BACKGROUND: Ketogenic diets are increasingly popular for addressing obesity, but their impacts on the gut microbiota and metabolome remain unclear. This paper aimed to investigate how a ketogenic diet affects intestinal microorganisms and metabolites in obesity.
METHODS: Male mice were provided with one of the following dietary regimens: normal chow, high-fat diet, ketogenic diet, or high-fat diet converted to ketogenic diet. Body weight and fat mass were measured weekly using high-precision electronic balances and minispec body composition analyzers. Metagenomics and non-targeted metabolomics data were used to analyze differences in intestinal contents.
RESULTS: Obese mice on the ketogenic diet exhibited notable improvements in weight and body fat. However, these were accompanied by a significant decrease in intestinal microbial diversity, as well as an increase in Firmicutes abundance and a 247% increase in the Firmicutes/Bacteroidetes ratio. The ketogenic diet also altered multiple metabolic pathways in the gut, including glucose, lipid, energy, carbohydrate, amino acid, ketone body, butanoate, and methane pathways, as well as bacterial secretion and colonization pathways. These changes were associated with increased intestinal inflammation and dysbiosis in obese mice. Furthermore, the ketogenic diet enhanced the secretion of bile and the synthesis of aminoglycoside antibiotics in obese mice, which may impair the gut microbiota and be associated with intestinal inflammation and immunity.
CONCLUSIONS: The study suggest that the ketogenic diet had an unfavorable risk-benefit trade-off and may compromise metabolic homeostasis in obese mice.

Ketogenic diets have attracted substantial interest in the treatment of chronic diseases, but there are health risks with long-term regimes. Despite the advancements in diagnostic and therapeutic methods in modern medicine, there is a huge gap in personalized health management of this dietary strategy. Hence, we present a wearable microneedle biosensor for real-time ketone and glucose monitoring. The microneedle array possesses excellent mechanical properties, allowing for consistent sampling of interstitial biomarkers while reducing the pain associated with skin puncture. Vertical graphene with outstanding electrical conductivity provides the resulting sensor with a high sensitivity of 234.18 μA mM-1 cm-2 and a low limit detection of 1.21 μM. When this fully integrated biosensor was used in human volunteers, it displayed an attractive analytical capability for tracking the dynamic metabolite levels. Moreover, the results of the on-body evaluation established a significant correlation with commercial blood measurements. Overall, this cost-effective and efficient sensing platform can accelerate the application of a ketogenic diet in personal nutrition and wellness management.

Type 2 diabetes mellitus (T2DM) is a major risk factor of a number of neurodegenerative diseases (NDDs). Ketogenic diet (KD) has significant beneficial effects on glycemic control and may act effectively against NDDs, but the mechanism remains unclear. In this study, we aimed to investigate the potential effects of KD on gene expressions in the brains of T2DM model mice. Male db/db mice at the age of 9 weeks were fed with KD or normal diet to the age of 6 months, and the whole brains were subjected to mRNA-seq analysis for differentially expressed genes. KD significantly lowered fasting glucose and body weights in db/db mice (P < 0.05), and the expression of 189 genes in the brain were significantly changed (P < 0.05, |log2| > 1). Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses revealed that the differentially expressed genes upon KD are involved in inflammatory responses and the functions of biosynthesis. In inflammatory responses, NF-κB signaling pathway, viral protein interaction with cytokine and cytokine receptor, and cytokine-cytokine receptor interaction pathways were enriched, and in biosynthesis pathways, genes functioning in lipid and amino acid metabolism, protein synthesis, and energy metabolism were enriched. Moreover, consistent with the gene set enrichment analysis results, proteasomal activity measured biochemically were enhanced in KD-fed T2DM mice. These data may facilitate the understanding of how KD can be protective to the brain in T2DM background. KD could be a new strategy for the prevention of NDDs in T2DM patients.

