Ketogenesis protects against MASLD-MASH progression through mechanisms that extend beyond overall fat oxidation rate.

The progression of metabolic-dysfunction-associated steatotic liver disease (MASLD) to metabolic-dysfunction-associated steatohepatitis (MASH) involves complex alterations in both liver-autonomous and systemic metabolism that influence the liver's balance of fat accretion and disposal. Here, we quantify the relative contribution of hepatic oxidative pathways to liver injury in MASLD-MASH. Using NMR spectroscopy, UHPLC-MS, and GC-MS, we performed stable-isotope tracing and formal flux modeling to quantify hepatic oxidative fluxes in humans across the spectrum of MASLD-MASH, and in mouse models of impaired ketogenesis.

Gender-based heterogeneity of FAHFAs in trained runners.

Fatty acid esters of hydroxy fatty acid (FAHFA) are anti-diabetic and anti-inflammatory lipokines. Recently FAHFAs were also found to predict cardiorespiratory fitness in a cross-sectional study of recreationally trained runners. Here we report the influences of body composition and gender on static FAHFA abundances in circulation.

Disruption of hepatic mitochondrial pyruvate and amino acid metabolism impairs gluconeogenesis and endurance exercise capacity in mice.

Exercise robustly increases the glucose demands of skeletal muscle. This demand is met by not only muscle glycogenolysis but also accelerated liver glucose production from hepatic glycogenolysis and gluconeogenesis to fuel mechanical work and prevent hypoglycemia during exercise. Hepatic gluconeogenesis during exercise is dependent on highly coordinated responses within and between muscle and liver.

Exercise training adaptations in liver glycogen and glycerolipids require hepatic AMP-activated protein kinase in mice.

Regular exercise elicits adaptations in glucose and lipid metabolism that allow the body to meet energy demands of subsequent exercise bouts more effectively and mitigate metabolic diseases including fatty liver. Energy discharged during the acute exercise bouts that comprise exercise training may be a catalyst for liver adaptations. During acute exercise, liver glycogenolysis and gluconeogenesis are accelerated to supply glucose to working muscle.

Elevated liver glycogenolysis mediates higher blood glucose during acute exercise in Barth syndrome.

Unlabelled: Barth syndrome (BTHS) is an X-linked recessive genetic disorder due to mutations in the Tafazzin (TAFAZZIN) gene that lead to cardiac and skeletal muscle mitochondrial dysfunction. Previous studies in humans with BTHS demonstrate that the defects in muscle mitochondrial oxidative metabolism result in an enhanced reliance on anaerobic metabolism during exercise to meet energy demands of muscular work. During exercise, the liver normally increases glucose production via glycogenolysis and gluconeogenesis to match the elevated rate of muscle glucose uptake and meet the ATP requirements of working muscle.

Gender-based heterogeneity of FAHFAs in trained runners.

Fatty acid esters of hydroxy fatty acid (FAHFA) are anti-diabetic and anti-inflammatory lipokines. Recently FAHFAs were also found to predict cardiorespiratory fitness in trained runners. Here we compared the association between circulating FAHFA baseline concentrations and body composition, determined by dual x-ray absorptiometry, in female runners who were lean (BMI < 25 kg/m, n = 6), to those who were overweight (BMI ≥ 25 kg/m, n = 7).

Identification of alkaline-induced thiolyl-chlorogenic acid conjugates with cysteine and glutathione.

Alkaline reactions of chlorogenic acid (CGA) yield undesirable development of brown or green pigments, limiting the utilization of alkalized CGA-rich foods. Thiols such as cysteine and glutathione mitigate pigment formation through several mechanisms, including redox coupling to reduce CGA quinones, and thiol conjugation, which forms colorless thiolyl-CGA compounds that do not readily participate in color-generating reactions. This work provided evidence of the formation of both aromatic and benzylic thiolyl-CGA conjugate species formed with cysteine and glutathione under alkaline conditions in addition to hydroxylated conjugate species hypothesized to arise from reactions with hydroxyl radicals.

Mitochondrial citrate metabolism and efflux regulate BeWo differentiation.

