American journal of physiology. Endocrinology and metabolism最新文献

Physical activity and exercise are widely recognized as effective ways to promote physical fitness and prevent disease; however, their underlying molecular mechanisms remain to be fully elucidated. Within the last few years, the discovery of lactylation has propelled the well-known exercise metabolite lactate into the scientific spotlight. As the end product of glycolysis, lactate was initially considered to be a "metabolic waste" leading to muscle fatigue; however, subsequent studies have demonstrated the importance of lactate as an energy substrate and a signal transduction molecule to coordinate various physiological processes. Importantly, the novel posttranslational modification, lactylation, establishes a bridge between lactate and epigenetics, and provides new perspectives for understanding the role of lactate in exercise-mediated health promotion. Although some recent evidence in rodents suggests that exercise increases protein lactylation, there are mixed findings in this area, with limited human studies showing no effects. This review summarizes current knowledge of exercise-mediated lactylation, why mixed findings in the literature may exist, and suggests future research that can add further clarity to this area of molecular biology.

Early complete weaning may increase the risk of developing metabolic diseases. This study investigated whether early complete weaning in mice leads to the development of steatosis. Institute of Cancer Research (ICR) mouse male pups were weaned at 17 days [early complete weaning (EW)] or 21 days [normal complete weaning (NW)] and subsequently fed the AIN93G diet until 32 weeks of age. We measured the diameter of lipid droplets, primary metabolites, protein expression related to phospholipid synthesis, and histone modifications of the Pemt in the liver. The lipid droplet diameter was larger in EW mice than in NW mice. A set of phosphatidylcholine (PC) species, particularly PC(38:6), demonstrated lower mRNA and protein expression of Pemt and methylenetetrahydrofolate reductase, as well as decreased primary metabolites related to S-adenosylmethionine/choline, and a reduction in an antioxidative marker in EW mice. Moreover, histone methylation (H3K4 tri-methyl and H3K36 di-/tri-methyl) and acetylation around Pemt were also lower in these mice. The steatosis development due to early complete weaning in mice is closely and positively associated with a reduced amount of PC.NEW & NOTEWORTHY The development of steatosis due to early complete weaning in mice is closely positively associated with a reduced amount of PC and related metabolites, transcriptome changes including Pemt, and alterations in histone modifications around Pemt.

Obesity and diabetes are interlinked diseases, but it was unclear how obesity vs. diabetes modifies the risk and severity of gut bacterial infection. We aimed to determine how obesity or hyperglycemia, indicative of diabetes, altered metabolic endotoxemia and severity of enteric infection. Metabolic endotoxemia was determined using TLR4 activity reporter assay in serum from humans with obesity or diabetes, and from hyperglycemic Akita^+/- mice and genetically obese ob/ob mice. Diarrhea severity during Escherichia coli infection was determined in humans during a previous community outbreak. The enteropathogen Citrobacter rodentium was used to define the mechanisms of action that altered the severity of enteric infection in ob/ob and Akita^+/- mice. We found that elevated blood glucose, indicative of diabetes, was associated with increased occurrence and severity of diarrhea during an E. coli outbreak in humans. Metabolic endotoxemia occurred in a separate cohort of people with obesity who were normoglycemic or hyperglycemic, and in mice with either obesity or hyperglycemia. Hyperglycemia, not obesity, increased mortality during infection with the diarrhea-causing pathogen C. rodentium in mouse models of type 1 and type 2 diabetes. Common indicators of poor prognosis, such as gut pathology, systemic bacteraemia, or metabolic endotoxemia, did not predict worse outcomes during enteric infection in diabetic mice. Hyperglycemia activated intestinal Wnt/β-catenin and increased mortality, which could be reversed by blocking Wnt/β-catenin, lowering blood glucose, or restoring fluid balance during infection. The increased severity of infection via overactivation of intestinal Wnt/β-catenin during hyperglycemia may be a potential target for therapeutics.NEW & NOTEWORTHY We show that elevated blood glucose is associated with worse diarrhea during an Escherichia coli outbreak in humans. Obesity or hyperglycemia was sufficient to promote metabolic endotoxemia in humans and mice. Hyperglycemia promotes worse enteric infection outcomes independent of obesity. Finally, we showed that blocking of Wnt/β-catenin, lowering blood glucose, or restoring fluids improved enteric infection outcomes in hyperglycemic mice.

