reveals that the proximal convoluted tubule is specifically injured in septic PPARα deficient mice. In this experimental group, serum metabolomic analysis reveals unanticipated metabolic derangements in tryptophan‐kynurenine‐NAD+ and pantothenate pathways. We also show that a subgroup of children with sepsis whose genome‐wide expression profiles are characterized by repression of the PPARα signaling pathway has increased incidence of severe AKI. These findings point toward interesting associations between sepsis‐associated AKI and PPARα‐driven fatty acid metabolism that merit further investigation. Sepsis‐associated acute kidney injury (SA‐AKI) is a significant problem in the critically ill children. Using a mouse model of sepsis, we show that expression of PPARα, a nuclear hormone receptor transcription factor that regulates fatty acid oxidation and inflammation, protects against the development of SA‐AKI and other metabolic derangements. We also show that children with septic shock whose genome‐wide expression profiles are characterized by decreased PPARα expression have greater incidence of SA‐AKI, which points toward the exciting possibility of treating this condition with clinically available PPARα agonists.

Leucine modulates synthetic and degradative pathways in muscle, possibly providing metabolic benefits for both athletes and diseased populations. Leucine has become popular among athletes for improving performance and body composition, however little is known about the metabolic effects of the commonly consumed leucine-derived metabolite β-hydroxy-β-methyl butyrate (HMB). Our work measured the effects of HMB on metabolic protein expression, mitochondrial content and metabolism, as well as lipid content in skeletal muscle cells. Specifically, cultured C2C12 myotubes were treated with either a control or HMB ranging from 6.25 to 25 μM for 24 h and mRNA and/or protein expression, oxygen consumption, glucose uptake, and lipid content were measured. Contrary to leucine’s stimulatory effect on metabolism, HMB-treated cells exhibited significantly reduced regulators of lipid oxidation including peroxisome proliferator-activated receptor alpha (PPARα) and PPARβ/δ, as well as downstream target carnitine palmitoyl transferase, without alterations in glucose or palmitate oxidation. Furthermore, HMB significantly inhibited activation of the master regulator of energetics, AMP-activated protein kinase. As a result, HMB-treated cells also displayed reduced total mitochondrial content compared with true control or cells equivocally treated with leucine. Additionally, HMB treatment amplified markers of lipid biosynthesis (PPARγ and fatty acid synthase) as well as consistently promoted elevated total lipid content versus control cells. Collectively, our results demonstrate that HMB did not improve mitochondrial metabolism or content, and may promote elevated cellular lipid content possibly through heightened PPARγ expression. These observations suggest that HMB may be most beneficial for populations interested in stimulating anabolic cellular processes.

ABSTRACT Fibrotic disease involves excessive fibrous connective tissue accumulation in organs, leading to dysfunction and irreversible damage. Metabolic alterations can sometimes contribute to fibrosis development. This study aimed to develop dual agonists for farnesoid X receptor (FXR) and peroxisome proliferator‐activated receptor alpha (PPARα), targeting anti‐fibrosis and metabolic regulation. Benzoxazole derivatives were found to potently activate both FXR and PPARα in hepatocytes. Among them, MHY5396 showed the most potent effects with low EC50 values. MHY5396 reduced lipid synthesis and enhanced beta‐oxidation in hepatocytes, decreasing lipid accumulation. It also suppressed TGFβ‐induced fibrosis in hepatic stellate cells. In a methionine/choline‐deficient diet mouse model, MHY5396 reduced lipid accumulation, liver damage, and fibrosis. In a thioacetamide‐induced liver fibrosis model, MHY5396 had an anti‐fibrotic effect comparable to obeticholic acid, a potent FXR agonist. MHY5396 also significantly reduced inflammation and fibrosis in renal cells and a folic acid‐induced renal fibrosis mouse model. Pharmacokinetic studies showed that orally administered MHY5396 was well absorbed (F = 98.6%) and primarily metabolized by hepatic CYP1A2 with negligible urinary excretion. Overall, MHY5396, with dual FXR and PPARα agonist activity, exhibited significant anti‐fibrotic and metabolic regulatory properties in liver and kidney fibrosis models, presenting a novel therapeutic potential for fibrotic diseases. MHY5396, a benzoxazole derivative, functions as a potent dual FXR and PPARα agonist. It exhibits significant anti‐fibrotic and metabolic regulatory effects, effectively improving liver and kidney fibrosis in experimental models. These findings highlight its potential as a therapeutic candidate for fibrosis and metabolic disorders.

