Pub Date : 2026-04-01Epub Date: 2025-12-06DOI: 10.1016/j.jnutbio.2025.110227
Zou-Han Lin , Pin-I Chou , Jia-Wei Chang , Zong-Chen Lin , Yuan-Ting Sun , Ming-Hui Chang , Shih-En Huang , Yu-Min Yeh , Chien-Chin Chen , I-Chen Peng
Dysregulated lipid metabolism in hepatocytes heightens the risk of metabolic dysfunction-associated steatotic liver disease (MASLD). Fatty acid synthase (FAS), one of the key enzymes regulating lipid production in the liver, is upregulated in MASLD patients, making it a prime target for treatment. However, the regulatory mechanisms governing FAS expression and its post-translational modification in MASLD, as well as their potential contribution to hepatic inflammation, remain incompletely understood. In this study, we find that ten-eleven translocation 2 (TET2), thymine DNA glycosylase (TDG), FAS, and glutamine synthetase (GS) are upregulated in lipid mixture- or high-fat diet-induced hepatic steatosis, both in vitro and in vivo. The lipid mixture increases FAS and GS expression through TDG-mediated promoter demethylation. It also promotes hepatic lipid droplet accumulation and inflammation through TDG, FAS, and GS. Additionally, GS is essential for lipid mixture-induced O-linked N-acetylglucosaminylation (O-GlcNAcylation) of FAS, which enhances its stability in hepatocytes. These findings demonstrate that upregulation of FAS through TDG-mediated promoter demethylation and GS-mediated O-GlcNAcylation accelerates hepatic steatosis and inflammation in MASLD, providing mechanistic insights and highlighting these regulatory pathways as potential targets for therapeutic intervention.
肝细胞脂质代谢失调会增加代谢功能障碍相关脂肪变性肝病（MASLD）的风险。脂肪酸合成酶（FAS）是调节肝脏脂质生成的关键酶之一，在MASLD患者中上调，使其成为治疗的主要靶点。然而，FAS表达的调控机制及其在MASLD中的翻译后修饰，以及它们对肝脏炎症的潜在贡献，仍然不完全清楚。在这项研究中，我们发现在体外和体内，10 - 11易位2 （TET2）、胸腺嘧啶DNA糖基化酶（TDG）、FAS和谷氨酰胺合成酶（GS）在脂质混合物或高脂肪饮食诱导的肝脂肪变性中上调。脂质混合物通过tdg介导的启动子去甲基化增加FAS和GS的表达。它还通过TDG、FAS和GS促进肝脂滴积聚和炎症。此外，GS对于脂质混合物诱导的FAS的O-linked n -乙酰氨基葡萄糖酰化（o - glcnac酰化）至关重要，这增强了其在肝细胞中的稳定性。这些发现表明，通过tdg介导的启动子去甲基化和gs介导的o - glcn酰化，FAS的上调加速了MASLD的肝脂肪变性和炎症，提供了机制上的认识，并突出了这些调节途径作为治疗干预的潜在靶点。
{"title":"Promoter demethylation and protein O-GlcNAcylation-mediated enhancement of fatty acid synthase contributes to hepatic steatosis and inflammation in MASLD","authors":"Zou-Han Lin , Pin-I Chou , Jia-Wei Chang , Zong-Chen Lin , Yuan-Ting Sun , Ming-Hui Chang , Shih-En Huang , Yu-Min Yeh , Chien-Chin Chen , I-Chen Peng","doi":"10.1016/j.jnutbio.2025.110227","DOIUrl":"10.1016/j.jnutbio.2025.110227","url":null,"abstract":"<div><div>Dysregulated lipid metabolism in hepatocytes heightens the risk of metabolic dysfunction-associated steatotic liver disease (MASLD). Fatty acid synthase (FAS), one of the key enzymes regulating lipid production in the liver, is upregulated in MASLD patients, making it a prime target for treatment. However, the regulatory mechanisms governing FAS expression and its post-translational modification in MASLD, as well as their potential contribution to hepatic inflammation, remain incompletely understood. In this study, we find that ten-eleven translocation 2 (TET2), thymine DNA glycosylase (TDG), FAS, and glutamine synthetase (GS) are upregulated in lipid mixture- or high-fat diet-induced hepatic steatosis, both <em>in vitro</em> and <em>in vivo</em>. The lipid mixture increases FAS and GS expression through TDG-mediated promoter demethylation. It also promotes hepatic lipid droplet accumulation and inflammation through TDG, FAS, and GS. Additionally, GS is essential for lipid mixture-induced O-linked N-acetylglucosaminylation (O-GlcNAcylation) of FAS, which enhances its stability in hepatocytes. These findings demonstrate that upregulation of FAS through TDG-mediated promoter demethylation and GS-mediated O-GlcNAcylation accelerates hepatic steatosis and inflammation in MASLD, providing mechanistic insights and highlighting these regulatory pathways as potential targets for therapeutic intervention.</div></div>","PeriodicalId":16618,"journal":{"name":"Journal of Nutritional Biochemistry","volume":"150 ","pages":"Article 110227"},"PeriodicalIF":4.9,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145708298","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-04-01Epub Date: 2025-12-29DOI: 10.1016/j.jnutbio.2025.110245
Huiyoung Kwon , Dong Soo Seo , Yusra Ahmad , Sungjun Park , Jeongwoo Yoo , Junhyeok Lee , Ho Jung Bae , Younghoon Jang
