A new way for punicalagin to alleviate insulin resistance: regulating gut microbiota and autophagy

Background: Insulin resistance, defined as a diminished ability to respond to the stimulation of insulin, is the main line for a variety of metabolic-related diseases. Punicalagin (PU), a hydrolyzable tannin of pomegranate juice, exhibits multiple biological properties, including anti-oxidant, anti-cancer and anti-inflammatory activities. Objective: This research study aimed at determining the protective effect of PU on insulin resistance and to uncover the underlying mechanism based on the gut microbiota, IKKβ/NF-κB pathway, and autophagy. Design: An insulin resistance animal model was established using C57BL/6 mice fed with a high-fat diet (HFD) for 8 weeks. The model included two groups continuing a HFD for 12 weeks with or without administering via gavage with PU 20 mg/kg/day. Changes in fasting plasma glucose levels, fasting serum insulin levels, glucose and insulin tolerance, glycolipid metabolism, gut microbiota composition (16S rRNA gene sequencing), inflammatory responses, and autophagy in the liver were evaluated. Body weight gain, glycolipid metabolic disorder, liver injury, as well as systemic and hepatic insulin sensitivity, were significantly attenuated after supplementing with PU. Results: This research study revealed that PU alleviated HFD-induced glucose and lipid disorders, liver injury and insulin resistance; decreased the Firmicutes/Bacteroides ratio, decreased the abundance of Coprococcus and Anaerotruncus, and increased Rikenellaceae; and decreased serum and liver tumor necrosis factor-alpha and interleukin-1β levels, inhibited liver IKKβ and NF-κB phosphorylation; and increased liver autophagy-related proteins LC3-II, P62, and Beclin1, and increased the number of liver autophagosomes. Conclusion: PU can improve HFD-induced insulin resistance, improved liver glucose and lipid metabolism disorder and liver injury, and the potential mechanism is that PU inhibited the IKKβ/NF-κB inflammatory pathway by regulating gut microbiota homeostasis and up-regulating liver autophagy

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Yoghurt Consumption is Associated With Transient Changes in the Composition of the Human Gut Microbiome

10.21203/rs.3.rs-99718/v1 ◽

2020 ◽

Author(s):

Caroline Ivanne Le Roy ◽

Alexander Kurilshikov ◽

Emily Leeming ◽

Alessia Visconti ◽

Ruth Bowyer ◽

...

Keyword(s):

16S Rrna ◽

Gut Microbiota ◽

Visceral Fat ◽

Gut Microbiome ◽

Body Weight Gain ◽

Healthy Eating Index ◽

Rrna Gene ◽

Metagenomic Sequencing ◽

Sequencing Data ◽

Shotgun Metagenomic Sequencing

Abstract Background: Yoghurt contains live bacteria that could contribute via modulation of the gut microbiota to its reported beneficial effects such as reduced body weight gain and lower incidence of type 2 diabetes. To date, the association between yoghurt consumption and the composition of the gut microbiota is underexplored. Here we used clinical variables, metabolomics, 16S rRNA and shotgun metagenomic sequencing data collected on over 1000 predominantly female UK twins to define the link between the gut microbiota and yoghurt-associated health benefits. Results: According to food frequency questionnaires (FFQ), 73% of subjects consumed yoghurt. Consumers presented a healthier diet pattern (healthy eating index: beta = 2.17±0.34; P = 2.72x10-10) and improved metabolic health characterised by reduced visceral fat (beta = -28.18±11.71 g; P = 0.01). According to 16S rRNA gene analyses and whole shotgun metagenomic sequencing approach consistent taxonomic variations were observed with yoghurt consumption. More specifically, we identified higher abundance of species used as yoghurt starters Streptococcus thermophilus (beta = 0.41±0.051; P = 6.14x10-12) and sometimes added Bifidobacterium animalis subsp. lactis (beta = 0.30±0.052; P = 1.49x10-8) in the gut of yoghurt consumers. Replication in 1103 volunteers from the LifeLines-DEEP cohort confirmed the increase of S. thermophilus among yoghurt consumers. Using food records collected the day prior to faecal sampling we showed that increase in these two yoghurt bacteria could be transient. Metabolomics analysis revealed that B. animalis subsp. lactis was associated with 13 faecal metabolites including a 3-hydroxyoctanoic acid, known to be involved in the regulation of gut inflammation.Conclusions: Yoghurt consumption is associated with reduced visceral fat mass and changes in gut microbiome including transient increase of yoghurt-contained species (i.e. S. thermophilus and B. lactis).

