npj Metabolic Health and Disease最新文献

MASH is a leading cause of liver transplantation. Here, we investigated formoterol, a long-acting β2 adrenergic receptor agonist (LABA), in MASH. Mice treated with a high-fat diet (HFD) for sixteen weeks developed liver steatosis and were treated with formoterol or vehicle for four weeks. Steatosis largely resolved following formoterol treatment. To investigate mechanism, we evaluated mitochondrial biogenesis and found in HFD mice treated with formoterol versus vehicle that: PGC1α levels and electron transport chain components were significantly higher; mitochondrial number was increased; and lipids were decreased. Human HepaRG liver cells were then exposed to free fatty acids and/or formoterol. Formoterol attenuated lipid accumulation and increased ATP-linked basal and maximal respiration. Finally, a retrospective analysis of 59,644 patients with MASH showed that patients taking LABAs had fewer complications of advanced liver disease and lower mortality. Together, these data raise the possibility that LABAs, especially formoterol, could be a novel MASH treatment.

Chronic elevations in interleukin-6 (IL6) signaling have been shown to exacerbate features of cardiometabolic disease. A common variant in the IL6 promoter (location -174 G/C, identifier rs1800795) is associated with increased circulating IL6, and increased cardiometabolic disease incidence in some populations. This study's objective was to isolate the impact of this gene variant on cardiometabolic responses to metabolic stress, using knock-in mice with a GG wildtype or variant CC genotype for the murine homolog of rs1800795. Male and female IL6 variant CC mice on a high fat diet exhibited enhanced systemic IL6 levels but similar weight gain, energy expenditure, adipose tissue inflammation, glucose homeostasis, and cardiac function relative to control GG mice. Sex differences in the effect of the IL6 variant on cardiomyocyte dimensions were observed, with male variant mice exhibiting smaller cardiomyocyte volume, and female variant mice exhibiting larger cardiomyocyte volume with smaller raw heart mass relative to control GG mice. These findings suggest that, in a controlled experimental setting, the IL6 promoter variant (-174 G/C) does not increase susceptibility to cardiometabolic disease. Further work is required to understand the mechanistic link between this IL6 variant and associated increased cardiometabolic risk observed in population studies.

Exercise responses vary widely among individuals, yet the biological basis of this variability remains poorly understood. Microbiota-derived metabolites operate on timescales of hours to days, making them insufficient to explain rapid gastrointestinal and performance changes that emerge within minutes of exercise. We propose that the enteric nervous system (ENS) fills this regulatory gap by integrating mechanical, immune, and microbial signals in real time. We review evidence that the ENS modulates gut motility, barrier function, and microbial ecology during exercise, engages in bidirectional crosstalk with the microbiota, and relays gut-derived signals to muscle and brain via neural and humoral routes. We further introduce the concept of neuro-enteric phenotypes to account for inter-individual differences in exercise tolerance and adaptation.

Recent evidence has highlighted the importance of employing culture media designed to emulate the metabolic environment cells would be exposed to in vivo. Here, we utilize the physiologic medium Plasmax to examine the impact of nutrient availability on the human hepatocyte cell line, HepG2. Incubation of HepG2 cells in Plasmax suppressed a transcriptional program driven by Hepatocyte Nuclear Factor 4 (HNF4A), a master regulator of hepatocyte identity, leading to a dedifferentiated phenotype. Given that HepG2 cells were originally isolated from a patient with hepatoblastoma, this suggested reversion to the native state in physiologic medium. Importantly, exclusion of iron from Plasmax reinstated the HNF4A-driven transcriptional program. These studies suggest a relationship between iron availability and the fidelity of hepatocyte cell fate and highlight the importance of more faithfully recapitulating in vivo metabolite availability in vitro.

There is growing evidence that lifestyle habits influence neurodegenerative disease risk. Dietary strategies and exercise are among the most important lifestyle approaches to promote brain health. This review highlights the primary mechanisms by which three dietary approaches (metabolic switching, calorie restriction, high diet quality) and exercise may promote neuroprotection and inhibit neurodegeneration. Neuroprotective mechanisms induced by a healthful lifestyle include reduced inflammation, increased autophagy, neurogenesis, decreased neuronal cell death, and attenuation of pathological protein burden.

Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by hepatocellular injury, macrophage activation, and severe fibrosis, and often progresses to liver cirrhosis and hepatocellular carcinoma. Excessive accumulation of visceral fat exacerbates hepatic inflammation and fibrosis independently of fatty liver, but the underlying molecular mechanisms have remained unclear. We here identify MFG-E8 (milk fat globule-EGF8) as a secreted protein that is overexpressed in adipose tissue of obese mice and contributes to such exacerbation. MFG-E8 deficiency in MASH model (STAM-MASH) mice was associated with reduced hepatic expression of inflammation- and fibrosis-related genes without attenuation of steatosis. Conversely, MFG-E8 supplementation in MFG-E8 knockout mice intensified hepatic inflammation and promoted the formation of hepatic crownlike structures. Coculture of macrophages with apoptotic hepatocytes induced expression of inflammatory cytokine genes, and this effect was enhanced by the presence of exogenous MFG-E8 in the culture medium. Our findings suggest that adipose tissue-derived MFG-E8 infiltrates the liver and promotes macrophage-hepatocyte interaction, thereby contributing to hepatic inflammation and fibrosis in MASH.

Developing cells undergo extensive metabolic adaptations to support growth and differentiation. Here, using spatially resolved mass spectrometry imaging and stable isotope tracing, we systematically investigate metabolic remodeling in mouse brains at postnatal day 14 and day 28, a period coinciding with the transition from a maternal milk diet to solid food. Untargeted metabolomics reveals global shifts in lipid composition, and region-specific remodeling of central energy metabolism, including increased glycolytic intermediates in grey matter-enriched regions and a global decrease in tricarboxylic acid (TCA) cycle metabolites after weaning. Despite these marked changes in metabolite levels, the glucose incorporation rate remains constant across these developmental stages. Notably, weaning mice onto a milk-replacement diet demonstrates that the observed metabolic adaptations are largely diet-independent. Together, our data suggest that postnatal brain metabolic remodeling is an intrinsically programmed feature of maturation providing region-specific metabolic reorganization to support developmental demands.

Certain metabolic enzymes localize to the nucleus, where they perform regulatory functions that extend far beyond canonical metabolism. Once inside, they influence chromatin organization, transcription, DNA repair, and cell cycle progression. This review summarizes recent advances that redefine metabolism as a nuclear process and reshape our understanding of metabolic regulation. It further defines the emerging hallmarks of nuclear metabolism and discusses how these insights open new avenues for cancer therapies.

Obesity remains the most common risk factor for cardiovascular disease in Western nations. While considerable effort has focused on identifying risk factors, which contribute to the increase incidence of complications and disease, an emerging concept is the existence of resilience factors, which mitigate disease. An important resilience factor gaining increased appreciation is the amount of skeletal muscle mass. In this review, we will explore how obesity increases the most-identified vascular component of metabolic vascular disease - endothelial dysfunction-how increases in muscle mass may protect vascular function in the obese population. This review advances the concept the obesity is less a disease of body mass than body composition which is reflected in the degree of negative vascular outcomes and may be of increased relevance in consideration of therapies that promote loss of muscle mass while reducing overall body size.