A dietary ketone ester mitigates histological outcomes of NAFLD and markers of fibrosis in high-fat diet fed mice

2021 ◽  
Author(s):  
Mary P Moore ◽  
Rory P Cunningham ◽  
Rachel A. H. Davis ◽  
Sarah E. Deemer ◽  
Brandon M. Roberts ◽  
...  
Keyword(s):  
High Fat Diet ◽  
Inflammatory Markers ◽  
Metabolic Diseases ◽  
Stellate Cell ◽  
High Fat ◽  
Nonalcoholic Fatty Liver ◽  
Hepatic Markers ◽  
Nafld Activity Score ◽  
Ketone Ester

Nutritional ketosis as a therapeutic tool has extended to the treatment of metabolic diseases including - obesity, type 2 diabetes and nonalcoholic fatty liver disease. The purpose of this study was to determine whether dietary administration of the ketone ester (KE), R,S-1,3-butanediol diacetoacetate (BD-AcAc2), attenuates markers of hepatic stellate cell (HSC) activation and hepatic fibrosis in the context of high fat diet (HFD)-induced obesity. Six-week-old male C57BL/6J mice were placed on a 10-week ad libitum HFD (45% FAT, 32% CHO, 23% PRO). Mice were then randomized to 1 of 3 groups (n = 10 per group) for an additional 12 weeks: 1) control (CON), continuous HFD, 2) pair-fed (PF) to KE; and 3) KE (HFD+30% energy from BD-AcAc2, KE). KE feeding significantly reduced histological steatosis, inflammation and total NAFLD activity score vs CON, beyond improvements observed for calorie restriction alone (PF). Dietary KE supplementation also reduced the protein content and gene expression of pro-fibrotic markers (α-SMA, Col1a1, PDGF-β, MMP9) vs CON (p<0.05), beyond reductions observed for PF vs CON. Furthermore, KE feeding increased hepatic markers of anti-inflammatory M2 macrophages (CD163) and also reduced pro-inflammatory markers (TRAIL and CCN1) vs CON and PF (p ≤ 0.05), in the absence of changes in markers of total hepatic macrophage content (F4/80 and CD68; p > 0.05). These data highlight that the dietary ketone ester, BD-AcAc2, ameliorates histological NAFLD and inflammation and reduces pro-fibrotic and pro-inflammatory markers. Future studies to further explore potential mechanisms are warranted.

scholarly journals Disrupting phosphatase SHP2 in macrophages protects mice from high-fat diet-induced hepatic steatosis and insulin resistance by elevating IL-18 levels

2020 ◽  
Vol 295 (31) ◽  
pp. 10842-10856 ◽  
Author(s):  
Wen Liu ◽  
Ye Yin ◽  
Meijing Wang ◽  
Ting Fan ◽  
Yuyu Zhu ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Hepatic Steatosis ◽  
High Fat Diet ◽  
Metabolic Disorders ◽  
Metabolic Diseases ◽  
Low Grade ◽  
High Fat ◽  
Caspase 1

Chronic low-grade inflammation plays an important role in the pathogenesis of type 2 diabetes. Src homology 2 domain-containing tyrosine phosphatase-2 (SHP2) has been reported to play diverse roles in different tissues during the development of metabolic disorders. We previously reported that SHP2 inhibition in macrophages results in increased cytokine production. Here, we investigated the association between SHP2 inhibition in macrophages and the development of metabolic diseases. Unexpectedly, we found that mice with a conditional SHP2 knockout in macrophages (cSHP2-KO) have ameliorated metabolic disorders. cSHP2-KO mice fed a high-fat diet (HFD) gained less body weight and exhibited decreased hepatic steatosis, as well as improved glucose intolerance and insulin sensitivity, compared with HFD-fed WT littermates. Further experiments revealed that SHP2 deficiency leads to hyperactivation of caspase-1 and subsequent elevation of interleukin 18 (IL-18) levels, both in vivo and in vitro. Of note, IL-18 neutralization and caspase-1 knockout reversed the amelioration of hepatic steatosis and insulin resistance observed in the cSHP2-KO mice. Administration of two specific SHP2 inhibitors, SHP099 and Phps1, improved HFD-induced hepatic steatosis and insulin resistance. Our findings provide detailed insights into the role of macrophagic SHP2 in metabolic disorders. We conclude that pharmacological inhibition of SHP2 may represent a therapeutic strategy for the management of type 2 diabetes.

scholarly journals High-Fat Diet Alters the Intestinal Microbiota in Streptozotocin-Induced Type 2 Diabetic Mice

2019 ◽  
Vol 7 (6) ◽  
pp. 176 ◽  
Author(s):  
Sheng Liu ◽  
Panpan Qin ◽  
Jing Wang
Keyword(s):  
Intestinal Microbiota ◽  
High Fat Diet ◽  
Metabolic Diseases ◽  
16S Rrna Gene Sequencing ◽  
Chow Diet ◽  
Rrna Gene ◽  
Standard Diet ◽  
High Fat ◽  
Diabetes Status