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EVALUATION OF CYCLIC ADENOSINE MONOPHOSPHATE AND NEUROTRANSMITTERS IN EXPERIMENTAL OBESITY: IMPACT OF BLACK PEPPER AND COFFEE AQUEOUS EXTRACTS

Asian Journal of Pharmaceutical and Clinical Research ◽

10.22159/ajpcr.2016.v9s3.14592 ◽

2016 ◽

Vol 9 (9) ◽

pp. 87 ◽

Cited By ~ 1

Author(s):

Yasmin Abdel Latif ◽

Shadia Fathy ◽

Zakaria El-khayat ◽

Maha Moustafa ◽

Abdel Razik Farrag ◽

...

Keyword(s):

Insulin Resistance ◽

Blood Glucose ◽

Lipid Profile ◽

High Performance ◽

Energy Homeostasis ◽

Body Weight Gain ◽

Serum Insulin ◽

Cyclic Adenosine Monophosphate ◽

Adenosine Monophosphate ◽

Black Pepper

ABSTRACTObjective: This study aims to evaluate the effect of black pepper and coffee extracts on chronic and acute experimental-induced obesity and energyhomeostasis.Methods: Rats were divided into 10 groups including control, high-fat diet (HFD), triton, HFD+triton, black pepper+HFD, black pepper+HFD+triton,coffee+HFD, coffee+HFD+triton, mixture+HFD, and mixture+HFD+triton groups. Blood glucose, serum insulin, and insulin resistance were estimated.Body mass index, food efficiency intake, and body weight gain were calculated. Lipid profile, liver and kidney functions were measured, serum and braincyclic adenosine monophosphate (cAMP) was estimated, and brain neurotransmitters were measured by high-performance liquid chromatography.Furthermore, histopathology of liver was performed.Results: Findings showed that blood glucose, insulin resistance, lipid profile, kidney and liver functions as well as brain cAMP and neurotransmitterswere significantly increased, concomitant with a significant decrease in insulin resistance and serum cAMP in both HFD and triton-induced obesitygroups compared to control.Conclusion: Supplementation with black pepper extract, coffee extract, and a mixture of both significantly improved these findings. In conclusion,black pepper and coffee extracts are overlooked as promising weight reduction and antihyperlipidemic agents.Keywords: Energy homeostasis, Obesity, Black pepper extract, Coffee extract, Cyclic adenosine monophosphate, Neurotransmitters.

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Dietary Proteins Relevant to Human Consumption Impact the Development of Obesity and Type 2 Diabetes in Association with Major Changes in the Gut Microbiota in a Mouse Model (OR27-03-19)

Current Developments in Nutrition ◽

10.1093/cdn/nzz046.or27-03-19 ◽

2019 ◽

Vol 3 (Supplement_1) ◽

Author(s):

Noëmie Daniel ◽

Béatrice Choi ◽

Vanessa Houde ◽

Thibault Varin ◽

Cecile Vors ◽

...

Keyword(s):

Animal Models ◽

Gut Microbiota ◽

Insulin Signaling ◽

Body Weight Gain ◽

Bacterial Species ◽

Human Consumption ◽

Oral Glucose ◽

Rrna Gene ◽

Dietary Proteins ◽

The Impact

Abstract Objectives Animal models fed a high-fat high-sucrose (HFHS) diet are commonly used to study obesity and cardiometabolic diseases. While much attention is paid to the impact of fat and carbohydrates sources, very little consideration is given to the composition of dietary proteins. Indeed, casein is often the only source of protein in rodent's diet. This study aimed to evaluate the impact of a dietary protein mix that is more relevant to typical intakes of proteins in humans and its influences on body weight gain, metabolic health and gut microbiota. Methods Our new diet contained a mix of 10 protein sources based on NHANES data that were incorporated into low-fat low-sucrose (LFLS) and HFHS diets. C57BL/6J mice were fed these diets or control diets containing identical amounts of casein as the only source of protein for 12 weeks. Feces were collected for gut microbiota investigation, an oral glucose tolerance test was performed and tissues were harvested for analysis of insulin signaling and mTOR/S6K1 activation. Results 16S rRNA gene sequencing of fecal samples showed that both LFLS and HFHS mice fed the protein mix had increased gut microbiota diversity, and significant changes in the relative abundance of several bacterial species (higher Adlercreutzia or Tyzzerella, lower Bacteroides or Akkermansia) as compared to mice fed casein only. Importantly, inclusion of the protein mix amplified the effects of the HFHS diet on the development of obesity, glucose intolerance and hyperinsulinemia as compared to casein-fed animals, whereas no difference was observed in the context of LFLS feeding. Evaluation of insulin signaling in the liver also revealed that the protein mix potentiated the effect of HFHS feeding on the mTORC1/S6K1 pathway, increasing inhibitory phosphorylation of IRS-1 on Ser1101 and leading to further impairment of Akt activation by insulin. Conclusions Our results reveal that compared to pure casein, feeding a protein mixture causes major changes in the gut microbiota profile and greater impact on HFHS-induced obesity and associated metabolic impairments. This study illustrates the importance of considering a diverse source of dietary proteins when using laboratory animal models to more reliably reproduce the development of metabolic syndrome in humans, and to enhance the clinical relevance of nutritional and therapeutic interventions. Funding Sources N/A.

