Calorie Restriction Using High-Fat/Low-Carbohydrate Diet Suppresses Liver Fat Accumulation and Pancreatic Beta-Cell Dedifferentiation in Obese Diabetic Mice.

In diabetes, pancreatic ß-cells gradually lose their ability to secrete insulin with disease progression. ß-cell dysfunction is a contributing factor to diabetes severity. Recently, islet cell heterogeneity, exemplified by ß-cell dedifferentiation and identified in diabetic animals, has attracted attention as an underlying molecular mechanism of ß-cell dysfunction. Previously, we reported ß-cell dedifferentiation suppression by calorie restriction, not by reducing hyperglycemia using hypoglycemic agents (including sodium-glucose cotransporter inhibitors), in an obese diabetic mice model (db/db). Here, to explore further mechanisms of the effects of food intake on ß-cell function, db/db mice were fed either a high-carbohydrate/low-fat diet (db-HC) or a low-carbohydrate/high-fat diet (db-HF) using similar calorie restriction regimens. After one month of intervention, body weight reduced, and glucose intolerance improved to a similar extent in the db-HC and db-HF groups. However, ß-cell dedifferentiation did not improve in the db-HC group, and ß-cell mass compensatory increase occurred in this group. More prominent fat accumulation occurred in the db-HC group livers. The expression levels of genes related to lipid metabolism, mainly regulated by peroxisome proliferator-activated receptor α and γ, differed significantly between groups. In conclusion, the fat/carbohydrate ratio in food during calorie restriction in obese mice affected both liver lipid metabolism and ß-cell dedifferentiation.

Efficacy and Safety of Ketogenic Diet Treatment in Pediatric Patients with Mitochondrial Disease.

Mitochondrial diseases (MDs) are a heterogeneous group of disorders resulting from abnormal mitochondrial function. Currently, there is no causal treatment for MDs. The aim of the study was to assess the effectiveness and safety of the ketogenic diet (KD) in patients with MD and to analyse selected biochemical and clinical parameters evaluating the effectiveness of KD treatment in patients with MDs. A total of 42 paediatric patients were assigned to four groups: group 1-patients with MD in whom KD treatment was started (n = 11); group 2-patients with MD remaining on an ordinary diet (n = 10); group 3-patients without MD in whom KD treatment was initiated (n = 10), group 4-patients without MD on a regular diet (n = 11). Clinical improvement was observed in 9/11 patients with MD treated with KD. Among patients with MD without KD, the clinical condition deteriorated in 7/10 patients, improved in 2/10 patients, and remained unchanged in one patient. Adverse events of KD occurred with a comparable frequency in groups 1 and 3. There was no significant difference in changes in biomarker concentrations over the course of the study among patients treated and untreated with KD.

Carbohydrate quality, not quantity, linked to reduced colorectal cancer incidence and mortality in US populations: evidence from a prospective study.

BACKGROUND: Carbohydrates have been implicated in colorectal cancer (CRC) risk, but the specific impact of carbohydrate quality and quantity on CRC susceptibility in US populations remains unclear. METHODS: We followed 101,694 participants from Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. The carbohydrate quality index (CQI) and low-carbohydrate diet score (LCDs) were used to evaluate the daily carbohydrate quality and quantity separately, where higher scores indicated greater adherence. Cox proportional hazards regression was used to compute HRs and 95% CIs for incident CRC and related death. Subgroup analyses were conducted to identify potential effect modifiers. RESULTS: During follow-up, we documented 1085 incident cases of CRC, of whom 311 died from CRC. Individuals in the highest compared with the lowest quartiles of CQI had a lower CRC incidence (Q4 vs Q1: HR 0.80, 95% CI 0.67-0.96, Ptrend = 0.012) and mortality (Q4 vs Q1: HR 0.61, 95% CI 0.44-0.86, Ptrend = 0.004). The inverse association between CQI and CRC risk was observed for distal colon and rectum but not for proximal colon cancer. Regarding mortality, this association was only significant for rectum cancer. Subgroup analyses indicated this inverse association of CQI with CRC risk was only observed in participants with lower LCDs. No significant associations were found between LCDs and CRC incidence or mortality. CONCLUSIONS: Our findings suggest focusing on higher quality, rather than restricting the quantity, of carbohydrate consumption may be an effective approach to reduce the risk of CRC in the US population, particularly for distal colon and rectal cancers.

Nutritional strategies cause memory damage and alter biochemical parameters without causing neuroinflammation.