High-fat diet (HFD)-induced obesity impairs cognition and hippocampal neurogenesis, linked to reduced metabolic flexibility between mitochondrial fatty acid β-oxidation (FAO) and cytosolic de novo lipogenesis (DNL). It is not fully understood if switching to a high-carbohydrate diet (HCD) or a ketogenic diet (KD) could reverse these HFD-induced deficits, or if they do so through different mechanisms. Male C57BL/6J mice received HFD for 8 weeks to induce obesity. Mice were then either maintained on the HFD or switched to an HCD or KD for an additional 8 weeks. We evaluated systemic metabolism (body weight, serum biochemistry), tissue-specific metabolic remodeling (RNA-seq, histology, RT-qPCR, Western blot) and cognitive function (Y-maze test, novel object recognition test). Both HCD and KD interventions reversed HFD‑induced systemic abnormalities, including reducing ALT/AST, cholesterol, and LDL, and attenuating hepatic steatosis and adipocyte hypertrophy. Metabolically, KD markedly increased β‑hydroxybutyrate, whereas HCD showed a distinct triglyceride profile. Both diets improved hippocampus-dependent working and recognition memory. Hippocampal RNA‑seq revealed diet-specific mechanisms. HCD enriched anabolic processes, including upregulation of glucose transporters (Glut 1, 2, 3, 4) and DNL pathway (ACLY-ACC-FASN-SCD1). Conversely, KD enriched AMPK signaling, increasing monocarboxylate transporters (Mct 1, 2, 4) for ketone uptake and activating the neurotrophic AMPK–ERK–CREB–BDNF pathway. In conclusion, post-HFD switching to HCD or KD restores hippocampal structure and cognition via complementary mechanisms. HCD drives a substrate-centric, lipogenic program supporting proliferation, whereas KD engages a signaling-centric, neurotrophic program enhancing plasticity. Metabolic flexibility is a promising target for obesity-associated cognitive decline.
{"title":"Complementary mechanisms of high-carbohydrate diets and ketogenic diets restore adult hippocampal neurogenesis and cognitive function in high-fat diet induced obesity in mice","authors":"Huiyoung Kwon , Dong Soo Seo , Yusra Ahmad , Sungjun Park , Jeongwoo Yoo , Junhyeok Lee , Ho Jung Bae , Younghoon Jang","doi":"10.1016/j.jnutbio.2025.110245","DOIUrl":"10.1016/j.jnutbio.2025.110245","url":null,"abstract":"<div><div>High-fat diet (HFD)-induced obesity impairs cognition and hippocampal neurogenesis, linked to reduced metabolic flexibility between mitochondrial fatty acid <em>β</em>-oxidation (FAO) and cytosolic <em>de novo</em> lipogenesis (DNL). It is not fully understood if switching to a high-carbohydrate diet (HCD) or a ketogenic diet (KD) could reverse these HFD-induced deficits, or if they do so through different mechanisms. Male C57BL/6J mice received HFD for 8 weeks to induce obesity. Mice were then either maintained on the HFD or switched to an HCD or KD for an additional 8 weeks. We evaluated systemic metabolism (body weight, serum biochemistry), tissue-specific metabolic remodeling (RNA-seq, histology, RT-qPCR, Western blot) and cognitive function (Y-maze test, novel object recognition test). Both HCD and KD interventions reversed HFD‑induced systemic abnormalities, including reducing ALT/AST, cholesterol, and LDL, and attenuating hepatic steatosis and adipocyte hypertrophy. Metabolically, KD markedly increased β‑hydroxybutyrate, whereas HCD showed a distinct triglyceride profile. Both diets improved hippocampus-dependent working and recognition memory. Hippocampal RNA‑seq revealed diet-specific mechanisms. HCD enriched anabolic processes, including upregulation of glucose transporters (<em>Glut</em> 1, 2, 3, 4) and DNL pathway (ACLY-ACC-FASN-SCD1). Conversely, KD enriched AMPK signaling, increasing monocarboxylate transporters (<em>Mct</em> 1, 2, 4) for ketone uptake and activating the neurotrophic AMPK–ERK–CREB–BDNF pathway. In conclusion, post-HFD switching to HCD or KD restores hippocampal structure and cognition via complementary mechanisms. HCD drives a substrate-centric, lipogenic program supporting proliferation, whereas KD engages a signaling-centric, neurotrophic program enhancing plasticity. Metabolic flexibility is a promising target for obesity-associated cognitive decline.</div></div>","PeriodicalId":16618,"journal":{"name":"Journal of Nutritional Biochemistry","volume":"150 ","pages":"Article 110245"},"PeriodicalIF":4.9,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145878532","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-04-01Epub Date: 2025-12-11DOI: 10.1016/j.jnutbio.2025.110232
Jiayue Su , Chenran Cai , Ying Zhang , Donglan Wang , Sijia Yan , Xueqiong Yao
Gestational diabetes mellitus (GDM) is a prevalent complication, affecting approximately 14% of pregnancies worldwide, and is associated with an elevated risk of both maternal and infant complications. It also exerts long-term adverse effects on offspring health, including metabolic, cardiovascular, and neurodevelopmental disorders, thereby compromising maternal and infant well-being. During pregnancy, an imbalance between folic acid and vitamin B12 has been linked to an increased risk of GDM and unfavorable metabolic outcomes in offspring, underscoring the potential clinical value of maintaining their balance and implementing early interventions. This review summarizes the role of folic acid and vitamin B12 in gestational diabetes and offspring development, aiming to bridge the gap between mechanistic insights and clinical evidence. It highlights the potential for reverse causality in linking vitamin B12-folic acid imbalance to GDM risk and underscores the need to integrate novel metabolic and epigenetic concepts into future intervention trials.