Intestinal microbiota is closely associated with various metabolic diseases such as type 2 diabetes (T2D), and microbiota is definitely affected by diet. However, more work is required to gain detailed information about gut metagenome and their associated impact with diet in T2D patients. We used a streptozotocin-high-fat diet (HFD) to induce a T2D mouse model and investigated the effect of standard chow diet and HFD on the composition and function of gut microbiota. We found that a HFD could worsen the diabetes status compared with a standard diet. 16S rRNA gene sequencing revealed that a HFD caused a large disturbance to the microbial structure and was linked to an increased ratio of Firmicutes to Bacteroidetes. A HFD increased the bacteria of the Ruminococcaceae and Erysipelotrichaceae family and decreased the bacteria of S24-7 and Rikenellaceae. Meanwhile, a HFD decreased the abundance of Parabacteroides distasonis and Eubacterium dolichum, both of which have previously been reported to alleviate obesity and metabolic dysfunctions. Moreover, PICRUSt-predicted KEGG pathways related to membrane transport, lipid metabolism, and xenobiotics biodegradation and metabolism were significantly elevated in HFD-fed T2D mice. Our results provide insights into dietary and nutritional approaches for improving host metabolism and ameliorating T2D.

scholarly journals Gegen Qinlian Decoction Attenuates High-Fat Diet-Induced Steatohepatitis in Rats via Gut Microbiota

2018 ◽  
Vol 2018 ◽  
pp. 1-8 ◽  
Author(s):  
Yi Guo ◽  
Pang-hua Ding ◽  
Li-juan Liu ◽  
Lei Shi ◽  
Tang-you Mao ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Group Treatment ◽  
High Fat Diet ◽  
Metabolic Diseases ◽  
Intestinal Flora ◽  
Underlying Mechanism ◽  
Control Group ◽  
High Fat ◽  
Nonalcoholic Fatty Liver ◽  
Traditional Chinese Herbal Medicine

Gut microbiota play an important role in modulating energy contribution, metabolism, and inflammation, and disruption of the microbiome population is closely associated with chronic metabolic diseases, such as nonalcoholic fatty liver disease (NAFLD). Gegen Qinlian decoction (GGQLD), a well-known traditional Chinese herbal medicine (CHM), was previously found to regulate lipid metabolism and attenuate inflammation during NAFLD pathogenesis. However, the underlying mechanism of this process, as well as how the gut microbiome is involved, remains largely unknown. In this study, we investigated the effect of varying doses of GGQLD on the total amount and distribution of gut bacteria in rats fed a high-fat diet (HFD) for 8 weeks. Our analysis indicates that Oscillibacter and Ruminococcaceae_g_unclassified are the dominant families in the HFD group. Further, HFD-dependent differences at the phylum, class, and genus levels appear to lead to dysbiosis, characterized by an increase in the Firmicutes/Bacteroidetes ratio and a dramatic increase in the Oscillibacter genus compared to the control group. Treatment with GGQLD, especially the GGQLL dose, improved these HFD-induced changes in intestinal flora, leading to increased levels of Firmicutes, Clostridia, Lactobacillus, bacilli, and Erysipelotrichales that were similar to the controls. Taken together, our data highlight the efficacy of GGQLD in treating NAFLD and support its clinical use as a treatment for NAFLD/NASH patients.

scholarly journals TNFSF14-Derived Molecules as a Novel Treatment for Obesity and Type 2 Diabetes

2021 ◽  
Vol 22 (19) ◽  
pp. 10647
Author(s):  
Mark Agostino ◽  
Jennifer Rooney ◽  
Lakshini Herat ◽  
Jennifer Matthews ◽  
Allyson Simonds ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Glucose Intolerance ◽  
High Fat Diet ◽  
Metabolic Diseases ◽  
Liver Steatosis ◽  
Western World ◽  
Acid Oxidation ◽  
High Fat

Obesity is one of the most prevalent metabolic diseases in the Western world and correlates directly with glucose intolerance and insulin resistance, often culminating in Type 2 diabetes (T2D). Importantly, our team has recently shown that the TNF superfamily (TNFSF) member protein, TNFSF14, has been reported to protect against high fat diet induced obesity and pre-diabetes. We hypothesized that mimics of TNFSF14 may therefore be valuable as anti-diabetic agents. In this study, we use in silico approaches to identify key regions of TNFSF14 responsible for binding to the Herpes virus entry mediator and Lymphotoxin β receptor. In vitro evaluation of a selection of optimised peptides identified six potentially therapeutic TNFSF14 peptides. We report that these peptides increased insulin and fatty acid oxidation signalling in skeletal muscle cells. We then selected one of these promising peptides to determine the efficacy to promote metabolic benefits in vivo. Importantly, the TNFSF14 peptide 7 reduced high fat diet-induced glucose intolerance, insulin resistance and hyperinsulinemia in a mouse model of obesity. In addition, we highlight that the TNFSF14 peptide 7 resulted in a marked reduction in liver steatosis and a concomitant increase in phospho-AMPK signalling. We conclude that TNFSF14-derived molecules positively regulate glucose homeostasis and lipid metabolism and may therefore open a completely novel therapeutic pathway for treating obesity and T2D.