Obesity results from an energy imbalance and has been considered an epidemic due to its increasing rates worldwide. It is classified as a low-grade chronic inflammatory disease and has associated comorbidities. Different nutritional strategies are used for the purpose of weight loss, highlighting low-carbohydrate (LC) diets, ketogenic diets, and intermittent fasting (IF). These strategies can lead to metabolic and behavioral changes as they stimulate different biochemical pathways. Therefore, this study evaluated memory, energy metabolism, neuroinflammation, oxidative stress, and antioxidant defense parameters in mice subjected to an LC diet, ketogenic diet (KD), or IF. Eighty male Swiss mice, 60 days old, were divided into 4 groups: control, LC, KD, or IF. Body weight was measured weekly, and food intake every 48 h. After 15 days of nutritional interventions, the animals were subjected to the behavioral object recognition test and subsequently euthanized. Then, visceral fat was removed and weighed, and the brain was isolated for inflammatory and biochemical analysis. We concluded from this study that the LC and KD strategies could damage memory, IF improves the production of adenosine triphosphate (ATP), and the LC, KD, and IF strategies do not lead to neuroinflammatory damage but present damage at the level of oxidative stress.

A search for factors associated with reduced carbohydrate intake and NTD risk in two population-based studies.

BACKGROUND: Two population-based case-control studies have reported an increased risk of neural tube defect (NTD)-affected pregnancies among women with low carbohydrate diet in the periconceptional period. Given that only two studies have investigated this association, it is unclear to what degree the findings could be impacted by residual confounding. Here, we further interrogated both studies that observed this association with the objective to identify factors from a much larger number of factors that might explain the association. METHODS: By employing a machine learning algorithm (random forest), we investigated a baseline set of over 200 variables. These analyses produced the top 10 variables in each data set for cases and controls that predicted periconceptional low carbohydrate intake. RESULTS: Examining those prediction variables with logistic regression modeling, we did not observe any particular variable that substantially contributed to the NTD-low carbohydrate association in either data set. CONCLUSIONS: If there are underlying factors that explain the association, our findings suggest that none of the 200+ variables we examined were sufficiently correlated with what that true explanatory exposure may be. Alternatively, our findings may suggest that there are other unidentified factor(s) at play, or the association observed in two independent data sets is directly related to low carbohydrate intake.

The association of dietary carbohydrate quality and quantity with obesity among Iranian adolescents: a case-control study.

BACKGROUND: Adolescent obesity is considered as a major health concern worldwide which is closely linked to the quality of diet. The purpose of the present study was to assess the carbohydrate quality and quantity in relation to odds of overweight and obesity in adolescents. METHODS: This case-control study with a 1:1 ratio was conducted on 406 adolescents (14 to 18 years old) matched for age and gender. Participants were selected by multistage cluster random sampling method from March to October 2019 in Shiraz, Iran. Dietary intakes of the study population were assessed by a validated semi-quantitative food frequency questionnaire. Also anthropometric indices were measured using standard methods and demographic information was recorded via face to face interview. The relation between low carbohydrate diet score (LCDS) and carbohydrate quality index (CQI), and odds of obesity was evaluated by multiple Logistic regression. RESULTS: After adjusting the role of potential confounders, the participants in the third tertiles of LCDS (OR = 0.443, 95% CI = (0.260 to 0.755)) and CQI (OR = 0.005, 95% CI = (0.001 to 0.025)) had less odds of being overweight and obese compared to the first tertile. CONCLUSION: The present study found an inverse relationship between dietary quantity and quality of carbohydrate intake and the odds of overweight and obesity in a sample of Iranian adolescents.

Dietary and Metabolic Approaches for Treating Autism Spectrum Disorders, Affective Disorders and Cognitive Impairment Comorbid with Epilepsy: A Review of Clinical and Preclinical Evidence.

Epilepsy often occurs with other neurological disorders, such as autism, affective disorders, and cognitive impairment. Research indicates that many neurological disorders share a common pathophysiology of dysfunctional energy metabolism, neuroinflammation, oxidative stress, and gut dysbiosis. The past decade has witnessed a growing interest in the use of metabolic therapies for these disorders with or without the context of epilepsy. Over one hundred years ago, the high-fat, low-carbohydrate ketogenic diet (KD) was formulated as a treatment for epilepsy. For those who cannot tolerate the KD, other diets have been developed to provide similar seizure control, presumably through similar mechanisms. These include, but are not limited to, the medium-chain triglyceride diet, low glycemic index diet, and calorie restriction. In addition, dietary supplementation with ketone bodies, polyunsaturated fatty acids, or triheptanoin may also be beneficial. The proposed mechanisms through which these diets and supplements work to reduce neuronal hyperexcitability involve normalization of aberrant energy metabolism, dampening of inflammation, promotion of endogenous antioxidants, and reduction of gut dysbiosis. This raises the possibility that these dietary and metabolic therapies may not only exert anti-seizure effects, but also reduce comorbid disorders in people with epilepsy. Here, we explore this possibility and review the clinical and preclinical evidence where available.