{"title":"The role of folic acid and vitamin B12 in gestational diabetes mellitus and offspring development: A narrative review","authors":"Jiayue Su , Chenran Cai , Ying Zhang , Donglan Wang , Sijia Yan , Xueqiong Yao","doi":"10.1016/j.jnutbio.2025.110232","DOIUrl":"10.1016/j.jnutbio.2025.110232","url":null,"abstract":"<div><div>Gestational diabetes mellitus (GDM) is a prevalent complication, affecting approximately 14% of pregnancies worldwide, and is associated with an elevated risk of both maternal and infant complications. It also exerts long-term adverse effects on offspring health, including metabolic, cardiovascular, and neurodevelopmental disorders, thereby compromising maternal and infant well-being. During pregnancy, an imbalance between folic acid and vitamin B12 has been linked to an increased risk of GDM and unfavorable metabolic outcomes in offspring, underscoring the potential clinical value of maintaining their balance and implementing early interventions. This review summarizes the role of folic acid and vitamin B12 in gestational diabetes and offspring development, aiming to bridge the gap between mechanistic insights and clinical evidence. It highlights the potential for reverse causality in linking vitamin B12-folic acid imbalance to GDM risk and underscores the need to integrate novel metabolic and epigenetic concepts into future intervention trials.</div></div>","PeriodicalId":16618,"journal":{"name":"Journal of Nutritional Biochemistry","volume":"150 ","pages":"Article 110232"},"PeriodicalIF":4.9,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145751816","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-04-01Epub Date: 2025-12-16DOI: 10.1016/j.jnutbio.2025.110239
Jingyi Ren , Xiaoxin Jiang , Gejun Yu , Wentao Wu , Mengyuan Chen , Yun Zhao , Mengjie Yang , Zuquan Zou , Canxia He
Sulforaphane (SFN), an isothiocyanate derived from cruciferous vegetables, has shown therapeutic potential in inflammatory diseases. Our previous studies demonstrated that SFN ameliorates ulcerative colitis (UC) and restores gut microbiota composition in dextran sulfate sodium (DSS)-induced mice. In the present study, we further investigate the protective effects and underlying mechanisms of SFN against secondary liver injury associated with UC. The results revealed that SFN significantly alleviated pathological damage in both the colon and liver, improved liver function parameters, upregulated intestinal tight junction proteins and Muc2 expression, and inhibited inflammation in DSS-induced colitis mice. Additionally, SFN significantly elevated short-chain fatty acid (SCFA) concentrations, enhanced the expression of SCFA receptors (free fatty acid receptors 2 and 3, FFAR2/3), and modulated macrophage polarization by inhibiting M1 and promoting M2 phenotypes in the colon and liver. Collectively, these findings suggest that SFN may alleviate colitis and secondary liver injury by enhancing intestinal barrier function and reducing inflammatory responses, potentially via the SCFAs-FFAR2/3-macrophage polarization signaling cascade. Thus, SFN may serve as a promising adjunctive therapeutic agent for the prevention and treatment of UC.