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Jiao-Tai-Wan Ameliorates the Insulin Resistance and Lipid Metabolism in T2DM Rats by Regulating Neurotransmitters

10.21203/rs.3.rs-857847/v1 ◽

2021 ◽

Author(s):

Jianhua Chen ◽

Ziqi Jing ◽

Xue Wang ◽

Chu Li ◽

Yanyi Li ◽

...

Keyword(s):

Insulin Resistance ◽

Lipid Metabolism ◽

Protein Expression ◽

Serum Insulin ◽

Fasting Blood Glucose ◽

Sprague Dawley ◽

Lipid Metabolism Disorder ◽

Peripheral Tissues ◽

Mrna And Protein Expression ◽

The Brain

Abstract Background: Type 2 diabetes mellitus (T2DM) is a metabolic disease characterized by insulin resistance and β-cell dysfunction, and accompanied by neuroendocrine disorders. Recently, Jiao-Tai-Wan (JTW) has been reported to exert hypoglycemic effects against diabetes. However, its mechanism has not been clarified. Therefore, we attempted to explore the effect of JTW on alleviating insulin resistance and lipid metabolism disorder in T2DM rats by regulating the level of neurotransmitters. Methods: Sprague-Dawley (SD) rats were treated with a high-fat diet/streptozotocin to induce T2DM and then gavaged with JTW for 4 weeks. Afterwards, endpoints including body weight, fasting blood glucose, glucose tolerance, serum insulin, and lipid index were determined, and we analyzed pathological changes in the liver and kidney. Meanwhile, the level of neurotransmitter neurotransmitters in the central nervous system and peripheral tissues was measured by UPLC-MS/MS. Furthermore, the expression of neurotransmitter transporter mRNA and protein levels in the brain and kidney of T2DM rats was analyzed by qRT-PCR and WB. Results: The results showed that JTW ameliorated glucose homeostasis, insulin resistance, and lipid metabolism in T2DM rats by regulating the disorder of neurotransmitter distribution in the brain, kidney, intestine, adrenal gland, blood, and urine of T2DM rats. Mechanically, JTW may improve neurotransmitter disturbance by reducing mRNA and protein expression of SERT, DAT, and GAT-1 and increasing mRNA and protein expression of NET in the brain and kidney of T2DM rats.Conclusion: Our findings confirm that JTW can play a hypoglycemic role by regulating the disorder level of neurotransmitter distribution in T2DM rats, which may have potential therapeutic implications for the treatment of T2DM.

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Respiratory and Gut Microbiota in Commercial Turkey Flocks with Disparate Weight Gain Trajectories Display Differential Compositional Dynamics

10.1101/2020.02.19.957092 ◽

2020 ◽

Author(s):

Kara J.M. Taylor ◽

John M. Ngunjiri ◽

Michael C. Abundo ◽

Hyesun Jang ◽

Mohamed Elaish ◽

...

Keyword(s):