Should carbohydrate-modified diets be the first option for weight loss in people with impaired glucose metabolism? A scoping review.

While the "precision nutrition" movement is at an early stage of development, several investigations have compared low-fat versus carbohydrate (CHO)-modified diets (i.e., low-or-reduced-CHO, low glycemic index/load diets, and high-fiber) in people with normal versus impaired glucose metabolism. The purpose of this scoping review was to summarize evidence in support of the hypothesis that CHO-modified diets are more effective for weight loss among people with impaired glucose metabolism. Fifteen articles were included in this review: seven retrospective analyses of randomized clinical trials and eight prospective randomized clinical trials with prespecified hypotheses related to a diet (low-fat vs. CHO-modified) × phenotype (normal vs. impaired) interaction. Evidence in support of the hypothesis was identified in six of seven retrospective and three of eight prospective studies, which led to a recommendation of CHO-modified diets as a first-line option for people with impaired glucose metabolism. However, the evidence in support of this recommendation is relatively weak, and dietary prescriptions should consider additional contextual information that may influence overall dietary adherence. Additional and rigorous research using innovative randomized experimental approaches is needed for stronger dietary weight loss recommendations based on pretreatment glycemic status.

The Role of the FODMAP Diet in IBS.

The low FODMAP (fermentable oligosaccharide, disaccharide, monosaccharide, and polyol) diet is a beneficial therapeutic approach for patients with irritable bowel syndrome (IBS). However, how the low FODMAP diet works is still not completely understood. These mechanisms encompass not only traditionally known factors such as luminal distension induced by gas and water but also recent evidence on the role of FOMAPs in the modulation of visceral hypersensitivity, increases in intestinal permeability, the induction of microbiota changes, and the production of short-chain fatty acids (SCFAs), as well as metabolomics and alterations in motility. Although most of the supporting evidence is of low quality, recent trials have confirmed its effectiveness, even though the majority of the evidence pertains only to the restriction phase and its effectiveness in relieving abdominal bloating and pain. This review examines potential pathophysiological mechanisms and provides an overview of the existing evidence on the effectiveness of the low FODMAP diet across various IBS subtypes. Key considerations for its use include the challenges and disadvantages associated with its practical implementation, including the need for professional guidance, variations in individual responses, concerns related to microbiota, nutritional deficiencies, the development of constipation, the necessity of excluding an eating disorder before commencing the diet, and the scarcity of long-term data. Despite its recognized efficacy in symptom management, acknowledging these limitations becomes imperative for a nuanced comprehension of the role of a low FODMAP diet in managing IBS. By investigating its potential mechanisms and evidence across IBS subtypes and addressing emerging modulations alongside limitations, this review aims to serve as a valuable resource for healthcare practitioners, researchers, and patients navigating the intricate landscape of IBS.

The Efficacy of Dietary Interventions in Patients with Gastroesophageal Reflux Disease: A Systematic Review and Meta-Analysis of Intervention Studies.

BACKGROUND: International guidelines recommend dietary interventions as one of the most important treatments for patients with gastroesophageal reflux disease (GERD). Evidence to confirm the efficacy of these treatment modalities is lacking. The present study aims to evaluate the efficacy of dietary interventions on GERD-related outcomes evaluated in intervention studies on GERD patients. METHODS: A systematic review and meta-analysis was performed according to PRISMA. The PubMed/MEDLINE, Web of Sciences, and Scopus databases were utilized for the literature search. Two independent researchers searched for relevant publications published up until June 2023. Intervention studies evaluating the efficacy of dietary interventions in patients with GERD were included. RESULTS: A total of 577 articles were identified during the initial literature search. After reviewing, 21 studies with 16 different types of dietary interventions were included in the analysis. The interventions were divided into low-carbohydrate diets (3 studies), high-fat diets (2 studies), speed of eating studies (3 studies), low-FODMAP diets (2 studies), and other interventions (12 studies). A meta-analysis could be performed for low-carbohydrate diets and speed of eating interventions. Low-carbohydrate diets resulted in a significant reduction in esophageal acid exposure time (mean difference = -2.834%, 95% confidence interval (CI): -4.554 to -1.114), while a slow speed of eating did not lead to a lower percentage of reflux events compared to fast eating (risk ratio = 1.044, 95% CI: 0.543-2.004). Most other interventions showed positive effects in only a single study. CONCLUSION: Low-carbohydrate diets showed a significant improvement in GERD-related outcomes, while a slow eating speed did not result in a reduction in reflux events. The overall evidence regarding dietary interventions in GERD remains scarce. High-quality, long-term RCTs are still required to confirm the effects of dietary interventions in GERD patients.