{"title":"Sulforaphane ameliorates DSS-induced colitis and secondary liver injury in mice: Proposed mechanism in the SCFAs-FFAR2/3-macrophage polarization axis","authors":"Jingyi Ren , Xiaoxin Jiang , Gejun Yu , Wentao Wu , Mengyuan Chen , Yun Zhao , Mengjie Yang , Zuquan Zou , Canxia He","doi":"10.1016/j.jnutbio.2025.110239","DOIUrl":"10.1016/j.jnutbio.2025.110239","url":null,"abstract":"<div><div>Sulforaphane (SFN), an isothiocyanate derived from cruciferous vegetables, has shown therapeutic potential in inflammatory diseases. Our previous studies demonstrated that SFN ameliorates ulcerative colitis (UC) and restores gut microbiota composition in dextran sulfate sodium (DSS)-induced mice. In the present study, we further investigate the protective effects and underlying mechanisms of SFN against secondary liver injury associated with UC. The results revealed that SFN significantly alleviated pathological damage in both the colon and liver, improved liver function parameters, upregulated intestinal tight junction proteins and Muc2 expression, and inhibited inflammation in DSS-induced colitis mice. Additionally, SFN significantly elevated short-chain fatty acid (SCFA) concentrations, enhanced the expression of SCFA receptors (free fatty acid receptors 2 and 3, FFAR2/3), and modulated macrophage polarization by inhibiting M1 and promoting M2 phenotypes in the colon and liver. Collectively, these findings suggest that SFN may alleviate colitis and secondary liver injury by enhancing intestinal barrier function and reducing inflammatory responses, potentially via the SCFAs-FFAR2/3-macrophage polarization signaling cascade. Thus, SFN may serve as a promising adjunctive therapeutic agent for the prevention and treatment of UC.</div></div>","PeriodicalId":16618,"journal":{"name":"Journal of Nutritional Biochemistry","volume":"150 ","pages":"Article 110239"},"PeriodicalIF":4.9,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145781376","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-04-01Epub Date: 2025-12-24DOI: 10.1016/j.jnutbio.2025.110242
Elvira Marquez-Paradas , Maria Torrecillas-Lopez , Alfredo Corell-Almuraza , Teresa Gonzalez-de la Rosa , Luna Barrera-Chamorro , Beatriz Bermudez , Carmen M Claro-Cala , Sergio Montserrat-de la Paz
The postprandial period represents a critical and dynamic phase during which dietary components can acutely influence metabolic and immune functions. While the chronic effects of dietary fat quality are well characterized, their immediate postprandial immunometabolic impact remains poorly understood. To investigate the acute effects of energy-matched test meals enriched in saturated (SFA), monounsaturated (MUFA), or omega-3 long-chain polyunsaturated fatty acids (ω3-LCPUFA), compared to a fat-free control, on systemic metabolic and immune parameters in healthy adults. In this randomized, crossover pilot study, ten healthy participants consumed four test meals separated by 2-week washouts. Blood samples were collected at fasting, 2–3 h (peak), and 5–6 h (late phase) postprandially. Biochemical and immunological biomarkers were assessed. Statistical analyses included two-way repeated-measures ANOVA, linear mixed models, and area under the curve (AUC/iAUC) calculations. MUFA- and ω3-LCPUFA-enriched meals induced significantly greater postprandial changes in glucose, triacylglycerides, LDL-C, and C-peptide compared to the SFA and fat-free meals, particularly at the late postprandial phase. These effects were confirmed by AUC and iAUC analyses. In contrast, although transient changes in immune cell counts and humoral markers were observed over time, no significant differences between fat types were detected in postprandial immune responses. In healthy adults, the fatty acid composition of energy-matched meals acutely modulates key metabolic pathways in a fat-type-specific manner, whereas systemic immune parameters remain largely unchanged. These preliminary findings suggest a functional dissociation between postprandial metabolic and immune response and underscore the need to more sensitive or compartment-specific immune readouts in future nutritional research.
{"title":"Fatty acid composition of isoenergetic meals drives distinct postprandial immunometabolic responses in healthy adults: A randomized crossover pilot study","authors":"Elvira Marquez-Paradas , Maria Torrecillas-Lopez , Alfredo Corell-Almuraza , Teresa Gonzalez-de la Rosa , Luna Barrera-Chamorro , Beatriz Bermudez , Carmen M Claro-Cala , Sergio Montserrat-de la Paz","doi":"10.1016/j.jnutbio.2025.110242","DOIUrl":"10.1016/j.jnutbio.2025.110242","url":null,"abstract":"<div><div>The postprandial period represents a critical and dynamic phase during which dietary components can acutely influence metabolic and immune functions. While the chronic effects of dietary fat quality are well characterized, their immediate postprandial immunometabolic impact remains poorly understood. To investigate the acute effects of energy-matched test meals enriched in saturated (SFA), monounsaturated (MUFA), or omega-3 long-chain polyunsaturated fatty acids (ω3-LCPUFA), compared to a fat-free control, on systemic metabolic and immune parameters in healthy adults. In this randomized, crossover pilot study, ten healthy participants consumed four test meals separated by 2-week washouts. Blood samples were collected at fasting, 2–3 h (peak), and 5–6 h (late phase) postprandially. Biochemical and immunological biomarkers were assessed. Statistical analyses included two-way repeated-measures ANOVA, linear mixed models, and area under the curve (AUC/iAUC) calculations. MUFA- and ω3-LCPUFA-enriched meals induced significantly greater postprandial changes in glucose, triacylglycerides, LDL-C, and C-peptide compared to the SFA and fat-free meals, particularly at the late postprandial phase. These effects were confirmed by AUC and iAUC analyses. In contrast, although transient changes in immune cell counts and humoral markers were observed over time, no significant differences between fat types were detected in postprandial immune responses. In healthy adults, the fatty acid composition of energy-matched meals acutely modulates key metabolic pathways in a fat-type-specific manner, whereas systemic immune parameters remain largely unchanged. These preliminary findings suggest a functional dissociation between postprandial metabolic and immune response and underscore the need to more sensitive or compartment-specific immune readouts in future nutritional research.</div></div>","PeriodicalId":16618,"journal":{"name":"Journal of Nutritional Biochemistry","volume":"150 ","pages":"Article 110242"},"PeriodicalIF":4.9,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145843726","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Unhealthy dietary patterns may impair renal function through elevated intake of methylglyoxal (MG) and advanced glycation end products (AGEs). While adipose tissue stores triglycerides (TG), its dysfunction promotes ectopic lipotoxicity, a process exacerbated by MG or AGEs. This study investigated if long-term dietary MG causes renal damage, mediated by adipose tissue dysfunction and ectopic lipid deposition. Eight-week-old male ICR mice were randomized into four groups for 52 weeks: normal diet and obesogenic high-fat diet (HFD), each with or without 1% MG in drinking water. Results showed that HFD significantly increased MG-AGEs in both adipose tissue and kidneys. Although HFD caused adipocyte hypertrophy and renal injury, no significant renal lipid accumulation was observed. In contrast, MG administration alone induced renal lipotoxicity and injury, manifested by increased TG concentrations in both the cortex and medulla. In HFD-fed mice, MG further exacerbated adipose tissue dysfunction by inhibiting angiogenesis and increasing interstitial collagen accumulation. Notably, the MG co-administration reduced adipocyte size, counteracting the hypertrophy caused by HFD alone. Furthermore, in the kidneys of these HFD-fed mice, MG led to increased medullary TG concentration and elevated collagen expression. In conclusion, HFD alone caused nonlipotoxic kidney injury without significant adipose dysfunction. However, MG administration consistently induced adipose tissue dysfunction and progressive renal lipotoxicity regardless of the diet. These findings suggest that MG-induced renal damage is primarily mediated by the dysfunction of adipose tissue, establishing a critical link between dietary MG intake and kidney disease progression, independent of obesogenic diet status.
