Ketogenic diets induced glucose intolerance and lipid accumulation in mice with alterations in gut microbiota and metabolites

Abstract Background: A ketogenic diet (KD), which is extremely high in fat with a very low carbohydrate level and can induce changes in gut microbiota, has shown benefits for epilepsy and several neurodegenerative diseases. However, the effects of a KD on glucose and lipid metabolism remain inconclusive.Results: Using two formulas of ketogenic diets (KDR with 89.5% fat and KDH with 91.3% fat), which are commonly used in mouse trials, we found that KDR but not KDH induced insulin resistance and damaged glucose homeostasis, while KDH induced more fat accumulation in mice. In addition to the differences in the proportions of nutrients between the two kinds of KD, we found that the sources of fat in KDR were mainly trans-fatty acids. Further study showed that KD impacted glucose metabolism, which was related to the sources of fat, while both the sources and proportions of fat affected lipid metabolism. We found that both the sources and proportions of fat changed the abundance of specific bacteria in Lachnospiraceae and Oscillibacter, which positively correlated with parameters related to lipid accumulation. The abundances of specific bacteria in Bacteroides and Ruminococcaceae were only affected by the sources of fat, and specific bacteria from Lactococcus and Roseburia were only affected by the proportions of fat. Moreover, alterations in the concentrations of SCFAs and tryptophan metabolites, which were negatively correlated with parameters related to lipid accumulation, were also affected by the sources of fat. In addition, the ketogenic diet widely used in human studies still induced insulin resistance and fat accumulation in mice; enhanced Roseburia, Ruminococcaceae and Lachnospiraceae; reduced Turicibacter; increased bile acids and decreased SCFAs.Conclusions: Overall, our study demonstrated that ketogenic diets induced glucose intolerance and lipid accumulation in mice, which is closely related to the source and proportion of fat in the diet, likely due to changes in the gut microbiota and metabolites.

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Ketogenic Diets Induced Glucose Intolerance and Lipid Accumulation in Mice with Alterations in Gut Microbiota and Metabolites

mBio ◽

10.1128/mbio.03601-20 ◽

2021 ◽

Vol 12 (2) ◽

Author(s):

Yue Li ◽

Xin Yang ◽

Jing Zhang ◽

Tianyi Jiang ◽

Ziyi Zhang ◽

...

Keyword(s):

Insulin Resistance ◽

Lipid Metabolism ◽

Gut Microbiota ◽

Neurodegenerative Diseases ◽

Ketogenic Diet ◽

Glucose Intolerance ◽

Lipid Accumulation ◽

Fat Accumulation ◽

Glucose And Lipid Metabolism ◽

Ketogenic Diets

ABSTRACT The ketogenic diet (KD), which can induce changes in gut microbiota, has shown benefits for epilepsy and several neurodegenerative diseases. However, the effects of a KD on glucose and lipid metabolism remain inconclusive. Using two formulas of ketogenic diets (KDR with 89.5% fat and KDH with 91.3% fat), which are commonly used in mouse trials, we found that KDR but not KDH induced insulin resistance and damaged glucose homeostasis, while KDH induced more fat accumulation in mice. Further study showed that KD impacted glucose metabolism, which was related to the sources of fat, while both the sources and proportions of fat affected lipid metabolism. And the KD widely used in human studies still induced insulin resistance and fat accumulation in mice. Moreover, KDs changed the gut microbiota and metabolites in mice, and the sources and proportions of fat in the diets respectively changed the abundance of specific bacteria and metabolites which were correlated with parameters related to glucose intolerance and lipid accumulation. Overall, our study demonstrated that the metabolic disorders induced by KDs are closely related to the source and proportion of fat in the diet, which may be associated with the changes of the gut microbiota and metabolites. IMPORTANCE The ketogenic diet with extremely high fat and very low carbohydrate levels is very popular in society today. Although it has beneficial effects on epilepsy and neurodegenerative diseases, how ketogenic diets impact host glucose and lipid metabolism and gut microbiota still needs further investigation. Here, we surveyed the effects of two ketogenic diets which are commonly used in mouse trials on metabolic phenotypes, gut microbiota, and metabolites in mice. We found that both ketogenic diets impaired glucose and lipid metabolism in mice, and this may be due to the sources and proportions of fat in the diets. This work highlights the potential risk of glucose and lipid metabolism disorders and the importance of evaluating the sources and proportions of fat in the diets, when using ketogenic diets for weight loss and the treatment of diseases.