Ayuno intermitente: efectos en diversos escenarios clínicos / Intermittent fasting: effects in diverse clinical settings

Introducción: los esquemas de ayuno intermitente (AI) proponen limitar la ingestión de alimentos durante periodos específicos. Se han propuestocomo estrategia dietoterapéutica para tratar distintas condiciones metabólicas en diversos padecimientos, sin embargo, la heterogeneidad entrecada contexto de ayuno intermitente pudiera generar diferentes resultados en parámetros metabólicos.Objetivo: evaluar la aplicación clínica del ayuno intermitente y discernir si ofrece ventajas sobre otras estrategias tradicionales.Métodos: se formularon preguntas estructuradas (PICO) y la metodología se apegó a las guías establecidas por la declaración PRISMA 2020.Se realizó una búsqueda de literatura científica en las plataformas de PubMed, Cochrane Library y Google Scholar.Resultados: se encontraron 3.962 artículos, de los cuales se incluyeron finalmente 56, eliminando 3.906 trabajos que no contestaban directao indirectamente las preguntas estructuradas.Conclusiones: frente a las dietas convencionales, los diversos esquemas de AI no generan ventajas ni desventajas en cuanto a pérdida de pesoo perfil lipídico, aunque en la variante a días alternos se producen mayores reducciones de insulina a las observadas en la restricción energéticacontinua. La heterogeneidad de las intervenciones y poblaciones estudiadas, así como los comparadores, los desenlaces y el tipo de diseñoimposibilitan extrapolar los efectos a todos los escenarios clínicos y generalizar las recomendaciones.(AU)

Introduction: intermittent fasting plans propose to limit food intake during specific periods as nutritional therapeutic strategies to treat differentmetabolic conditions in various clinical entities. However, the heterogeneity between each context of intermittent fasting could generate differentresults in metabolic parameters.Objective: to evaluate the clinical application of intermittent fasting and to discern whether it offers advantages over other traditional strategies.Methods: structured questions were formulated (PICO), and the methodology followed the guidelines established by the PRISMA 2020 statement.The search was conducted in different databases (PubMed, Cochrane Library and Google Scholar).Results: we found 3,962 articles, of which 56 were finally included; 3,906 articles that did not directly or indirectly answer the structuredquestions were excluded.Conclusions: compared to conventional diets, the various AI schemes do not generate advantages or disadvantages in terms of weight loss andlipid profile, although in the alternate-day variant there are greater insulin reductions than those observed in the continuous energy restriction. Theheterogeneity of the interventions, the populations studied, the comparators, the results, and the type of design make it impossible to extrapolatethe effects found in all clinical scenarios and generalize the recommendations.(AU)

Low-carbohydrate-diet score, dietary macronutrient intake, and depression among adults in the United States.

BACKGROUND: The aim was to ascertain whether low-carbohydrate-diet (LCD) score and dietary macronutrient intake are associated with depression. METHODS: This cross-sectional study included 23,204 United States adults from the National Health and Nutrition Examination Survey (NHANES) 2005-2018. Dietary macronutrient intake was evaluated by the average of two 24-h dietary recall interviews. LCD score was calculated by summing the 11 quantiles values of the percentages of energy derived from carbohydrate, protein, and fat. Major depression was defined as a nine-item Patient Health Questionnaire score of 10 or more. Logistic regression and restricted cubic spline models were used to explore the relationship between LCD score, dietary macronutrient intake, and depression. RESULTS: LCD score was significantly associated with the risk of depression after adjustment for covariates (odds ratio, 0.98; 95 % confidence interval, 0.97-0.99; p < 0.001). Restricted cubic splines showed that the pattern of this inverse association was nonlinear. Among macronutrients, carbohydrate and protein intake was nonlinearly associated with the risk of depression, whereas fat intake was not related to the risk of depression. A decreased risk of depression was observed when the carbohydrate intake was moderate (45.3 %-59.1 %). The pattern of the association between protein intake and the risk of depression was L-shaped. CONCLUSIONS: LCD score was inversely associated with the risk of depression in a nonlinear manner in a nationally representative sample of adults from the United States. Furthermore, moderate carbohydrate intake and high protein intake were correlated with a lower risk of depression.