{"title":"Dietary methylglyoxal induces renal lipotoxicity primarily through adipose tissue dysfunction in mice fed normal or obesogenic high-fat diets","authors":"Medhavi Paramita Kondanna , Yu-Ho Chang , Hsin-Yi Yang , Chi-Hao Wu , Wan-Ju Yeh","doi":"10.1016/j.jnutbio.2025.110244","DOIUrl":"10.1016/j.jnutbio.2025.110244","url":null,"abstract":"<div><div>Unhealthy dietary patterns may impair renal function through elevated intake of methylglyoxal (MG) and advanced glycation end products (AGEs). While adipose tissue stores triglycerides (TG), its dysfunction promotes ectopic lipotoxicity, a process exacerbated by MG or AGEs. This study investigated if long-term dietary MG causes renal damage, mediated by adipose tissue dysfunction and ectopic lipid deposition. Eight-week-old male ICR mice were randomized into four groups for 52 weeks: normal diet and obesogenic high-fat diet (HFD), each with or without 1% MG in drinking water. Results showed that HFD significantly increased MG-AGEs in both adipose tissue and kidneys. Although HFD caused adipocyte hypertrophy <strong>and</strong> renal injury, no significant renal lipid accumulation was observed. In contrast, MG administration alone induced renal lipotoxicity and injury, manifested by increased TG concentrations in both the cortex and medulla. In HFD-fed mice, MG further exacerbated adipose tissue dysfunction by inhibiting angiogenesis and increasing interstitial collagen accumulation. Notably, the MG co-administration reduced adipocyte size, counteracting the hypertrophy caused by HFD alone. Furthermore, in the kidneys of these HFD-fed mice, MG led to increased medullary TG concentration and elevated collagen expression. In conclusion, HFD alone caused nonlipotoxic kidney injury without significant adipose dysfunction. However, MG administration consistently induced adipose tissue dysfunction and progressive renal lipotoxicity regardless of the diet. These findings suggest that MG-induced renal damage is primarily mediated by the dysfunction of adipose tissue, establishing a critical link between dietary MG intake and kidney disease progression, independent of obesogenic diet status.</div></div>","PeriodicalId":16618,"journal":{"name":"Journal of Nutritional Biochemistry","volume":"150 ","pages":"Article 110244"},"PeriodicalIF":4.9,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145843736","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-04-01Epub Date: 2025-12-20DOI: 10.1016/j.jnutbio.2025.110240
Jiaming Ji , Jinyan Guo , Yin Huang , Ke Chen , Yuheng Xu , Weijian Liang , Zhenjia Lin , Chang Xiong , Xue Han , Jun Liu , Ziqing Hei , Sufang Chen , Weifeng Yao , Chaojin Chen
Electroconvulsive therapy (ECT) stands as the most effective intervention for treatment-resistant depression; however, its interaction with dietary regulation of the gut-brain axis has not been thoroughly explored. This study aimed to elucidate the mechanistic link between ECT, gut microbiota remodeling, short-chain fatty acid (SCFA) production, and neural plasticity. In this study, mice were subjected to chronic restraint stress (6 h/d for 28 consecutive days) to establish a depression-like model. Utilizing a translational approach that incorporated behavioral assessments, multimodal neuroimaging techniques such as PET-CT and laser speckle contrast imaging, along with multiomics analyses including metagenomics, metabolomics, and transcriptomics in rodent models, we demonstrated that ECT induced significant gut microbiota remodeling, characterized by an enrichment of SCFA-producing genera like Lactobacillus and Bifidobacterium. This remodeling was associated with restored intestinal barrier integrity and elevated plasma SCFA levels. Mechanistically, these microbial metabolites activated hippocampal Wnt/β-catenin signaling pathways, enhancing synaptic plasticity restoration, while concurrent probiotic supplementation further amplified brain-derived neurotrophic factor (BDNF) expression via SCFA-dependent epigenetic mechanisms. Neuroimaging corroborated the normalization of cerebral glucose metabolism and hemodynamic function post-ECT. In conclusion, our findings unveil a novel gut-brain communication pathway by which ECT exerts its antidepressant effects, positioning SCFAs as vital mediators connecting microbial metabolic alterations to neural plasticity. This research not only redefines the role of nutritional biochemistry in neuromodulation but also suggests the potential of microbial metabolite monitoring to tailor antidepressant therapies for enhanced efficacy.
