The widely consumed high-fructose corn syrup has been linked to neurological disorders. In a recent article published in Nature, Wang et al. extend the harms of excessive fructose intake on neurodevelopment to the prenatal and lactation stages. They reveal that fructose uptake via GLUT5 reprograms microglial metabolism toward a low-ATP production state, suppressing microglial phagocytosis and impairing neurodevelopment.
Xi Chen, Sophie Dogné, Yanru Deng, Huiqiao Li, Jieyi Meng, Charlise Giang, Jan-Bernd Funcke, Leon G Straub, Michelle Dias, Sundararajah Thevananther, Qiang Tong, Abu Hena Mostafa Kamal, Chandra Shekar R Ambati, Yu’e Liu, Nagireddy Putluri, Xia Gao, Miao-Hsueh Chen, Dongyin Guan, Hari Krishna Yalamanchili, Shangang Zhao, Nathalie Caron, Yi Zhu·13 May 2025
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Hepatic gluconeogenesis is a critical process that generates glucose from non-carbohydrate precursors during fasting to support vital organs like the brain and red blood cells. Postprandially, this process is rapidly suppressed to allow for glucose storage as glycogen and lipids in the liver. Failure to suppress gluconeogenesis after meals leads to elevated postprandial glucose levels, a key feature of type 2 diabetes. This dynamic switch is regulated by insulin and glucagon, but insulin resistance impairs this regulation. In this study, we identified a novel mechanism involving postprandial circulating hyaluronan (HA) and lysosomal hyaluronidase-1 (HYAL1) that suppresses hepatic gluconeogenesis by rewiring hepatic metabolism and mitochondrial function. Hyal1 knockout (Hyal1 KO) mice exhibited increased gluconeogenesis, while liver-specific Hyal1 overexpression (Liv-Hyal1) mice showed reduced gluconeogenic activity. Transcriptomic analysis revealed minimal changes in liver gene expression due to Hyal1 deletion, but metabolomic profiling demonstrated that Hyal1 overexpression mitigated high-fat diet (HFD)-induced elevations in gluconeogenic pathway metabolites. Mechanistically, HYAL1-mediated HA digestion activates a feedback loop in HA synthesis, repartitioning the cellular uridine diphospho-N-acetyl-D-glucosamine (UDP-GlcNAc) pool. This reduces O-linked N-acetylglucosamine modification (O-GlcNAcylation) of mitochondrial ATP synthase subunits, decreasing ATP production and suppressing gluconeogenesis. Importantly, this pathway remains intact in the livers of HFD-fed, insulin-resistant mice. In summary, our findings reveal a new postprandial mechanism for regulating hepatic gluconeogenesis, highlighting the potential of enhancing postprandial HA levels or hepatic HYAL1 activity as a therapeutic strategy for managing excessive gluconeogenesis in insulin-resistant conditions, such as type 2 diabetes.
Understanding the specific metabolic changes in multiple regions of the kidney is crucial to revealing the underlying mechanism and developing effective targets for diabetic nephropathy (DN). In this study, integrated spatially resolved metabolomics and proteomics combined with mass spectrometry imaging (MSI) revealed a multi-scale region profile of the diabetic kidney. Based on anatomic location, spatial metabolomics revealed eight region-specific metabolite biomarkers uniquely localized to kidney segments, which were closely correlated to clinical parameters of patients with DN. Specifically, treatment with metformin (MET) enriched inosinic acid, adenosine 3’,5’-diphosphate, nicotinamide adenine dinucleotide (NADH), and hydrated NADH (NADHX) levels in the cortex (Cor) and the outer stripe of kidney medulla (OM) anatomical subregions, while in the inner stripe of kidney medulla (IM) segmentation, the p-cresol sulfate level was downregulated. Comparing differently expressed proteins in each region showed that nephrosis 2 (Nphs2) was the highest loading feature. A further region-specific analysis of pathway enrichment characteristics indicated that the purine and ether lipid metabolism pathways were enriched in the Cor and OM regions, whereas the pantothenate and coenzyme A (CoA) biosynthesis pathways were mainly enriched in the IM region in response to MET treatment. Taken together, the spatially segregated metabolomics and proteomics studies had revealed MET-mediated proteins and function-specific therapeutic pathways related to the anatomical multiregion of diabetic mouse kidneys.