We aimed to evaluate the role of central leucine administration in the modulation of peripheral energy metabolism in fish. For this, rainbow trout (Oncorhynchus mykiss) were administered via intracerebroventricular 1 μL·100 g^-1 body mass of saline solution alone (Control) or containing 10 μg·μL^-1 of leucine. Samples of plasma, liver, adipose tissue, white muscle, and red muscle were collected 1- and 3-h postinjection. Firstly, metabolite levels were assessed in plasma and liver and a decrease in liver triglyceride at 1 h and an increase in plasma fatty acid at 3 h were observed. Metabolites levels were also assessed in white muscle, revealing decreased levels of α-amino acids and glycogen at 1 h. In addition, liver enzymatic activity and mRNA levels related to glucose, fatty acid, and amino acid metabolism showed no relevant changes. Then, energy metabolism in adipose tissue and muscle was assessed by examining the mRNA abundance of genes related to metabolism and oxidative capacity, thermogenesis, mitochondrial dynamics (mitochondrial fusion and fission), and other metabolic regulatory factors. Mitochondrial fusion was significantly influenced at 1-h postinjection in white muscle (upregulation of mfn1, mfn2, tfam, and opa1) and to a lesser extent in red muscle (upregulation of tfam). These findings differ from studies in mammals with leucine and in fish with other nutrients, in which liver metabolism is modulated. This also highlights the importance of leucine and its relationship with muscle and mitochondrial dynamics in controlling energy homeostasis in fish.NEW & NOTEWORTHY We studied how central leucine administration affects peripheral energy metabolism in rainbow trout. No significant changes were found in liver metabolism, differing from mammalian comparable studies and from changes in hypothalamic energy status elicited by other nutrients in fish. Mitochondrial fusion was notably influenced in white muscle and to a lesser extent in red muscle. These findings highlight the unique role of leucine in the maintenance of energy homeostasis in fish.

Thermogenic adipose tissue, specialized in dissipating chemical energy as heat, represents a promising therapeutic target for combating obesity and type 2 diabetes. S100A8/S100A9 is an inflammatory alarmin and biomarker implicated in various diseases, including obesity. Here, we investigated the role of S100A8/S100A9 in thermogenesis and whole-body energy homeostasis. Wild-type (WT) and S100A8/S100A9-deficient (S100a9^-/-) mice were subjected to a 14-wk high-fat diet (HFD). Thermogenic responses were assessed through cold exposure and administration of the β3-adrenergic receptor agonist CL-316,423, with additional experiments involving exogenous S100A8/S100A9 administration in WT mice. Under normal chow, S100a9^-/- mice exhibited a leaner phenotype compared with WT controls. Following HFD-induced obesity, S100a9^-/- mice displayed reduced weight gain, improved insulin sensitivity, increased lipid storage in epididymal adipose tissue, and attenuated hepatic steatosis. Physiological studies using metabolic cages revealed higher oxygen consumption and heat production in lean S100a9^-/- mice following chronic CL-316,423 treatment. In line, S100a9^-/- mice exhibited increased beiging in inguinal white adipose tissue (ingWAT), but not in brown adipose tissue (BAT), under cold exposure as well as acute and chronic CL-316,423. Conversely, exogenous S100A8/S100A9 administration under both cold challenge and chronic CL-316,423 suppressed thermogenic gene expression in ingWAT, with no significant effect in BAT. In vitro, stimulation of immortalized beige adipocytes with S100A9 led to downregulation of beige adipocyte marker genes. Collectively, these findings identify S100A8/S100A9 as a negative regulator of ingWAT beiging and energy expenditure, thereby contributing to impaired metabolic homeostasis and exacerbation of diet-induced obesity.NEW & NOTEWORTHY Obesity is a disorder characterized by disrupted energy homeostasis. During obesity, thermogenic pathways decline, making strategies that enhance energy expenditure a promising avenue for intervention. The alarmin complex S100A8/S100A9 is upregulated in both human and experimental models of obesity and type 2 diabetes. In this study, we identify a critical pathogenic role of S100A8/S100A9 in impairing thermogenesis in subcutaneous adipose tissue, reducing energy expenditure, and exacerbating obesity and its related complications.

Metabolic dysfunction-associated steatotic liver disease (MASLD) ranges from simple steatosis to hepatocellular injury, inflammation, and fibrosis, ultimately leading to end-stage liver disease. Despite its rising prevalence, treatment options remain limited, highlighting the need for novel therapeutic strategies. In recent years, ketone metabolism has emerged as a key modulator of hepatic metabolic health. Hepatic ketogenesis provides a mechanism for fatty acid mobilization. Endogenously synthesized ketone metabolites can then provide energy for hepatic nonparenchymal cells and extrahepatic tissues. Ketones also function as signaling molecules that can reduce key pathological drivers of MASLD progression. Impaired ketogenesis is observed in MASLD, contributing to metabolic inflexibility and liver dysfunction. Conversely, ketogenic interventions, including exogenous ketone supplementation and ketogenic diets, have been shown to be hepatoprotective, attenuating steatosis, inflammation, and fibrosis. Ketogenic enzyme loss- and gain-of-function studies have highlighted the roles of ketogenesis, ketolysis, and ketone metabolite conversion in MASLD, providing insights to refine keto-therapeutic strategies for disease management. This review seeks to offer a thorough examination of ketone metabolism in MASLD, exploring the mechanistic roles of ketone metabolites in disease progression, and highlighting gaps in the current literature to optimize keto-therapeutics and combat MASLD progression.