{"title":"Electroconvulsive therapy modulates brain plasticity in male depression: Links to gut microbial metabolites and diet-derived regulation of Wnt/BDNF signaling","authors":"Jiaming Ji , Jinyan Guo , Yin Huang , Ke Chen , Yuheng Xu , Weijian Liang , Zhenjia Lin , Chang Xiong , Xue Han , Jun Liu , Ziqing Hei , Sufang Chen , Weifeng Yao , Chaojin Chen","doi":"10.1016/j.jnutbio.2025.110240","DOIUrl":"10.1016/j.jnutbio.2025.110240","url":null,"abstract":"<div><div>Electroconvulsive therapy (ECT) stands as the most effective intervention for treatment-resistant depression; however, its interaction with dietary regulation of the gut-brain axis has not been thoroughly explored. This study aimed to elucidate the mechanistic link between ECT, gut microbiota remodeling, short-chain fatty acid (SCFA) production, and neural plasticity. In this study, mice were subjected to chronic restraint stress (6 h/d for 28 consecutive days) to establish a depression-like model. Utilizing a translational approach that incorporated behavioral assessments, multimodal neuroimaging techniques such as PET-CT and laser speckle contrast imaging, along with multiomics analyses including metagenomics, metabolomics, and transcriptomics in rodent models, we demonstrated that ECT induced significant gut microbiota remodeling, characterized by an enrichment of SCFA-producing genera like <em>Lactobacillus</em> and <em>Bifidobacterium</em>. This remodeling was associated with restored intestinal barrier integrity and elevated plasma SCFA levels. Mechanistically, these microbial metabolites activated hippocampal Wnt/<em>β</em>-catenin signaling pathways, enhancing synaptic plasticity restoration, while concurrent probiotic supplementation further amplified brain-derived neurotrophic factor (BDNF) expression via SCFA-dependent epigenetic mechanisms. Neuroimaging corroborated the normalization of cerebral glucose metabolism and hemodynamic function post-ECT. In conclusion, our findings unveil a novel gut-brain communication pathway by which ECT exerts its antidepressant effects, positioning SCFAs as vital mediators connecting microbial metabolic alterations to neural plasticity. This research not only redefines the role of nutritional biochemistry in neuromodulation but also suggests the potential of microbial metabolite monitoring to tailor antidepressant therapies for enhanced efficacy.</div></div>","PeriodicalId":16618,"journal":{"name":"Journal of Nutritional Biochemistry","volume":"150 ","pages":"Article 110240"},"PeriodicalIF":4.9,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145810429","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
This study investigates the therapeutic potential of γ-glutamyl valine (γ-EV) in 4 week-old male db/db mice, a well-established model for type 2 diabetes. Mice were fed an AIN-93 G diet and administered γ-EV (500 mg/kg body weight) via drinking water for 3 weeks. Blood, liver, muscle, and intestinal tissues were collected to assess blood glucose, peptide bioavailability, liver function, glycogen levels, protein expression, and transcriptomic changes. γ-EV was bioavailable in circulation (2.07±1.59 μM) and significantly improved food efficiency (+79%, P<.0001), despite reduced calorie intake (-27%, P<.0001). Treated mice exhibited markedly reduced polyuria and water intake (−80%, P<.0001), and showed substantial reductions in blood glucose under both fasted (−76%, P<.0001) and non-fasted (−29%, P=.0054) conditions. Although γ-EV increased the hepatosomatic index (+66%, P<.0001), serum ALT levels remained unchanged (P=.0765), indicating no hepatotoxicity. RNA-seq revealed 1308 differentially expressed genes in the liver and 147 in the jejunum, with 26 genes overlapping between the two. Key upregulated GO terms included fatty acid metabolism (jejunum) and oxidoreductase activity (liver). Hepatic p-AMPKα levels increased (+86%, P=.0137) alongside decreased liver glycogen (−79%, P<.0001), suggesting γ-EV induces beneficial catabolic signaling. Overall, γ-EV shows promise as an anti-diabetic peptide.
