npj Metabolic Health and Disease最新文献

Low birthweight is a risk factor for hypertension and chronic kidney disease. Kidneys of low birthweight babies typically have a low nephron endowment, which is permanent. Therefore, strategies to boost or rescue nephron endowment in low birthweight offspring might be expected to decrease the prevalence of these chronic conditions. We previously reported that a high-fat diet (17% protein, 43% carbohydrate, 40% fat) fed to mice before mating and until weaning boosted nephron endowment in mice by 20%. Here, we show that offspring from dams fed a normal diet during pregnancy and switched to a high-fat diet at birth had a 14% augmented nephron endowment. Additionally, transition to a high-fat diet at birth completely rescued a 20% nephron deficit induced by feeding dams a low-protein diet (8% protein, 76% carbohydrate, 16% fat) during gestation. The augmentation and rescue of nephron endowment were associated with increased maternal caloric intake on day 1, as well as increased maternal fat and reduced carbohydrate intake during the postnatal period of rapid nephrogenesis. These findings indicate that the balance between the three macronutrients in the maternal diet, both pre- and postnatally, is crucial for nephron endowment.

The aquaporin-7 (AQP7) channel mediates glycerol release from adipocytes. Genetic variants decreasing AQP7 expression are associated with adiposity and metabolic complications in humans. Using human data, mouse models, and cellular systems, we investigated how AQP7 influences adipose tissue maturation and homeostasis. Negative correlations between methylation on the AQP7 locus, expression of AQP7 in the adipose tissue and BMI were observed in humans. Mice lacking Aqp7 had increased body weight and visceral fat accumulation, due to adipocyte hypertrophy and chronic inflammation, impairing transport across the peritoneal membrane. These changes were further intensified by a high-glucose diet. Mechanistically, AQP7 deficiency disrupted the expression of genes related to adipogenesis and adipocyte function, resulting in a shift toward fibrosis and inflammation, while secreted factors from AQP7-null adipocytes promoted fibroblast activation. These findings establish AQP7 as a key regulator of adipose tissue homeostasis, metabolic dysregulation, and inflammation/fibrosis, exacerbated by glucose-induced obesity.

Protein acetylation is a fundamental regulatory mechanism occurring primarily on lysine amino acids. Here we report systematic in vivo characterization of cysteine S-acetylation as a widespread post-translational modification in mammalian tissues. By developing specialized sample preparation methods that preserve the labile thioester bond, we identified over 400 sites of cysteine acetylation in mouse liver, mirroring the abundance of lysine acetylation. Proteomic surveys across nine murine tissues revealed tissue-specific acetylation patterns that are enriched on metabolic enzymes in the cytoplasm. Cold exposure in mice triggers coordinated remodeling of the brown adipose tissue cysteine acetylome. Functional studies demonstrate that the acetylation of GAPDH Cys150 abolishes catalytic activity and correlates with nuclear enrichment, paralleling the known effects of S-nitrosylation on this enzyme. These findings establish cysteine acetylation as a widespread modification of metabolic proteins that responds to changes in cellular acetyl-CoA availability, fundamentally expanding the landscape of protein acetylation beyond lysine.

Left ventricular hypertrophy (LVH) is associated with increased cardiac expression of fibroblast growth factor-23 (FGF23) in mice and men. To further elucidate the role of cardiac FGF23 in LVH, we specifically ablated Fgf23 in cardiomyocytes, and employed transverse aortic constriction (TAC) to induce LVH by pressure overload. LVH developed independently of cardiac FGF23, but cardiomyocyte-specific Fgf23 knock-out (Fgf23^CKO) TAC mice were characterized by ameliorated hypertension and a distinct reduction of cardiac fibrosis, relative to Fgf23^fl/fl TAC controls. Spatial metabolomics revealed reduced intracellular glucose abundance and lowered cardiac energy charge in Fgf23^CKO TAC mice, whereas treatment of cultured cardiomyocytes with FGF23 increased intracellular glucose abundance. Spatial transcriptomics showed a downregulation of glucose transporters and glycolytic enzymes, but an upregulation of enzymes involved in fatty acid oxidation in Fgf23^CKO TAC mice. These findings suggest that reduced cardiac FGF23 signaling promotes cardiac metabolic health by downregulating glucose consumption and favoring fatty acid oxidation. Created in https://BioRender.com.