OBJECTIVE: The past few decades have witnessed a rapid growth in the prevalence of nonalcoholic fatty liver disease (NAFLD). While the ketogenic diet (KD) is considered for managing NAFLD, the safety and efficacy of the KD on NAFLD has been a controversial topic. Here, we aimed to investigate the effect of KD of different durations on metabolic endpoints in mice with NAFLD and explore the underlying mechanisms.
METHODS: NAFLD mice were fed with KD for 1, 2, 4 and 6 weeks, respectively. The blood biochemical indexes (blood lipids, AST, ALT and etc.) and liver fat were measured. The LC-MS/MS based proteomic analysis was performed on liver tissues. Metallothionein-2 (MT2) was knocked down with adeno-associated virus (AAV) or small interfering RNA (siRNA) in NAFLD mice and AML-12 cells, respectively. H&E, BODIPY and ROS staining were performed to examine lipid deposition and oxidative stress. Furthermore, MT2 protein levels, nucleus/cytoplasm distribution and DNA binding activity of peroxisome proliferators-activated receptors α (PPARα) were evaluated.
RESULTS: KD feeding for 2 weeks showed the best improvement on NAFLD phenotype. Proteomic analysis revealed that MT2 was a key candidate for different metabolic endpoints of NAFLD affected by different durations of KD feeding. MT2 knockdown in NAFLD mice blocked the effects of 2 weeks of KD feeding on HFD-induced steatosis. In mouse primary hepatocytes and AML-12 cells, MT2 protein levels were induced by β-hydroxybutyric acid (β-OHB). MT2 Knockdown blunted the effects of β-OHB on alleviating PA-induced lipid deposition. Mechanistically, 2 weeks of KD or β-OHB treatment reduced oxidative stress and upregulated the protein levels of MT2 in nucleus, which subsequently increased its DNA binding activity and PPARα protein expression.
CONCLUSIONS: Collectively, these findings indicated that KD feeding prevented NAFLD in a time dependent manner and MT2 is a potential target contributing to KD improvement on steatosis.

Bone health encompasses not only bone mineral density but also bone architecture and mechanical properties that can impact bone strength. While specific dietary interventions have been proposed to treat various diseases such as obesity and diabetes, their effects on bone health remain unclear. The aim of this review is to examine literature published in the past decade, summarize the effects of currently popular diets on bone health, elucidate underlying mechanisms, and provide solutions to neutralize the side effects. The diets discussed in this review include a ketogenic diet (KD), a Mediterranean diet (MD), caloric restriction (CR), a high-protein diet (HP), and intermittent fasting (IF). Although detrimental effects on bone health have been noticed in the KD and CR diets, it is still controversial, while the MD and HP diets have shown protective effects, and the effects of IF diets are still uncertain. The mechanism of these effects and the attenuation methods have gained attention and have been discussed in recent years: the KD diet interrupts energy balance and calcium metabolism, which reduces bone quality. Ginsenoside-Rb2, metformin, and simvastatin have been shown to attenuate bone loss during KD. The CR diet influences energy imbalance, glucocorticoid levels, and adipose tissue, causing bone loss. Adequate vitamin D and calcium supplementation and exercise training can attenuate these effects. The olive oil in the MD may be an effective component that protects bone health. HP diets also have components that protect bone health, but their mechanism requires further investigation. In IF, animal studies have shown detrimental effects on bone health, while human studies have not. Therefore, the effects of diets on bone health vary accordingly.

BACKGROUND: The effectiveness of ketogenic diet (KD) in ameliorating fatty liver has been established, although its mechanism is under investigation. Fibroblast growth factor 21 (FGF21) positively regulates obesity-associated metabolic disorders and is elevated by KD. FGF21 conventionally initiates its intracellular signaling via receptor β-klotho (KLB). However, the mechanistic role of FGF21-KLB signaling for KD-ameliorated fatty liver remains unknown. This study aimed to delineate the critical role of FGF21 signaling in the ameliorative effects of KD on hepatic steatosis.
METHODS: Eight-week-old C57BL/6 J mice were fed a chow diet (CD), a high-fat diet (HFD), or a KD for 16 weeks. Adeno-associated virus-mediated liver-specific KLB knockdown mice and control mice were fed a KD for 16 weeks. Phenotypic assessments were conducted during and after the intervention. We investigated the mechanism underlying KD-alleviated hepatic steatosis using multi-omics and validated the expression of key genes.
RESULTS: KD improved hepatic steatosis by upregulating fatty acid oxidation and downregulating lipogenesis. Transcriptional analysis revealed that KD dramatically activated FGF21 pathway, including KLB and fibroblast growth factor receptor 1 (FGFR1). Impairing liver FGF21 signaling via KLB knockdown diminished the beneficial effects of KD on ameliorating fatty liver, insulin resistance, and regulating lipid metabolism.
CONCLUSIONS: KD demonstrates beneficial effects on diet-induced metabolic disorders, particularly on hepatic steatosis. Liver FGF21-KLB signaling plays a critical role in the KD-induced amelioration of hepatic steatosis.