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GPR120 agonist ameliorated insulin resistance and improved ovarian function

Zygote ◽

10.1017/s0967199421000873 ◽

2021 ◽

pp. 1-6

Author(s):

Yang Liu ◽

Jiayi Ding ◽

Xiaofang Tan ◽

Ya Shen ◽

Li Xu ◽

...

Keyword(s):

Insulin Resistance ◽

Lipid Metabolism ◽

Rat Model ◽

Lipid Accumulation ◽

Ovarian Function ◽

Polycystic Ovary ◽

Vital Role ◽

Expression Levels ◽

Glucose And Lipid Metabolism

Summary GPR120 is implicated in the regulation of glucose and lipid metabolism, and insulin resistance. In the current study, we aimed to investigate the role of GPR120 in polycystic ovary syndrome (PCOS). With the adoption of dehydroepiandrosterone, a rat model was established to simulate PCOS in vitro. mRNA and protein expression levels of GPR120 were measured using RT-qPCR and western blot, respectively. In addition, expression levels of testosterone, estradiol, luteinizing hormone and follicle-stimulating hormone, serum total cholesterol and triglyceride were assessed using the corresponding kits. Moreover, haematoxylin and eosin staining was used to detect pathological changes in ovary or liver and oil red staining was utilized to evaluate lipid accumulation. In the present study, GPR120 was downregulated in plasma, liver and ovary in the PCOS rat model. In addition, the GPR120 agonist regulated lipid metabolism in the liver and weight in the PCOS rat model. Furthermore, the GPR120 agonist decreased insulin resistance in the PCOS rat model but improved the ovarian function. It is suggested that GPR120 plays a vital role in suppressing insulin resistance, regulating ovary function and decreasing lipid accumulation in the liver, demonstrating that targeting GPR120 could be an effective method for the improvement of PCOS.

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FGF21 as an Endocrine Regulator in Lipid Metabolism: From Molecular Evolution to Physiology and Pathophysiology

Journal of Nutrition and Metabolism ◽

10.1155/2011/981315 ◽

2011 ◽

Vol 2011 ◽

pp. 1-8 ◽

Cited By ~ 45

Author(s):

Yusuke Murata ◽

Morichika Konishi ◽

Nobuyuki Itoh

Keyword(s):

Insulin Resistance ◽

Lipid Metabolism ◽

Molecular Evolution ◽

Ketogenic Diet ◽

Metabolic Diseases ◽

Cultured Cells ◽

Pharmacological Effects ◽

Glucose And Lipid Metabolism ◽

Physiological Regulator ◽

Related Proteins

The FGF family comprises twenty-two structurally related proteins with functions in development and metabolism. TheFgf21gene was generated early in vertebrate evolution. FGF21 acts as an endocrine regulator in lipid metabolism. HepaticFgf21expression is markedly induced in mice by fasting or a ketogenic diet. Experiments withFgf21transgenic mice and cultured cells indicate that FGF21 exerts pharmacological effects on glucose and lipid metabolism in hepatocytes and adipocytes via cell surface FGF receptors. However, experiments withFgf21knockout mice indicate that FGF21 inhibits lipolysis in adipocytes during fasting and attenuates torpor induced by a ketogenic diet but maybe not a physiological regulator for these hepatic functions. These findings suggest the pharmacological effects to be distinct from the physiological roles. Serum FGF21 levels are increased in patients with metabolic diseases having insulin resistance, indicating that FGF21 is a metabolic regulator and a biomarker for these diseases.