scholarly journals Astragaloside IV Improves High-Fat Diet–Induced Hepatic Steatosis in Nonalcoholic Fatty Liver Disease Rats by Regulating Inflammatory Factors Level via TLR4/NF-κB Signaling Pathway

2021 ◽  
Vol 11 ◽  
Author(s):  
Ying-Li Liu ◽  
Qiu-Zan Zhang ◽  
Yan-Rong Wang ◽  
Li-Na Fu ◽  
Jing-Shu Han ◽  
...  
Keyword(s):  
Liver Disease ◽  
Normal Saline ◽  
High Fat Diet ◽  
Fatty Liver Disease ◽  
Intragastric Administration ◽  
Astragaloside Iv ◽  
High Fat ◽  
Nonalcoholic Fatty Liver ◽  
Tnf Α ◽  
Nafld Activity Score

Objective: Astragaloside IV (AS-IV) is the primary bioactive component purified from Astragalus membranaceus which is one of the traditional Chinese medicines. Research studies found that AS-IV has significant pharmacological effects on focal cerebral ischemia/reperfusion, cardiovascular disease, pulmonary disease, liver cirrhosis, and diabetic nephropathy, but little is known about the effects of AS-IV on nonalcoholic fatty liver disease (NAFLD). In this study, we investigated whether AS-IV has beneficial effects on NAFLD in rats and its potential mechanisms.Methods: Male SD rats were fed with high-fat diet (HFD) for 12 weeks to establish NAFLD rat model, and then, the rats were divided into five groups. The control group rats were fed with normal diet for 12 weeks and then were given normal saline (1.0 ml kg−1 day−1) by intragastric administration for 4 weeks. The model group rats were fed with HFD for 12 weeks and then were given normal saline (1.0 ml kg−1 day−1) by intragastric administration for 4 weeks. The AS-IV-L, AS-IV-M, and AS-IV-H groups were treated with 20, 40, and 80 mg kg−1 day−1 of AS-IV by intragastric administration for 4 weeks and given HFD diet. Then, we detected serum transaminase (ALT, AST), blood lipid (TG, TC), inflammatory cytokines (IL-6, IL-8 and TNF-α), liver histology(NAFLD activity score), TLR4/MyD88 signaling pathway in liver tissue.Results: We found AS-IV significantly reduced serum levels of AST, ALT, TG, TNF-α, IL-6, and IL-8 in NAFLD rats and downregulate the expression of TLR4 mRNA, MyD88 mRNA, NF-κB mRNA, and proteins in liver tissue. Moreover, AS-IV could significantly reduce the NAFLD activity score of NAFLD rat liver.Conclusion: In this study, we demonstrated that AS-IV have a protective effect on NAFLD by inhibiting TNF-α, IL-6 and IL-8 levels and down-regulating TLR4, MyD88 and NF-κB expression in rat liver tissues.

scholarly journals Characterizing the Retinal Phenotype in the High-Fat Diet and Western Diet Mouse Models of Prediabetes

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 464 ◽  
Author(s):  
Bright Asare-Bediako ◽  
Sunil Noothi ◽  
Sergio Li Calzi ◽  
Baskaran Athmanathan ◽  
Cristiano Vieira ◽  
...  
Keyword(s):  
Body Weight ◽  
High Fat Diet ◽  
Fundus Photography ◽  
Vascular Density ◽  
Sensitivity Index ◽  
High Fat ◽  
Permeability Studies ◽  
Induced Changes ◽  
Acellular Capillaries

We sought to delineate the retinal features associated with the high-fat diet (HFD) mouse, a widely used model of obesity. C57BL/6 mice were fed either a high-fat (60% fat; HFD) or low-fat (10% fat; LFD) diet for up to 12 months. The effect of HFD on body weight and insulin resistance were measured. The retina was assessed by electroretinogram (ERG), fundus photography, permeability studies, and trypsin digests for enumeration of acellular capillaries. The HFD cohort experienced hypercholesterolemia when compared to the LFD cohort, but not hyperglycemia. HFD mice developed a higher body weight (60.33 g vs. 30.17g, p < 0.0001) as well as a reduced insulin sensitivity index (9.418 vs. 62.01, p = 0.0002) compared to LFD controls. At 6 months, retinal functional testing demonstrated a reduction in a-wave and b-wave amplitudes. At 12 months, mice on HFD showed evidence of increased retinal nerve infarcts and vascular leakage, reduced vascular density, but no increase in number of acellular capillaries compared to LFD mice. In conclusion, the HFD mouse is a useful model for examining the effect of prediabetes and hypercholesterolemia on the retina. The HFD-induced changes appear to occur slower than those observed in type 2 diabetes (T2D) models but are consistent with other retinopathy models, showing neural damage prior to vascular changes.

Sign in / Sign up

Export Citation Format

Share Document