Cytotrophoblasts fuse to form and renew syncytiotrophoblasts necessary to maintain placental health throughout gestation. During cytotrophoblast to syncytiotrophoblast differentiation, cells undergo regulated metabolic and transcriptional reprogramming. Mitochondria play a critical role in differentiation events in cellular systems, thus we hypothesized that mitochondrial metabolism played a central role in trophoblast differentiation.

Cardiovascular and Pulmonary Responses to Acute Use of Electronic Nicotine Delivery Systems and Combustible Cigarettes in Long-Term Users.

Background: The acute cardiovascular and pulmonary effects of contemporary electronic nicotine delivery systems (ENDS) in long-term users are not known.

Research Question: What are the cardiovascular and pulmonary responses to an acute 15-min product use challenge with ENDS and combustible cigarettes in regular nicotine-containing product users compared with control participants who do not use tobacco or vape?

Study Design And Methods: Observational challenge study before and after nicotine-containing product use of 395 individuals who used ENDS exclusively (n = 164; exhaled carbon monoxide level, < 5 parts per million [ppm]; positive urine NicCheck I [Mossman Associates] results, 82%; fourth-generation ENDS), participants who smoked cigarettes exclusively (n = 117; carbon monoxide level, > 5 ppm; positive urine NicCheck I results), and control participants (n = 114; carbon monoxide level, < 5 ppm; negative urine NicCheck I results).

Results: During the 15-min product challenge, cigarette users took a median of 14.

Mitochondrial citrate metabolism and efflux regulates trophoblast differentiation.

Cytotrophoblasts fuse to form and renew syncytiotrophoblasts necessary to maintain placental health throughout gestation. During cytotrophoblast to syncytiotrophoblast differentiation, cells undergo regulated metabolic and transcriptional reprogramming. Mitochondria play a critical role in differentiation events in cellular systems, thus we hypothesized that mitochondrial metabolism played a central role in trophoblast differentiation.

Loss of hepatic phosphoenolpyruvate carboxykinase 1 dysregulates metabolic responses to acute exercise but enhances adaptations to exercise training in mice.

Acute exercise increases liver gluconeogenesis to supply glucose to working muscles. Concurrently, elevated liver lipid breakdown fuels the high energetic cost of gluconeogenesis. This functional coupling between liver gluconeogenesis and lipid oxidation has been proposed to underlie the ability of regular exercise to enhance liver mitochondrial oxidative metabolism and decrease liver steatosis in individuals with nonalcoholic fatty liver disease.

Integrating the contributions of mitochondrial oxidative metabolism to lipotoxicity and inflammation in NAFLD pathogenesis.

The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing globally. NAFLD includes non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH). NASH is the pathological form of the disease characterized by liver steatosis, inflammation, cell injury, and fibrosis.

Artifactual FA dimers mimic FAHFA signals in untargeted metabolomics pipelines.

FA esters of hydroxy FAs (FAHFAs) are lipokines with extensive structural and regional isomeric diversity that impact multiple physiological functions, including insulin sensitivity and glucose homeostasis. Because of their low molar abundance, FAHFAs are typically quantified using highly sensitive LC-MS/MS methods. Numerous relevant MS databases house in silico-spectra that allow identification and speciation of FAHFAs.

Acute aerobic exercise reveals that FAHFAs distinguish the metabolomes of overweight and normal-weight runners.

BackgroundResponses of the metabolome to acute aerobic exercise may predict maximum oxygen consumption (VO2max) and longer-term outcomes, including the development of diabetes and its complications.MethodsSerum samples were collected from overweight/obese trained (OWT) and normal-weight trained (NWT) runners prior to and immediately after a supervised 90-minute treadmill run at 60% VO2max (NWT = 14, OWT = 11) in a cross-sectional study. We applied a liquid chromatography high-resolution-mass spectrometry-based untargeted metabolomics platform to evaluate the effect of acute aerobic exercise on the serum metabolome.

Grayscale Ultrasound Texture Features of Carotid and Brachial Arteries in People With HIV Infection Before and After Antiretroviral Therapy.