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Uridine attenuates obesity, ameliorates hepatic lipid accumulation and modifies the gut microbiota composition in mice fed with a high-fat diet

Food & Function ◽

10.1039/d0fo02533j ◽

2021 ◽

Author(s):

Yilin Liu ◽

Chunyan Xie ◽

Zhenya Zhai ◽

Ze-yuan Deng ◽

Hugo R. De Jonge ◽

...

Keyword(s):

Gut Microbiota ◽

Lipid Accumulation ◽

High Fat Diet ◽

Microbiota Composition ◽

High Fat ◽

Fat Accumulation ◽

Hepatic Lipid ◽

Hepatic Lipid Accumulation ◽

Gut Microbiota Composition

This study aimed to investigate the effect of uridine on obesity, fat accumulation in liver, and gut microbiota composition in high-fat diet-fed mice.

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Effects of low-carbohydrate diet and ketogenic diet on glucose and lipid metabolism in type 2 diabetic mice

Nutrition ◽

10.1016/j.nut.2021.111230 ◽

2021 ◽

pp. 111230

Author(s):

Zi Yang ◽

Jingyi Mi ◽

Yu Wang ◽

Lamei Xue ◽

Jinxin Liu ◽

...

Keyword(s):

Lipid Metabolism ◽

Ketogenic Diet ◽

Diabetic Mice ◽

Carbohydrate Diet ◽

Low Carbohydrate Diet ◽

Glucose And Lipid Metabolism ◽

Low Carbohydrate ◽

Type 2 Diabetic

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Alanine Aminotransferase Levels and Fatty Liver in Childhood Obesity: Associations with Insulin Resistance, Adiponectin, and Visceral Fat

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2006-1010 ◽

2006 ◽

Vol 91 (11) ◽

pp. 4287-4294 ◽

Cited By ~ 243

Author(s):

Tania S. Burgert ◽

Sara E. Taksali ◽

James Dziura ◽

T. Robin Goodman ◽

Catherine W. Yeckel ◽

...

Keyword(s):

Lipid Metabolism ◽

Insulin Sensitivity ◽

Fatty Liver ◽

Visceral Fat ◽

Resonance Imaging ◽

Fat Accumulation ◽

Glucose And Lipid Metabolism ◽

The Metabolic Syndrome ◽

Hepatic Fat ◽

Fat Fraction

Abstract Background: Concurrent with the rise in obesity, nonalcoholic fatty liver disease is recognized as the leading cause of serum aminotransferase elevations in obese youth. Nevertheless, the complete metabolic phenotype associated with abnormalities in biomarkers of liver injury and intrahepatic fat accumulation remains to be established. Methods: In a multiethnic cohort of 392 obese adolescents, alanine aminotransferase (ALT) levels were related with parameters of insulin sensitivity, glucose, and lipid metabolism as well as adipocytokines and biomarkers of inflammation. A subset of 72 adolescents had determination of abdominal fat partitioning and intrahepatic fat accumulation using magnetic resonance imaging. Findings: Elevated ALT (>35 U/liter) was found in 14% of adolescents, with a predominance of male gender and white/Hispanic race/ethnicity. After adjusting for potential confounders, rising ALT was associated with reduced insulin sensitivity and glucose tolerance as well as rising free fatty acids and triglycerides. Worsening of glucose and lipid metabolism was already evident as ALT levels rose into the upper half of the normal range (18–35 U/liter). When hepatic fat fraction was assessed using fast magnetic resonance imaging, 32% of subjects had an increased hepatic fat fraction, which was associated with decreased insulin sensitivity and adiponectin, and increased triglycerides, visceral fat, and deep to superficial sc fat ratio. The prevalence of the metabolic syndrome was significantly greater in those with fatty liver. Interpretation: Deterioration in glucose and lipid metabolism is associated even with modest ALT elevations. Hepatic fat accumulation in childhood obesity is strongly associated with the triad of insulin resistance, increased visceral fat, and hypoadiponectinemia. Hence, hepatic steatosis may be a core feature of the metabolic syndrome.