{"title":"Dietary dipeptide γ-glutamyl valine (γ-EV) activates AMPK and improves glucose homeostasis in db/db mice","authors":"Bikram Upadhyaya , Chia-Sin Liew , Jean-Jack M Riethoven , Yoshinori Mine , Kaustav Majumder","doi":"10.1016/j.jnutbio.2025.110204","DOIUrl":"10.1016/j.jnutbio.2025.110204","url":null,"abstract":"<div><div>This study investigates the therapeutic potential of γ-glutamyl valine (γ-EV) in 4 week-old male db/db mice, a well-established model for type 2 diabetes. Mice were fed an AIN-93 G diet and administered γ-EV (500 mg/kg body weight) via drinking water for 3 weeks. Blood, liver, muscle, and intestinal tissues were collected to assess blood glucose, peptide bioavailability, liver function, glycogen levels, protein expression, and transcriptomic changes. γ-EV was bioavailable in circulation (2.07±1.59 μM) and significantly improved food efficiency (+79%, <em>P</em><.0001), despite reduced calorie intake (-27%, <em>P</em><.0001). Treated mice exhibited markedly reduced polyuria and water intake (−80%, <em>P</em><.0001), and showed substantial reductions in blood glucose under both fasted (−76%, <em>P</em><.0001) and non-fasted (−29%, <em>P</em>=.0054) conditions. Although γ-EV increased the hepatosomatic index (+66%, <em>P</em><.0001), serum ALT levels remained unchanged (<em>P</em>=.0765), indicating no hepatotoxicity. RNA-seq revealed 1308 differentially expressed genes in the liver and 147 in the jejunum, with 26 genes overlapping between the two. Key upregulated GO terms included fatty acid metabolism (jejunum) and oxidoreductase activity (liver). Hepatic p-AMPKα levels increased (+86%, <em>P</em>=.0137) alongside decreased liver glycogen (−79%, <em>P</em><.0001), suggesting γ-EV induces beneficial catabolic signaling. Overall, γ-EV shows promise as an anti-diabetic peptide.</div></div>","PeriodicalId":16618,"journal":{"name":"Journal of Nutritional Biochemistry","volume":"150 ","pages":"Article 110204"},"PeriodicalIF":4.9,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145634707","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-21DOI: 10.1016/j.jnutbio.2026.110350
Yun Wang, Lin Feng, Wei- Dan Jiang, Pei Wu, Yang Liu, Yao-Bin Ma, Hong-Yun Zhang, Hong-Mei Ren, Xiao-Wan Jin, Xiao-Qiu Zhou
B vitamins play an important role in improving lipid and glucose metabolism in fish, but there remains a lack of systematic and in-depth research on the effects of folic acid (FA) on lipid and glucose metabolism in the hepatopancreas of fish. This study aims to investigate the effects of dietary FA on lipid and glucose metabolism in the hepatopancreas of grass carp and the potential molecular mechanisms. The 450 healthy grass carp (686.83 ± 1.31 g) were randomly divided into 18 barrels, and fed diets containing levels of FA (0.57, 1.11, 1.53, 2.08, 2.64 and 3.15 mg/kg diet) for 8 weeks. The results showed that the appropriate level of dietary FA significantly up-regulated the protein expression of GLUT2, G6PD and p-AKT, down-regulated the protein expression of PCK1. Meanwhile, dietary FA significantly reduced the area of lipid droplets in hepatopancreas, up-regulated the protein expression of PPARα, and down-regulated the protein expression of PPARγ. In addition, our results demonstrated that dietary FA supplementation up-regulated the protein levels of LAMP1, LC3B and PLIN2. Finally, dietary FA significantly increased the ratio of SAM/SAH in the hepatopancreas, up-regulated the protein expression of MTHFR and DNMT3A, as well as the nuclear translocation of TFEB. In summary, based on the present findings, dietary FA may improve glucose metabolism through the AKT signaling pathway, and appears to alleviate hepatopancreas lipid accumulation through one-carbon metabolism-dependent DNA methylation and the TFEB-mediated autophagy pathway.
{"title":"Novel mechanisms of dietary folic acid in improving hepatopancreas health of grass carp (Ctenopharyngodon idellus): the perspectives of autophagy and DNA methylation.","authors":"Yun Wang, Lin Feng, Wei- Dan Jiang, Pei Wu, Yang Liu, Yao-Bin Ma, Hong-Yun Zhang, Hong-Mei Ren, Xiao-Wan Jin, Xiao-Qiu Zhou","doi":"10.1016/j.jnutbio.2026.110350","DOIUrl":"https://doi.org/10.1016/j.jnutbio.2026.110350","url":null,"abstract":"<p><p>B vitamins play an important role in improving lipid and glucose metabolism in fish, but there remains a lack of systematic and in-depth research on the effects of folic acid (FA) on lipid and glucose metabolism in the hepatopancreas of fish. This study aims to investigate the effects of dietary FA on lipid and glucose metabolism in the hepatopancreas of grass carp and the potential molecular mechanisms. The 450 healthy grass carp (686.83 ± 1.31 g) were randomly divided into 18 barrels, and fed diets containing levels of FA (0.57, 1.11, 1.53, 2.08, 2.64 and 3.15 mg/kg diet) for 8 weeks. The results showed that the appropriate level of dietary FA significantly up-regulated the protein expression of GLUT2, G6PD and p-AKT, down-regulated the protein expression of PCK1. Meanwhile, dietary FA significantly reduced the area of lipid droplets in hepatopancreas, up-regulated the protein expression of PPARα, and down-regulated the protein expression of PPARγ. In addition, our results demonstrated that dietary FA supplementation up-regulated the protein levels of LAMP1, LC3B and PLIN2. Finally, dietary FA significantly increased the ratio of SAM/SAH in the hepatopancreas, up-regulated the protein expression of MTHFR and DNMT3A, as well as the nuclear translocation of TFEB. In summary, based on the present findings, dietary FA may improve glucose metabolism through the AKT signaling pathway, and appears to alleviate hepatopancreas lipid accumulation through one-carbon metabolism-dependent DNA methylation and the TFEB-mediated autophagy pathway.