Increased low-density lipoprotein cholesterol on a low-carbohydrate diet in adults with normal but not high body weight: A meta-analysis.

BACKGROUND: Low-density lipoprotein (LDL) cholesterol change with consumption of a low-carbohydrate diet (LCD) is highly variable. Identifying the source of this heterogeneity could guide clinical decision-making. OBJECTIVES: To evaluate LDL cholesterol change in randomized controlled trials involving LCDs, with a focus on body mass index (BMI) in kg/m2. METHODS: Three electronic indexes (Pubmed, EBSCO, and Scielo) were searched for studies between 1 January, 2003 and 20 December, 2022. Two independent reviewers identified randomized controlled trials involving adults consuming <130 g/d carbohydrate and reporting BMI and LDL cholesterol change or equivalent data. Two investigators extracted relevant data, which were validated by other investigators. Data were analyzed using a random-effects model and contrasted with results of pooled individual participant data. RESULTS: Forty-one trials with 1379 participants and a mean intervention duration of 19.4 wk were included. In a meta-regression accounting for 51.4% of the observed variability on LCDs, mean baseline BMI had a strong inverse association with LDL cholesterol change [ß = -2.5 mg/dL/BMI unit, 95% confidence interval (CI): -3.7, -1.4], whereas saturated fat amount was not significantly associated with LDL cholesterol change. For trials with mean baseline BMI <25, LDL cholesterol increased by 41 mg/dL (95% CI: 19.6, 63.3) on the LCD. By contrast, for trials with a mean of BMI 25-<35, LDL cholesterol did not change, and for trials with a mean BMI ≥35, LDL cholesterol decreased by 7 mg/dL (95% CI: -12.1, -1.3). Using individual participant data, the relationship between BMI and LDL cholesterol change was not observed on higher-carbohydrate diets. CONCLUSIONS: A substantial increase in LDL cholesterol is likely for individuals with low but not high BMI with consumption of an LCD, findings that may help guide individualized nutritional management of cardiovascular disease risk. As carbohydrate restriction tends to improve other lipid and nonlipid risk factors, the clinical significance of isolated LDL cholesterol elevation in this context warrants investigation. This trial was registered at PROSPERO as CRD42022299278.

REduced-Carbohydrate intervention for managing Obesity and Reduction of gestational Diabetes (RECORD): A randomized controlled feasibility trial.

AIM: To test the feasibility and acceptability of a reduced-carbohydrate dietary program, intended to reduce the risk of gestational diabetes. MATERIALS AND METHODS: Fifty-one pregnant women at <20 weeks' gestation, with body mass index ≥30 kg/m2 , and a normal baseline oral glucose tolerance test (OGTT), were randomized 2:1 to an intervention or control group and followed-up until delivery. The dietary intervention aimed at providing 130-150 g carbohydrate/day. Feasibility outcomes assessed at 24-28 weeks' gestation, included adoption of the reduced-carbohydrate diet by the intervention group, and retention of all participants, assessed by completion of a second OGTT. Changes in glycemia, weight gain and dietary intake, and the maternal and neonatal outcomes were also assessed. Participants were interviewed about their experience of the intervention and the study. RESULTS: Forty-nine of 51 participants attended the follow-up OGTT, a retention rate of 96% (95% confidence interval [CI] 86.8%-98.9%). In the intervention group, carbohydrate intake at follow-up was 190.4 (95% CI 162.5-215.6) g/day, a reduction of -24.6 (95% CI -51.5-2.4) g/day from baseline. Potentially favourable effects of the intervention on glucose control, weight gain and blood pressure were observed, but the study was not powered to detect significant differences in these. Participants found the intervention acceptable, and were content with the study processes, but some reported barriers to sustained adherence, mainly pertaining to competing priorities. CONCLUSIONS: Retention was high, suggesting the study processes are feasible, but the carbohydrate reduction in the intervention group was small, and did not meet progression criteria, limiting the likelihood of achieving the desired goal to prevent gestational diabetes. TRIAL REGISTRATION NUMBER: ISRCTN16235884.

Effect of the pelleting process on diet formulations with varying levels of crystalline amino acids and reducing sugars on digestibility in growing pigs.