Xinna Li, Dan Li, Dan Tang, Xiaofang Huang, Hui Bao, Jiawei Wang, Shiqian Qi·26 May 2025
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Autophagy is a fundamental cellular process, conserved across species from yeast to mammals, that plays a crucial role in maintaining cellular homeostasis. The functionally conserved MON1-CCZ1 (MC1) complex serves as a guanine nucleotide exchange factor (GEF) for the RAB GTPase RAB7A and is indispensable for directing RAB7A recruitment to autophagosome or lysosomal membranes. Despite its critical role, the precise molecular mechanism underlying the assembly of the human MON1A-CCZ1 (HsMC1) complex and its specific GEF activity towards RAB7A has remained unclear. In this study, we report the high-resolution cryo-electron microscopy (cryo-EM) structure of the HsMC1 GEF domain in a complex with the nucleotide-free RAB7AN125I at 2.85 Å resolution. Our structural data demonstrate that engagement with the HsMC1 complex induces marked conformational shifts in the phosphate-binding loop (P-loop) and Switch Ⅰ/Ⅱ regions of RAB7A. A striking feature of this complex is the direct interaction between the P-loop of RAB7A and CCZ1, a structural detail not previously observed. Furthermore, biochemical assays targeting residues within Interface Ⅰ or Ⅱ of the HsMC1-RAB7A complex highlight their critical role in mediating the interaction and suggest a unique mechanism for nucleotide exchange facilitated by the HsMC1 complex. These findings provide novel molecular insights into the functional mechanisms of the HsMC1-RAB7A complex, offering a robust structural framework to inform future investigations into disease-related targets and therapeutic development.
Congling Chen, Zhen Ying, Qi Tang, Lin Zhao, Yibing Lu, Xiaofang Fan, Lan Xu, Si Si, Yuanyuan Li, Jiawei Xu, Yihua Wang, Yu Dong, Xiaoying Li, Ying Chen·12 Jun 2025
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Tirzepatide, a dual GIP/GLP-1 receptor agonist, has shown unprecedented efficacy in weight loss and improving metabolic parameters in clinical trials. However, the durability of these benefits after treatment cessation remains poorly understood. This study aimed to investigate the effect of tirzepatide cessation on body weight change in people with obesity or overweight. This real-world, observational 26-week follow-up study included participants who completed 52 weeks’ study treatment during SURMOUNT-CN (NCT05024032). The analysis excluded participants who received anti-obesity medications or bariatric procedures during the 26-week follow-up. Key outcomes were the changes in body weight and waist circumference after 26 weeks, from treatment cessation (Week 52) and trial baseline (Week 0), by the SURMOUNT-CN treatment groups (tirzepatide 10 or 15 mg, or placebo). Overall, 152 participants were included (tirzepatide 10 mg: n = 57; tirzepatide 15 mg: n = 51; placebo: n = 44). Following treatment cessation (Week 52), the mean (SD) percentage changes in body weight at Week 78 were 9.1% (7.4), 12.3% (9.9), and 1.8% (5.2), and the absolute changes in waist circumference were 2.9 cm (7.5), 5.5 cm (6.5) and −0.5 cm (5.6), in tirzepatide 10 and 15 mg, and placebo groups, respectively. From trial baseline to Week 78, the mean (SD) net percentage weight changes were −8.7% (6.9), −10.6% (10.2), and −2.5% (7.0), and the changes in waist circumference were −10.5 cm (8.1), −10.6 cm (9.3) and −4.0 cm (7.2), in the tirzepatide 10 and 15 mg, and placebo groups, respectively. At Week 78, residual improvements in multiple cardiometabolic indicators were evident in the tirzepatide groups. Despite weight gain following tirzepatide cessation, participants achieved a large net weight loss and reduction in waist circumference from trial baseline to Week 78, with residual improvements in several cardiometabolic indicators.