Weight Gain ◽

Gut Microbiota ◽

Body Weight Gain ◽

Poor Performance ◽

Rrna Gene ◽

Body Weights ◽

And Performance ◽

Brood Stage ◽

Commercial Turkey ◽

Respiratory Microbiota

ABSTRACTHost-associated communities of bacteria (microbiota) substantially contribute to the overall poultry health and performance. Gut microbiota are known to play roles in resistance to pathogen infection and optimal weight gain in turkey flocks. However, knowledge of turkey respiratory microbiota and its link to gut microbiota is lacking. This study presents a 16S rRNA gene-based census of the turkey respiratory microbiota (nasal cavity and trachea) alongside gut microbiota (cecum and ileum) in two identical commercial Hybrid Converter turkey flocks raised in parallel under typical field commercial conditions. The flocks were housed in adjacent barns during the brood stage and in geographically separated farms during the grow-out stage. Several bacterial taxa that were acquired in the respiratory tract (RT) at the beginning of the brood stage persisted throughout the flock cycle, primarily Staphylococcus. Late-emerging predominant taxa in RT included Deinococcus and Corynebacterium. Tracheal and nasal microbiota of turkeys were identifiably distinct from one another and from gut microbiota. Nevertheless, gut and RT microbiota changed in parallel over time and appeared to share many taxa. During the brood stage, the two flocks generally acquired similar gut and RT microbiota, and their average body weights were comparable. Separating the flocks during the grow-out stage resulted in divergent microbial profiles and body weight gain trajectories. Lower weight gain corresponded with emergence of Deinococcus and Ornithobacterium in RT, and Fusobacterium and Parasutterella in gut. This study provides an overview of turkey microbiota under field conditions and suggests several hypotheses concerning the respiratory microbiome.IMPORTANCETurkey meat is an important source of animal protein, and the industry around its production contributes significantly to the agricultural economy. The nonpathogenic symbionts present in the gut of turkeys are known to impact bird health and flock performance. However, the respiratory microbiota in turkeys are entirely unexplored. This study has elucidated the microbiota of respiratory tracts of turkeys from two commercial flocks raised in parallel throughout a normal flock cycle. Further, the study suggests that bacteria originating in the gut or in poultry house environments may influence respiratory communities and consequently induce poor performance, either directly or indirectly. Future attempts to develop microbiome-based interventions for turkey health should delimit the contributions of respiratory microbiota and aim to limit disturbances to those communities.

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Glucosamine Ameliorates Symptoms of High-Fat Diet-Fed Mice by Reversing Imbalanced Gut Microbiota

Frontiers in Pharmacology ◽

10.3389/fphar.2021.694107 ◽

2021 ◽

Vol 12 ◽

Author(s):

Xubing Yuan ◽

Junping Zheng ◽

Lishi Ren ◽

Siming Jiao ◽

Cui Feng ◽

...

Keyword(s):

Gut Microbiota ◽

High Fat Diet ◽

Inflammatory Responses ◽

Fasting Blood Glucose ◽

Intestinal Barrier ◽

Intestinal Bacteria ◽

High Fat ◽

Lipid Metabolism Disorder ◽

Metabolism Disorder ◽

Rdna Sequencing

Glucosamine (GlcN) is used as a supplement for arthritis and joint pain and has been proved to have effects on inflammation, cancer, and cardiovascular diseases. However, there are limited studies on the regulatory mechanism of GlcN against glucose and lipid metabolism disorder. In this study, we treated high-fat diet (HFD)-induced diabetic mice with GlcN (1 mg/ml, in drinking water) for five months. The results show that GlcN significantly reduced the fasting blood glucose of HFD-fed mice and improved glucose tolerance. The feces of intestinal contents in mice were analyzed using 16s rDNA sequencing. It was indicated that GlcN reversed the imbalanced gut microbiota in HFD-fed mice. Based on the PICRUSt assay, the signaling pathways of glucolipid metabolism and biosynthesis were changed in mice with HFD feeding. By quantitative real-time PCR (qPCR) and hematoxylin and eosin (H&E) staining, it was demonstrated that GlcN not only inhibited the inflammatory responses of colon and white adipose tissues, but also improved the intestinal barrier damage of HFD-fed mice. Finally, the correlation analysis suggests the most significantly changed intestinal bacteria were positively or negatively related to the occurrence of inflammation in the colon and fat tissues of HFD-fed mice. In summary, our studies provide a theoretical basis for the potential application of GlcN to glucolipid metabolism disorder through the regulation of gut microbiota.

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Streptococcus, the Predominant Bacterium to Predict the Severity of Liver Injury in Alcoholic Liver Disease

Frontiers in Cellular and Infection Microbiology ◽

10.3389/fcimb.2021.649060 ◽

2021 ◽

Vol 11 ◽

Author(s):

Xiaodan Zhong ◽

Ping Cui ◽

Junjun Jiang ◽

Chuanyi Ning ◽

Bingyu Liang ◽

...