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Lactobacillus plantarum Strain Ln4 Attenuates Diet-Induced Obesity, Insulin Resistance, and Changes in Hepatic mRNA Levels Associated with Glucose and Lipid Metabolism

Nutrients ◽

10.3390/nu10050643 ◽

2018 ◽

Vol 10 (5) ◽

pp. 643 ◽

Cited By ~ 33

Author(s):

Eunjung Lee ◽

So-Ra Jung ◽

So-Young Lee ◽

Na-Kyoung Lee ◽

Hyun-Dong Paik ◽

...

Keyword(s):

Insulin Resistance ◽

Lipid Metabolism ◽

Lactobacillus Plantarum ◽

Mrna Levels ◽

Glucose And Lipid Metabolism ◽

Diet Induced Obesity

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Abstract P274: Fruit Extract (blueberry, Cranberry, And Promegranate) Improved Insulin Resistance In Overweight Hypertensive And Normotensive Subjects

Hypertension ◽

10.1161/hyp.68.suppl_1.p274 ◽

2016 ◽

Vol 68 (suppl_1) ◽

Author(s):

Ludmila N Novaes ◽

Mariele Moraes ◽

Keyla Katayama ◽

Carine Sangaleti ◽

Maria Claudia Irigoyen ◽

...

Keyword(s):

Insulin Resistance ◽

Lipid Metabolism ◽

Repeated Measures ◽

Hdl Cholesterol ◽

Biochemical Tests ◽

Fruit Extract ◽

Hypertensive Patients ◽

Glucose And Lipid Metabolism ◽

Normotensive Subjects ◽

Group B

Arterial hypertension is frequently associated to glucose and lipid metabolism abnormalities. The purpose of this study was to determine if antioxidants (fruit extract) supplementation interfere with glucose and lipid metabolism in overweight hypertensive patients. A randomized clinical trial was conducted with 30 individuals, 23 hypertensive patients (group A) and 7 normotensive controls (group B). They were randomized to take 3 capsules of different fruits extract a day (blueberry, cranberry and pomegranate) or placebo for 4 weeks. This is a crossover study, which started with placebo changed to capsules and vice versa. Blood samples were collected after 12 hours fasting for biochemical tests (glucose, insulin, total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides), anthropometric assessment (weight, height, and body mass index), systolic BP, diastolic BP and heart rate were evaluated at baseline, after 4, and 8 weeks. The comparisons between groups were held with the GLM repeated measures. Twenty three hypertensive patients (age 47 years, 14 females) and 7 normotensive controls (age 40 years, 7 females) were evaluated. BMI, blood pressure, heart and lipid profile did not differ between groups. HOMAir decreased significantly in both groups. See results in table 1. Values are expressed as medians (±SD) In these preliminary results a 4-weeks supplementation of antioxidants (fruit extract) improved insulin resistance in overweight hypertensive and normotensive subjects. Financial support: FAPESP 2014/25808-3

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Black rice anthocyanins alleviate hyperlipidemia, liver steatosis and insulin resistance by regulating lipid metabolism and gut microbiota in obese mice

Food & Function ◽

10.1039/d1fo01394g ◽

2021 ◽

Author(s):

Haizhao Song ◽

Xinchun Shen ◽

Yang Zhou ◽

Xiaodong Zheng

Keyword(s):

Insulin Resistance ◽

Lipid Metabolism ◽

Gut Microbiota ◽

Hepatic Steatosis ◽

High Fat Diet ◽

Liver Steatosis ◽

Obese Mice ◽

Black Rice ◽

High Fat ◽

Diet Induced Obesity

Supplementation of black rice anthocyanins (BRAN) alleviated high fat diet-induced obesity, insulin resistance and hepatic steatosis by improvement of lipid metabolism and modification of the gut microbiota.

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