Diet, serving as a vital source of nutrients, exerts a profound influence on human health and disease progression. Recently, dietary interventions have emerged as promising adjunctive treatment strategies not only for cancer but also for neurodegenerative diseases, autoimmune diseases, cardiovascular diseases, and metabolic disorders. These interventions have demonstrated substantial potential in modulating metabolism, disease trajectory, and therapeutic responses. Metabolic reprogramming is a hallmark of malignant progression, and a deeper understanding of this phenomenon in tumors and its effects on immune regulation is a significant challenge that impedes cancer eradication. Dietary intake, as a key environmental factor, can influence tumor metabolism. Emerging evidence indicates that dietary interventions might affect the nutrient availability in tumors, thereby increasing the efficacy of cancer treatments. However, the intricate interplay between dietary interventions and the pathogenesis of cancer and other diseases is complex. Despite encouraging results, the mechanisms underlying diet-based therapeutic strategies remain largely unexplored, often resulting in underutilization in disease management. In this review, we aim to illuminate the potential effects of various dietary interventions, including calorie restriction, fasting-mimicking diet, ketogenic diet, protein restriction diet, high-salt diet, high-fat diet, and high-fiber diet, on cancer and the aforementioned diseases. We explore the multifaceted impacts of these dietary interventions, encompassing their immunomodulatory effects, other biological impacts, and underlying molecular mechanisms. This review offers valuable insights into the potential application of these dietary interventions as adjunctive therapies in disease management.

Ketogenic diet, characterized by high fat and low carbohydrate content, is gradually becoming a new perspective in the human diet; however, the mechanism of digestion of ketogenic diet remains unknown. In this study, we explored the oil-water interface to elucidate the digestion of a ketogenic diet based on typical representative medium- and long-chain triglycerides. The free fatty acids (FFAs) release indicated that glycerol trioctanoate with a shorter carbon chain (FFA = 920.55 ± 10.17 μmol) was significantly more digestible than glycerol tripalmitate (851.36 ± 9.48 μmol) and glycerol tristearate (805.81 ± 10.03 μmol). Particle size analysis revealed that the length of the carbon chain increased the size of triglycerides, resulting in a decreased contact area with lipase. The interfacial phenomenon indicated that the longer the carbon chain of triglycerides, the greater the reduction in binding capacity with salt ions in the digestive solution. Fluorescence spectroscopy analysis showed that the length of the carbon chain induced the displacement of the lipase peak, suggesting that the carbon chain length could alter the structure of lipase. Molecular dynamics simulation showed that the longer the carbon chain of triglycerides, the easier it was to loosen the structure of lipase. Bond energy analysis showed that the carbon chain length of triglycerides was positively correlated with the bond energy strength of the ester bonding. In conclusion, this study emphasizes that the ketogenic diet should primarily consist of shorter carbon chain triglycerides because carbon chain length can alter the digestion of triglycerides. This provides a new perspective on the quest for more effective ketogenic diet, in line with the current view of healthy diet.

OBJECTIVE: Ketogenic diets (KD) have been shown to alleviate insulin resistance (IR) by exerting anti-lipogenic and insulin sensitizing effects in the liver through a variety of pathways. The present study sought to investigate whether a ketogenic diet also improves insulin sensitization in skeletal muscle cells through alleviating endoplasmic reticulum stress.
METHODS: High-fat diet-induced IR mice were allowed to a 2-week ketogenic diet. Insulin resistance and glucose tolerance were evaluated through GTT, ITT, and HOMA-IR. The C2C12 myoblasts exposed to palmitic acid were used to evaluate the insulin sensitization effects of β-hydroxybutyric acid (β-OHB). Molecular mechanisms concerning ER stress signaling activation and glucose uptake were assessed.
RESULTS: The AKT/GSK3β pathway was inhibited, ER stress signaling associated with IRE1, PERK, and BIP was activated, and the number of Glut4 proteins translocated to membrane decreased in the muscle of HFD mice. However, all these changes were reversed after 2 weeks of feeding on a ketogenic diet. Consistently in C2C12 myoblasts, the AKT/GSK3β pathway was inhibited by palmitic acid (PA) treatment. The endoplasmic reticulum stress-related proteins, IRE1, and BIP were increased, and the number of Glut4 proteins on the cell membrane decreased. However, β-OHB treatment alleviated ER stress and improved the glucose uptake of C2C12 cells.
CONCLUSIONS: Our data reveal that KD ameliorated HFD-induced insulin resistance in skeletal muscle, which was partially mediated by inhibiting endoplasmic reticulum stress. The insulin sensitization effect of β-OHB is associated with up regulation of AKT/GSK3β pathway and the increase in the number of Glut4 proteins on the cell membrane.

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