The objective of this experiment was to determine the effects of pelleting on the standardized ileal digestibility (SID) of amino acids (AA) and crude protein (CP) in diets with or without increased concentrations of free AA and reducing sugars (RS). Eight individually housed, ileal cannulated barrows (initially 31.4 kg) were allotted to an 8 × 8 Latin square with eight diets and eight 7-d periods with ileal digesta collected on days 6 and 7. Treatments were arranged in a 2 × 2 × 2 factorial with the main effects of diet form (mash or pellet), crystalline AA (low or high), or RS (low or high), provided by distillers dried grains with solubles and bakery meal. Diets were pelleted to achieve a hot pellet temperature of 85 to 88 °C. Data were analyzed as a Latin square design using the GLIMMIX procedure of SAS 9.4. A feed form × RS interaction (P < 0.026) for SID of tryptophan was observed. Feeding pelleted low RS diets increased SID of tryptophan compared with mash high and low RS diets, and pelleted high RS diets. For the main effects of feed form, the SID of total AA, CP, and indispensable AA was greater (P < 0.042) in pelleted diets compared with mash diets. For the main effects of crystalline AA, pigs fed high crystalline AA had increased (P = 0.007) SID of tryptophan and decreased (P = 0.050) SID of histidine compared with those fed low crystalline AA diets. For the main effects of RS, high RS diets had decreased (P < 0.05) SID of total AA, CP, and indispensable AA compared with low RS diets. In conclusion, pelleting diets increased AA digestibility, and pelleting diets with increased crystalline AA or RS did not affect the improvement in AA digestibility from pelleting. Diets formulated with high crystalline AA had increased SID of tryptophan. Formulating diets with high RS resulted in decreased AA digestibility compared with corn-soybean meal-based diets.

The objective of this study was to determine the effects of pelleting on the standardized ileal digestibility (SID) of amino acids (AA) in diets with or without increased concentrations of free AA and reducing sugars (RS). Treatments were arranged in a 2 × 2 × 2 factorial with the main effects of diet form (mash or pellet), crystalline AA (low or high), or RS (low or high), provided by dried distillers grains with solubles and bakery meal. A total of 8 illeal cannulated barrows were fed treatments in an 8 × 8 Latin square design. Results indicated that there was no evidence of interactions between diet types and diet form, indicating that increasing amounts of crystalline AA and RS did not reduce amino acid digestibility when pelleting diets. Additionally, pelleting diets resulted in increased amino acid digestibility compared to mash diets. Diets formulated with 20% dried distillers grains with solubles and 15% bakery resulted in decreased amino acid digestibility compared with the corn­soybean meal-based diets. Crystalline amino acid concentration did not influence amino acid digestibility of indispensable AA, except for SID of tryptophan which was increased in diets with higher concentrations of crystalline AA.

Very low-carbohydrate diet with higher protein ratio improves lipid metabolism and inflammation in rats with diet-induced nonalcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is commonly associated with obesity, and it is mainly treated through lifestyle modifications. The very low-carbohydrate diet (VLCD) can help lose weight rapidly but the possible effects of extreme dietary patterns on lipid metabolism and inflammatory responses in individuals with NAFLD remain debatable. Moreover, VLCD protein content may affect its effectiveness in weight loss, steatosis, and inflammatory responses. Therefore, we investigated the effects of VLCDs with different protein contents in NAFLD rats and the mechanisms underlying these effects. After a 16-week inducing period, the rats received an isocaloric normal diet (NC group) or a VLCD with high or low protein content (NVLH vs. NVLL group, energy ratio:protein/carbohydrate/lipid=20/1/79 vs. 6/1/93) for the next 8 weeks experimental period. We noted that the body weight decreased in both the NVLH and NVLL groups; nevertheless, the NVLH group demonstrated improvements in ketosis. The NVLL group led to hepatic lipid accumulation, possibly by increasing very-low-density lipoprotein receptor (VLDLR) expression and elevating liver oxidative stress, subsequently activating the expression of Nrf2, and inflammation through the TLR4/TRIF/NLRP3 and TLR4/MyD88/NF-κB pathway. The NVLH was noted to prevent the changes in VLDLR and the TLR4-inflammasome pathway partially. The VLCD also reduced the diversity of gut microbiota and changed their composition. In conclusion, although low-protein VLCD consumption reduces BW, it may also lead to metabolic disorders and changes in microbiota composition; nevertheless, a VLCD with high protein content may partially alleviate these limitations.