Keyword(s):

Liver Disease ◽

Liver Injury ◽

Gut Microbiota ◽

Alcoholic Liver Disease ◽

Early Stage ◽

Characteristic Curve ◽

Hepatic Function ◽

Rrna Gene ◽

Alcoholic Fatty Liver ◽

Predominant Bacterium

BackgroundNew evidence implies that the imbalance of gut microbiota is associated with the progression of alcoholic liver disease (ALD) and that the composition of gut microbiota is altered in ALD patients. However, the predominant bacterium in patients involved in the progress of ALD has not been identified. The purpose of this study is to investigate the predominant bacterium in the early and end-stages of ALD as well as the relationship between the bacterium and the degree of liver injury.MethodsWe enrolled 21 alcoholic fatty liver (AFL) patients, 17 alcoholic liver cirrhosis (ALC) patients and 27 healthy controls, and sequenced the 16S rRNA gene of their fecal microbiota. The gut microbiota composition and its relationship with the indicators of clinical hepatic function were assessed using canonical correspondence analysis (CCA), spearman correlation heatmap and multivariate association with linear (MaAsLin) Models.ResultsThe composition and structure of gut microbiota changed greatly in different stages of ALD, and the degree of disorder was aggravated with the progression of ALD, even in the early stage. Moreover, the relative abundance of Streptococcus was highly enriched only in patients with ALC (P <0.001), and positively correlated with AST level (P = 0.029). The abundance of Streptococcus distinguished the liver injury of ALC patients from the controls with an area under the receiver-operating characteristic curve (AUC) of 0.877 (P < 0.001).ConclusionsThese findings indicate that the imbalance of gut microbiota exists at the early and end-stages of ALD, and the degree of disorder is aggravated with the progression of ALD. Streptococcus, as the predominant bacterium, may be a microbiological marker to evaluate the severity of liver injury in ALD patients.

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miRNA-10a-5p Alleviates Insulin Resistance and Maintains Diurnal Patterns of Triglycerides and Gut Microbiota in High-Fat Diet-Fed Mice

Mediators of Inflammation ◽

10.1155/2020/8192187 ◽

2020 ◽

Vol 2020 ◽

pp. 1-8

Author(s):

Yawei Guo ◽

Xiaohui Zhu ◽

Sha Zeng ◽

Mingyi He ◽

Xiurong Xing ◽

...

Keyword(s):

Insulin Resistance ◽

Gut Microbiota ◽

Glucose Intolerance ◽

Diurnal Rhythm ◽

High Fat Diet ◽

Clock Genes ◽

Body Weight Gain ◽

Strong Positive Correlation ◽

High Fat ◽

Diurnal Patterns

miRNA-10a is rhythmically expressed and regulates genes involved in lipid and glucose metabolism. However, the effects of miRNA-10a on obesity and glucose intolerance, as well as on the diurnal pattern of expression of circadian clock genes, remain unknown. We explored the effects of miRNA-10a-5p on insulin resistance and on the diurnal patterns of serum triglycerides and gut microbiota in high-fat diet- (HFD-) fed mice. The results showed that oral administration of miRNA-10a-5p significantly prevented body weight gain and improved glucose tolerance and insulin sensitivity in HFD-fed mice. Administration of miRNA-10a-5p also maintained the diurnal rhythm of Clock, Per2, and Cry1 expression, as well as serum glucose and triglyceride levels. Surprisingly, the diurnal oscillations of three genera of microbes, Oscillospira, Ruminococcus, and Lachnospiraceae, disrupted by HFD feeding, maintained by administration of miRNA-10a-5p. Moreover, a strong positive correlation was found between hepatic Clock expression and relative abundance of Lachnospiraceae, both in control mice (r=0.877) and in mice administered miRNA-10a-5p (r=0.853). Furthermore, we found that along with changes in Lachnospiraceae abundance, butyrate content in the feces maintained a diurnal rhythm after miRNA-10a-5p administration in HFD-fed mice. In conclusion, we suggest that miRNA-10a-5p may improve HFD-induced glucose intolerance and insulin resistance through the modulation of the diurnal rhythm of Lachnospiraceae and its metabolite butyrate. Therefore, miRNA-10a-5p may have preventative properties in subjects with metabolic disorders.

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Abstract MP28: A New Gut Microbial Metabolite Derived From Low Fibre Intake

Hypertension ◽

10.1161/hyp.76.suppl_1.mp28 ◽

2020 ◽

Vol 76 (Suppl_1) ◽

Author(s):

Chudan Xu ◽

Michael Nakai ◽

Rikeish Muralitharan ◽

Evany Dinakis ◽

Hamdi Jama ◽

...