The fundamental principle of energy balance, a statement of the first law of thermodynamics, overlooks the second law, resulting in gaps in our knowledge of body weight regulation and obesity. This study develops research tools to implement nonequilibrium thermodynamics in human subjects based on a mitochondrial energy conversion model. A key advancement measures ATP phosphorylation through its relationship to the mitochondrial redox couple, beta-hydroxybutyrate, and acetoacetate. Applying this methodology in humans, utilizing data from a recent study, provides a comprehensive understanding of the impact of the second law. The results demonstrate that oxidative phosphorylation efficiency is approximately 57%, with minor but significant variations among individuals. Four out of 24 healthy subjects exhibited a sufficiently higher efficiency of oxidative phosphorylation and lower free energy dissipation compared to the remaining subjects. Feeding is associated with lower efficiency, a higher rate of free energy dissipation, and a slight reduction in coupling. The amount of energy utilized for useful work represents only one-third of resting energy expenditure. These findings are integrated with the current principle of energy balance to adhere to the constraints of the first and second laws. Based on theoretical modeling, it is demonstrated that interindividual differences and variations in mitochondrial efficiency and energy dissipation during specific metabolic conditions can lead to discrepancies between total energy balance and the balance of the fraction of energy used for useful work. Consequently, the constraints imposed by the second law should be incorporated into the current understanding of energy balance and obesity.NEW & NOTEWORTHY This article introduces the second law of thermodynamics as an integral component of the study of human energy metabolism. The concepts of efficiency and energy dissipation are unified with the current understanding of energy balance in human subjects. It is important to note that the energy utilized in biological processes constitutes only a fraction of the total energy metabolism. Measurement of this fraction relative to total energy expenditure elucidates the body's mechanisms for adapting to fuel scarcity and abundance, as exemplified by weight gain and weight loss.

Rabson-Mendenhall syndrome (RMS) is a rare autosomal recessive disorder caused by mutations in the insulin receptor gene (INSR), leading to severe insulin resistance. Clinical manifestations of RMS include hypertrichosis and acanthosis nigricans. A 3-yr-old male patient presented with darkened skin on the neck, without any apparent precipitating factors, and did not exhibit symptoms of polyuria or polydipsia. Both the patient and his older sister displayed signs of hypertrichosis and acanthosis nigricans. Laboratory investigations revealed significantly elevated levels of insulin and C-peptide. Genetic testing identified two mutations in the INSR gene: c.3614C>T in exon 20 and c.3670G>A in exon 21, with the latter being a novel mutation previously unreported in RMS. His sister also exhibited similar clinical features and harbored the same mutations. Consequently, both siblings were diagnosed with RMS. The novel mutation c.3670G>A in exon 21, inherited from the father, is likely to impair insulin receptor function by disrupting tyrosine kinase activity, thereby contributing to the pathogenesis of genealogical RMS.

Alzheimer's disease (AD), a neurodegenerative disorder characterized by progressive cognitive decline, poses an increasing global health burden among aging populations. Despite decades of research, its pathogenesis remains incompletely understood, and effective therapies are urgently needed. Growing evidence links AD progression to inflammation and type 2 diabetes mellitus (T2DM), with hyperglycemia, insulin resistance, and chronic inflammation synergistically driving neuronal dysfunction. These factors perpetuate a pathogenic "metabolic-inflammatory cycle": inflammatory cytokines disrupt insulin signaling, exacerbating insulin resistance, which further amplifies neuroinflammation. Whereas anti-inflammatory and antidiabetic drugs show limited clinical efficacy in AD, bitter compounds, natural and synthetic agents with pleiotropic bioactivities, offer a novel therapeutic avenue. Notably, bitter compounds such as the alkaloid berberine, the flavonoid naringenin, and synthetic bitter compounds such as denatonium benzoate and metformin exhibit dual anti-inflammatory and metabolic regulatory effects. Preclinical studies have demonstrated their ability to suppress neuroinflammation, restore insulin sensitivity, and mitigate amyloid/tau pathology, potentially disrupting the metabolic-inflammatory cycle. Emerging insights also highlight their modulation of the gut-brain axis, linking intestinal homeostasis to neuroprotection. This mini-review synthesizes current evidence on the interplay of T2DM and inflammation in AD, emphasizing how bitter compounds target immunometabolic cross talk. This review also briefly discusses the metabolic and anti-inflammatory properties of bitter compounds via the gut-brain axis, alongside their potential for combination with current anti-AD drugs, suggesting multidisciplinary collaboration. Further mechanistic studies and clinical validation are warranted to translate bitter compound-based therapies into practice, addressing unmet needs in AD management.