Background We aimed to investigate novel grayscale ultrasound characteristics of the carotid and brachial arteries in people with HIV infection before and after starting initial antiretroviral therapy (ART). Methods and Results We performed grayscale ultrasound image analyses of the common carotid artery (CCA) and brachial artery before and after receipt of 1 of 3 randomly allocated ART regimens. We measured arterial wall echogenicity (grayscale median), contrast (gray-level difference statistic method), and entropy.

Disrupted liver oxidative metabolism in glycine N-methyltransferase-deficient mice is mitigated by dietary methionine restriction.

Objective: One-carbon metabolism is routinely dysregulated in nonalcoholic fatty liver disease. This includes decreased glycine N-methyltransferase (GNMT), a critical regulator of s-adenosylmethionine (SAM). Deletion of GNMT in mice increases SAM and promotes liver steatosis.

Regulation and role of glycophagy in skeletal muscle energy metabolism.

Glycophagy is the autophagic degradation of glycogen via the lysosomal enzyme GAA/alpha-acid glucosidase. Glycophagy is considered a housekeeping process to degrade poorly branched glycogen particles, but the regulation and role of glycophagy in skeletal muscle metabolism remains enigmatic. Herein, prior muscle contraction promoted glycogen supercompensation 24 and 48 h post contraction, an effect associated with reduced glycophagy.

Multitissue 2H/13C flux analysis reveals reciprocal upregulation of renal gluconeogenesis in hepatic PEPCK-C-knockout mice.

The liver is the major source of glucose production during fasting under normal physiological conditions. However, the kidney may also contribute to maintaining glucose homeostasis in certain circumstances. To test the ability of the kidney to compensate for impaired hepatic glucose production in vivo, we developed a stable isotope approach to simultaneously quantify gluconeogenic and oxidative metabolic fluxes in the liver and kidney.

Reciprocity Between Skeletal Muscle AMPK Deletion and Insulin Action in Diet-Induced Obese Mice.

Insulin resistance due to overnutrition places a burden on energy-producing pathways in skeletal muscle (SkM). Nevertheless, energy state is not compromised. The hypothesis that the energy sensor AMPK is necessary to offset the metabolic burden of overnutrition was tested using chow-fed and high-fat (HF)-fed SkM-specific AMPKα1α2 knockout (mdKO) mice and AMPKα1α2lox/lox littermates (wild-type [WT]).

Perfusion controls muscle glucose uptake by altering the rate of glucose dispersion in vivo.

These studies test, using intravital microscopy (IVM), the hypotheses that perfusion effects on insulin-stimulated muscle glucose uptake (MGU) are ) capillary recruitment independent and ) mediated through the dispersion of glucose rather than insulin. For , capillary perfusion was visualized before and after intravenous insulin. No capillary recruitment was observed.

Pyruvate Carboxylase Wields a Double-Edged Metabolic Sword.

Pyruvate carboxylase-mediated anaplerosis is a well-known regulator of gluconeogenesis. In this issue of Cell Metabolism, Cappel et al. (2019) show that pyruvate carboxylase action has far-reaching roles in metabolic homeostasis as it integrates glucose metabolism with tricarboxylic acid cycle flux, ureagenesis, redox potential, and defense against oxidative stress.

Iatrogenic Hyperinsulinemia, Not Hyperglycemia, Drives Insulin Resistance in Type 1 Diabetes as Revealed by Comparison With GCK-MODY (MODY2).

Although insulin resistance consistently occurs with type 1 diabetes, its predominant driver is uncertain. We therefore determined the relative contributions of hyperglycemia and iatrogenic hyperinsulinemia to insulin resistance using hyperinsulinemic-euglycemic clamps in three participant groups ( = 10/group) with differing insulinemia and glycemia: healthy control subjects (euinsulinemia and euglycemia), glucokinase-maturity-onset diabetes of the young (GCK-MODY; euinsulinemia and hyperglycemia), and type 1 diabetes (hyperinsulinemia and hyperglycemia matching GCK-MODY). We assessed the contribution of hyperglycemia by comparing insulin sensitivity in control and GCK-MODY and the contribution of hyperinsulinemia by comparing GCK-MODY and type 1 diabetes.