Keyword(s):

Gut Microbiota ◽

Gut Microbiome ◽

Mononuclear Cells ◽

Inflammatory Responses ◽

Fold Change ◽

Rrna Gene ◽

Microbial Metabolite ◽

Fibre Intake ◽

High Fibre

Low fermentable fibre intake has emerged as an important risk factor for hypertension through changes in the gut microbiota, but the biological pathways and specific metabolites involved are unknown. We performed untargeted liquid-chromatography mass spectrometry metabolomic profiling on plasma samples from 16 mice fed low or high fibre diets and 70 participants with ambulatory blood pressure recordings. Mouse gut microbiome was analysed using 16S rRNA gene sequencing . In vitro experiments were performed in human peripheral blood mononuclear cells (PBMCs) to assess the role of a new metabolite in inflammatory responses. The phenylalanine, tyrosine and tryptophan biosynthesis pathway was upregulated in hypertensive compared to normotensive participants, as well as in low compared to high fibre fed mice (both q <0.05, pathway impact factor=1.0). In particular, p-cresol glucuronide (pCG), an end-product of tyrosine metabolism, was higher in mice fed with low compared to high fibre in both angiotensin II-treated ( q =4.83 x10 -4 , fold change= 88) and sham groups ( q =1.56 x10 -4 , fold change= 297). pCG is derived from p-Cresol, which is produced by the gut microbiota. β-diversity analyses showed that distinct gut microbiome compositions were associated with levels of pCG in plasma (q<0.05). While diet had a major effect on the gut microbiome (~30%), we found that pCG levels were associated with 5.7-6.3% of the total gut microbiome variation. This is relevant as pCG’s precursor, p-cresol, may inhibit the growth of certain types of bacteria. To understand the possible role of pCG in hypertension, human PBMCs obtained commercially were treated with physiological levels of pCG for 24 hours. This resulted in an increase in proinflammatory IL-17A mRNA ( P =0.01, fold change= 1.79) and a decrease in anti-inflammatory IL-10 mRNA ( P =0.014, fold change= -2.32) when compared to untreated and mock-treated cells. In conclusion, tyrosine biotransformation was associated with both human hypertension and low fibre intake. pCG, a key microbial metabolite derived from the metabolism of tyrosine, was associated with distinct gut microbiome compositions and modulated inflammatory response, suggesting it may be involved in the genesis of hypertension.

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Dipeptidyl-Peptidase 4 Inhibitor Sitagliptin Ameliorates Hepatic Insulin Resistance by Modulating Inflammation and Autophagy in ob/ob Mice

International Journal of Endocrinology ◽

10.1155/2018/8309723 ◽

2018 ◽

Vol 2018 ◽

pp. 1-11 ◽

Cited By ~ 15

Author(s):

Wenbin Zheng ◽

Jing Zhou ◽

Shasha Song ◽

Wen Kong ◽

Wenfang Xia ◽

...

Keyword(s):

Insulin Resistance ◽

Hepatic Steatosis ◽

Inflammatory Responses ◽

Body Weight Gain ◽

Biological Activities ◽

Dipeptidyl Peptidase ◽

Hepatic Insulin Resistance ◽

Dipeptidyl Peptidase 4 ◽

Obesity And Diabetes ◽

Dipeptidyl Peptidase 4 Inhibitor

Obesity and type 2 diabetes are the most common metabolic diseases globally. They are associated with inflammation, oxidative stress, autophagy, and insulin resistance. Sitagliptin, a dipeptidyl-peptidase 4 inhibitor, has been reported to show multiple biological activities beyond the antidiabetic property. This study was aimed at investigating the effect of sitagliptin on hepatic steatosis, insulin resistance, inflammation, and autophagy and exploring the underlying molecular mechanism. In the current study, ob/ob mice, a mouse model of genetic obesity and diabetes, were administered via gavage with sitagliptin 50 mg/kg daily for 4 weeks. Changes in glycolipid metabolism, inflammatory responses, and autophagy in the liver were evaluated. Body weight gain, lipid metabolic disorder, and hepatic steatosis as well as systemic and hepatic insulin sensitivity in ob/ob mice were significantly attenuated after sitagliptin treatment. Furthermore, sitagliptin decreased inflammatory responses by regulating macrophage M1/M2 polarization and inhibiting the activities of NF-κB and JNK. Moreover, sitagliptin increased the levels of phosphorylation of AMPK and decreased those of mTOR. This study indicates that sitagliptin significantly ameliorates the development of hepatic steatosis and insulin resistance in ob/ob mice by inhibiting inflammatory responses and activating autophagy via AMPK/mTOR signaling pathway.

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