Summary Aims Prenatal maternal immune activation (MIA) is associated with a risk to develop schizophrenia and affects dopamine systems in the ventral tegmental area (VTA), key region in the neurobiology of psychoses. Considering the well‐described sex differences in schizophrenia, we investigated whether sex affects MIA impact on dopamine system and on schizophrenia‐related behavioral phenotype. Furthermore, considering peroxisome proliferator‐activated receptor‐α (PPARα) expression in the CNS as well as its anti‐inflammatory and neuroprotective properties, we tested if PPARα activation by prenatal treatment with a clinically available fibrate (fenofibrate) may mitigate MIA‐related effects. Methods We induced MIA in rat dams with polyriboinosinic‐polyribocytidylic acid (Poly I:C) and assessed prepulse inhibition and dopamine neuron activity in the VTA by means of electrophysiological recordings in male and female preweaned and adult offspring. Results Poly I:C‐treated males displayed prepulse inhibition deficits, reduced number and firing rate of VTA dopamine neurons, and paired‐pulse facilitation of inhibitory and excitatory synapses. Prenatal fenofibrate administration attenuated detrimental effects induced by MIA on both the schizophrenia‐like behavioral phenotype and dopamine transmission in male offspring. Conclusion Our study confirms previous evidence that females are less susceptible to MIA and highlights PPARα as a potential target for treatments in schizophrenia.

Spatial heterogeneity and plasticity of the mammalian liver are critical for systemic metabolic homeostasis in response to fluctuating nutritional conditions. Here, a spatially resolved transcriptomic landscape of mouse livers across fed, fasted and refed states using spatial transcriptomics is generated. This approach elucidated dynamic temporal‐spatial gene cascades and how liver zonation—both expression levels and patterns—adapts to shifts in nutritional status. Importantly, the pericentral nuclear receptor Nr1i3 (CAR) as a pivotal regulator of triglyceride metabolism is pinpointed. It is showed that the activation of CAR in the pericentral region is transcriptionally governed by Pparα. During fasting, CAR activation enhances lipolysis by upregulating carboxylesterase 2a, playing a crucial role in maintaining triglyceride homeostasis. These findings lay the foundation for future mechanistic studies of liver metabolic heterogeneity and plasticity in response to nutritional status changes, offering insights into the zonated pathology that emerge during liver disease progression linked to nutritional imbalances. Spatial transcriptomics reveals how mouse liver zonation adapts to nutritional changes, highlighting the pericentral nuclear receptor CAR as a key regulator of triglyceride metabolism. CAR activation, transcriptionally governed by PPARα, enhances lipolysis during fasting by upregulating carboxylesterase 2a, crucial for maintaining triglyceride homeostasis. This study provides insights into the liver's metabolic heterogeneity and plasticity.

The modulation of peroxisome proliferator-activated receptors (PPARs), the superfamily of steroid–thyroid–retinoid nuclear receptors, is expected to induce an amazing crosstalk between energy-demanding organs. Here, we aimed to study the effects of the novel selective PPARα modulator, pemafibrate, on metabolic parameters in patients with dyslipidemia. We retrospectively studied patients who had taken pemafibrate and compared metabolic parameters at baseline with the data at 3, 6 and 12 months after the start of pemafibrate. Serum triglyceride significantly decreased and high-density lipoprotein-cholesterol significantly increased at 3, 6 and 12 months after the start of pemafibrate. Serum aspartate aminotransferase levels significantly decreased at 3 and 6 after the start of pemafibrate as compared with baseline. Serum alanine aminotransferase and gamma-glutamyl transferase significantly decreased and albumin significantly increased after 3, 6 and 12 months. HbA1c levels significantly decreased after 3 months. Further, serum uric acid significantly decreased after 12 months. Such metabolic favorable changes due to pemafibrate were significantly correlated with changes in serum lipids. In conclusion, we observed a significant improvement of liver function, HbA1c and serum uric acid along with an amelioration of dyslipidemia after the start of pemafibrate.

Assess insulin sensitivity after treatment with a selective PPAR-alpha agonist compared to an HMG CoA reductase inhibitor in human subjects with type 2 diabetes mellitus. Thirteen subjects with Type 2 diabetes mellitus were studied in a double-blind crossover design with 4-week placebo run-in and washout and 12-week treatment periods, randomised to micronised fenofibrate 267mg or atorvastatin 10mg daily followed by the alternate drug in the second period. Insulin resistance was measured using the isoglycaemic hyperinsulinaemic clamp method with isotope dilution. Weight, physical activity and other medications did not change. Total cholesterol (mean +/− standard error) was 4.60+/−0.21 versus 3.9+/−0.22mmol/L after fenofibrate and atorvastatin respectively, p<0.05. LDL was 2.70+/−0.19 versus 1.95+/−0.23mmol/L, p<0.05 and triglyceride 1.64+/−0.23 versus 1.84+/−0.26mmol/L, p<0.05. Insulin-stimulated whole-body glucose disposal (35.4+/−3.1 versus 33.2+/−3.0μmol/kg/min) and nadir endogenous glucose production (6.2+/−1.4 versus 7.0+/−1.1μmol/kg/min) revealed no significant differences in effects of the treatments. In human subjects with Type 2 diabetes mellitus there were characteristic differences in lipid profile changes but no difference in insulin sensitivity after treatment with micronised fenofibrate compared to atorvastatin. This study finds no evidence of increased insulin sensitivity using this selective PPAR-alpha agonist over a commonly used statin at these doses.