</p>","PeriodicalId":16618,"journal":{"name":"Journal of Nutritional Biochemistry","volume":" ","pages":"110350"},"PeriodicalIF":4.9,"publicationDate":"2026-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147503655","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-20DOI: 10.1016/j.jnutbio.2026.110353
Yanzhe Xu, Yun Zhu, Kyuhong Lee, Jürgen Borlak
Metabolic dysfunction-associated steatotic liver disease (MASLD) ranges from simple steatosis (MASL) to fibrotic steatohepatitis (MASH). Yet, the molecular mechanisms initiating these divergent outcomes remain unclear. We addressed the question whether MASLD induced by a high-sucrose/ starch diet (MCS) is similar to a high-fat, methionine- and choline-deficient diet (MCD+HFD). To investigate early genomic programming events in these MASLD models, we fed C57BL/6N mice either an MCS or MCD+HFD for 14 days. Histopathology and serum biochemistries confirmed MASLD phenotypes and transcriptomics guided pathway enrichment analysis. Furthermore, ChIP-seq-validated transcription factor targets enabled construction of regulatory gene networks (RGNs) in glucose homeostasis and lipid metabolism. Importantly, the MCS and MCD+HFD caused 692 and 703 differentially expressed genes, and although transcriptomics revealed shared genomic responses, we also observed diet-specific adaptations. Both diets repressed glycolysis, yet MCS showed broader suppression. Furthermore, fatty acid β-oxidation and lipid droplet biogenesis was induced whereas lipogenesis, cholesterol biosynthesis and the kynurenine pathway were repressed. Strikingly, the high-sucrose/high-starch diet suppressed acute-phase, prostaglandin, redox, antigen presentation, and autophagy pathways. Conversely, the high-fat MCD-diet activated cytokine signalling, macrophage networks, and inflammatory programs. Intriguingly, RGNs aided an identification of diet-specific master regulatory networks with MCS stimulating Insig2, Id1, and Mafb signalling. Conversely, the high-fat MCD-diet silenced Srebf1, Scd1, and Acly. Together, our findings highlight early genomic reprogramming events in MASLD, and unlike the high-fat MCD-diet which stimulates MASH, we report high-sucrose/high-starch to elicit benign steatosis without inflammation.
{"title":"Distinct Mechanistic Pathways in Mouse MASLD Models: High-Sucrose/Starch Versus High-Fat, Methionine- and Choline-Deficient Diets.","authors":"Yanzhe Xu, Yun Zhu, Kyuhong Lee, Jürgen Borlak","doi":"10.1016/j.jnutbio.2026.110353","DOIUrl":"https://doi.org/10.1016/j.jnutbio.2026.110353","url":null,"abstract":"<p><p>Metabolic dysfunction-associated steatotic liver disease (MASLD) ranges from simple steatosis (MASL) to fibrotic steatohepatitis (MASH). Yet, the molecular mechanisms initiating these divergent outcomes remain unclear. We addressed the question whether MASLD induced by a high-sucrose/ starch diet (MCS) is similar to a high-fat, methionine- and choline-deficient diet (MCD+HFD). To investigate early genomic programming events in these MASLD models, we fed C57BL/6N mice either an MCS or MCD+HFD for 14 days. Histopathology and serum biochemistries confirmed MASLD phenotypes and transcriptomics guided pathway enrichment analysis. Furthermore, ChIP-seq-validated transcription factor targets enabled construction of regulatory gene networks (RGNs) in glucose homeostasis and lipid metabolism. Importantly, the MCS and MCD+HFD caused 692 and 703 differentially expressed genes, and although transcriptomics revealed shared genomic responses, we also observed diet-specific adaptations. Both diets repressed glycolysis, yet MCS showed broader suppression. Furthermore, fatty acid β-oxidation and lipid droplet biogenesis was induced whereas lipogenesis, cholesterol biosynthesis and the kynurenine pathway were repressed. Strikingly, the high-sucrose/high-starch diet suppressed acute-phase, prostaglandin, redox, antigen presentation, and autophagy pathways. Conversely, the high-fat MCD-diet activated cytokine signalling, macrophage networks, and inflammatory programs. Intriguingly, RGNs aided an identification of diet-specific master regulatory networks with MCS stimulating Insig2, Id1, and Mafb signalling. Conversely, the high-fat MCD-diet silenced Srebf1, Scd1, and Acly. Together, our findings highlight early genomic reprogramming events in MASLD, and unlike the high-fat MCD-diet which stimulates MASH, we report high-sucrose/high-starch to elicit benign steatosis without inflammation.</p>","PeriodicalId":16618,"journal":{"name":"Journal of Nutritional Biochemistry","volume":" ","pages":"110353"},"PeriodicalIF":4.9,"publicationDate":"2026-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147499331","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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