Profound social and economic changes in recent generations have led to reduced physical activity and increased calorie intake, leading to a higher incidence of metabolic disease. These effects may propagate across generations, amplifying the impact on descendants. Here we found that limited physical activity of dams brought about increased liver weight and lipid accumulation in the male offspring on a moderate fat calorie western-like diet from weaning to adulthood, while maternal voluntary exercise on running wheels during the postpartum period was sufficient to prevent the development of the phenotype in the otherwise sedentary offspring. Elevated fatty acid (FA) and reduced acylcarnitine levels in the liver of offspring of exercising mothers suggested increased FA flux for oxidation that, with elevated mitochondrial β-oxidation, indicated a maternally programmed mechanism to cope with increased fat calories. Finally, single-nucleus transcriptional profiling indicated dysregulated lipid metabolism in hepatocytes and upregulation of phagocytosis-related genes in Kupffer cells/macrophages and minimal response in stellate cells, indicating a moderate liver damage in the offspring of sedentary but not exercising mothers. A similar combination of maternal sedentary lifestyle and increased fat calorie intake from childhood could contribute to the increased incidence of obesity and NAFLD in recent generations.

Adolescence is a key developmental window of opportunity for nutrition promotion and cardiometabolic disease (CMD) prevention that can reap long-term significant health, economic and social advantages, however it is currently not a focus in the Developmental Origins of Health and Disease (DOHaD) framework. In this perspective, we argue that adolescence should be included in the DOHaD framework, by examining current evidence on the relationship between adolescent nutrition and risk factors for CMDs, physiological mechanisms, and potential interventions.

Metabolic dysfunction-associated steatotic liver disease (MASLD) and its advanced form, metabolic dysfunction-associated steatohepatitis (MASH), are major global health issues involving metabolic dysfunction, hepatic lipotoxicity, and chronic inflammation. A key driver of MASH pathogenesis is sterile inflammation, a non-infectious immune response triggered by molecules that are released from injured or dying liver cells. These molecules termed as damage-associated molecular patterns (DAMPs), which activate innate immune receptors, such as Toll-like receptors (TLRs), NOD-like receptors, and the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway to encourage inflammatory signaling, cytokine production, immune cell recruitment, and ultimately fibrogenic activation in MASH. Sterile inflammation sits at the crossroads of metabolic injury and immune activation in MASH and drives disease progression from simple fat build-up to irreversible liver damage. Targeting these sterile inflammatory pathways appears to be an attractive approach for halting or reversing hepatic inflammation and fibrogenic activation in MASH. Extracellular RNAs (eRNAs) have recently been identified as potent DAMPs that trigger sterile inflammation in MASH by engaging in TLR3 signaling. Furthermore, RNase1-based treatments have been proposed as novel therapeutic strategies to interrupt the self-sustaining loop of inflammatory signaling induced by eRNA in MASH. In this review, we discuss the key molecular mechanisms that fuel sterile inflammation in MASLD/MASH, highlighting eRNA as novel therapeutic targets to restrict inflammation in MASH.

Mitochondria play a central role in regulating cellular energy metabolism, redox homeostasis, and biosynthesis. Mitochondrial uncoupling, through the alteration in the permeability of the inner mitochondrial membrane (IMM) to the leak of protons without adenosine triphosphate (ATP) synthesis, regulates thermogenesis, glucose and lipid metabolism, and reactive oxygen species (ROS) generation. In brown adipose tissue (BAT), proton leak via uncoupling protein 1 (UCP1) is essential for thermogenesis and has been shown to improve systemic glucose homeostasis, and recent studies indicate that BAT activation can also suppress tumor growth by competing with cancer cells for glucose. Several small-molecule mitochondrial uncouplers have demonstrated anticancer effects in preclinical models, although endogenous UCPs-particularly UCP2-are often upregulated in tumors, where they may support tumor growth by buffering ROS and increasing metabolic flexibility. These seemingly contradictory observations highlight the context-dependent effects of mitochondrial uncoupling in cancer. Here, we review current understanding of mitochondrial uncoupling mechanisms, the roles of UCP isoforms, and the metabolic interplay between BAT, cancer cells, and the tumor microenvironment, with a focus on therapeutic implications.

Glucagon-like peptide 1 receptor (GLP-1R) agonists are used along with ethanol consumption, but their interactions are not understood. Our aim was to determine the effects of GLP-1R agonism on the liver in mouse models of high ethanol consumption. We identified that GLP-1R agonism reduced ethanol consumption, mitigated ethanol-induced upregulation of several liver metabolizing enzymes, including Cyp2e1 and also reduced Cyp2e1 independent of ethanol intake. As expected from a reduction in Cyp2e1, GLP-1R agonism resulted in increased blood ethanol levels. This occurred after a single dose of ethanol when given by gavage, and by the intraperitoneal route. This suggests that GLP-1R agonism can reduce ethanol-mediated hepatotoxicity despite continued ethanol consumption and elevate blood alcohol levels.