Methionine restriction diet has been extensively studied for its beneficial effects on metabolic health and aging. However, the impact of methionine deprivation on glucose metabolism per se and macrophage functions remains incompletely understood. In this study, we analyzed the functional roles of methionine deprivation on glucose flux and macrophage polarization. We used metabolic flux to investigate how methionine deprivation affected glucose metabolism. The functions of methionine deficiency on macrophage polarization and the underlying mechanisms were studied at both the cellular and animal levels. We found that short-term methionine deprivation represses the tricarboxylic acid (TCA) cycle in mitochondria, accompanied by rapid phosphorylation of the E1 subunit of pyruvate dehydrogenase (PDH) complex, PDHA1. This phosphorylation by methionine deprivation is dependent on increased levels of uncharged tRNA but is independent of GCN2. Furthermore, methionine deprivation promotes M1-like polarization of macrophages, consistent with metabolic reprogramming. Notably, the proinflammatory effect of methionine deprivation on macrophages is also mediated by PDHA1 phosphorylation and increases in uncharged tRNA, but independent of GCN2. Our study not only elucidates a direct regulatory role of methionine depletion on the TCA cycle but also reveals that such a regulation is tightly linked to the modulation of macrophage polarization.

Browning of white adipose tissue (WAT) contributes to the sustained hypermetabolism observed in patients with burns. How glycogen metabolism in WAT is linked to burn-induced hypermetabolism remains unknown. We discover that burn-induced UCP1 expression in subcutaneous WAT is accompanied by elevation of glycogen synthase 1 (GYS1). Adipose tissue-specific deletion of Gys1 suppresses burn-induced UCP1 expression. Gys1 deletion inhibits WAT lipolysis and mitigates hepatic steatosis. Mechanistically, the effects of Gys1 deletion on burn-induced hypermetabolism are mediated by an increase in uridine diphosphate glucose (UDPG), the substrate of GYS1. Both Gys1 deletion and UDPG administration attenuate signaling of interleukin-6. UDPG directly interacts with JAK2 and inhibits STAT3 phosphorylation. Administration of MZ-101, a small-molecule inhibitor of GYS1, suppresses post-burn hypermetabolism and improves the survival rate of mice. Our findings uncover the regulatory role of the GYS1-UDPG-JAK2-STAT3 cascade in WAT during post-burn hypermetabolism and underscore the potential of GYS1 inhibition as a therapeutic strategy for burn injury.

IntroductionNonalcoholic steatohepatitis (NASH), characterized by progressive liver injury, inflammation, and fibrosis, is a leading chronic liver disease worldwide. Pharmacotherapy for NASH is thus urgently needed. Through a strategy of in vivo lineage tracing, it was recently discovered that deletion of a protein methyltransferase SMYD2 has a protective role in hepatic steatosis. In this study, we evaluated the potential therapeutic effect of two SMYD2 inhibitors AZ505 and LLY-507 in a mouse NASH model.MethodsThe mouse NASH model was induced by a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) for 12 weeks. SMYD2 inhibitors AZ505 and LLY-507 were administered in the last 4 weeks at a dose of 10 mg/kg by intraperitoneal injection three times per week. A series of biochemical and histological analyses were conducted to determine the therapeutic potential of SMYD2 inhibitors.ResultsThe inhibitory effect of AZ505 and LLY-507 on histone methylation was confirmed with liver samples. CDAHFD was able to induce marked liver fibrosis and inflammation in the mice. However, treatment of the mice with AZ505 and LLY-507 failed to show any improvement in NASH scores, liver damage, liver fibrosis, macrophage infiltration, or hepatic inflammation in mice.DiscussionIn conclusion, our findings suggest that SMYD2 inhibition is not an effective strategy to alleviate NASH at least in mice.

Diabetes is caused by the interplay between genetic and environmental factors, therefore changes of lifestyle and dietary patterns are the most common practices for diabetes intervention. Protein restriction and caloric restriction have been shown to improve diabetic hyperglycemia in both animal models and humans. We report here the effectiveness of intermittent protein restriction (IPR) for the intervention of diabetes in Zucker diabetic fatty (ZDF) rats. Administration of IPR significantly reduced hyperglycemia and decreased glucose production in the liver. IPR protected pancreatic islets from diabetes-mediated damages as well as elevated the number and the proliferation activity of β cells. Single-cell RNA sequencing performed with isolated islets from the ZDF rats revealed that IPR was able to reverse the diabetes-associated β cell dedifferentiation. In addition, diabetic β cells in ZDF rats were associated with increased expressions of islet amyloid polypeptide, chromogranin and genes involved in endoplasmic reticulum stress. A β cell dedifferentiation marker Cd81 was also increased in the β cells of diabetic rats. In contrast, the expressions of D-box binding PAR bZIP transcription factor Dbp and immediate-early response genes were reduced in the diabetic β cells. In conclusion, these results indicated that IPR is effective in glycemic control and β cell protection in a diabetic rat model. In addition, diabetes in ZDF rats is associated with changes in the expression of genes involved in many facets of β cell functions.

Diabetes is caused by the interplay between genetics and environmental factors, tightly linked to lifestyle and dietary patterns. In this study, we explored the effectiveness of intermittent protein restriction (IPR) in diabetes control. IPR drastically reduced hyperglycemia in both streptozotocin-treated and leptin receptor-deficient db/db mouse models. IPR improved the number, proliferation, and function of β cells in pancreatic islets. IPR reduced glucose production in the liver and elevated insulin signaling in the skeletal muscle. IPR elevated serum level of FGF21, and deletion of the Fgf21 gene in the liver abrogated the hypoglycemic effect of IPR without affecting β cells. IPR caused less lipid accumulation and damage in the liver than that caused by continuous protein restriction in streptozotocin-treated mice. Single-cell RNA sequencing using mouse islets revealed that IPR reversed diabetes-associated β cell reduction and immune cell accumulation. As IPR is not based on calorie restriction and is highly effective in glycemic control and β cell protection, it has promising translational potential in the future.

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