Toll-like Receptor 2 (TLR2) Deficiency Abrogates Diabetic and Obese Phenotypes while Restoring Endothelial Function via Inhibition of NOX1

We have previously demonstrated a novel role of bone morphogenic protein-4 (BMP4) in inducing NOX1-dependent eNOS uncoupling, endothelial dysfunction, and inflammatory activation in type 2 diabetes mellitus (T2DM). However, it has remained unclear as to how BMP4 activates NOX1 and whether targeting the new mechanistic pathway revealed is effective in preserving endothelial function in T2DM. Here we observed that BMP4 induced marked, time-dependent increase in physiological binding between TLR2 and NOX1 in aortic endothelial cells, as well as increased binding of TLR2 to NOXO1. In high-fat diet fed Tlr2-/- (TLR2 knockout) mice, the body weight gain was significantly less compared to WT (wild-type) mice both in males and females. The high-fat diet induced increases in fasting blood glucose levels, as well as in circulating insulin and leptin levels, were absent in Tlr2-/- mice. High-fat feeding induced increases in overall fat mass, and fat mass of different pockets were abrogated in Tlr2-/- mice. Whereas energy intake was similar in high-fat fed WT and Tlr2-/- mice, TLR2 deficiency resulted in higher energy expenditure attributed to improved physical activity, which was accompanied by restored skeletal muscle mitochondrial function. In addition, TLR2 deficiency recoupled eNOS, reduced total superoxide production, improved H4B and NO bioavailabilities in aortas and restored endothelium-dependent vasorelaxation. Collectively, our data strongly indicate that TLR2 plays important roles in the development of metabolic features of T2DM, and its related endothelial/vascular dysfunction. Therefore, targeting TLR2 may represent a novel therapeutic strategy for T2DM, obesity and cardiovascular complications via specific inhibition of NOX1.

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Toll-like Receptor 2 (TLR2) Deficiency Abrogates Diabetic and Obese Phenotypes while Restoring Endothelial Function via Inhibition of NOX1

10.2337/figshare.14754585.v1 ◽

2021 ◽

Author(s):

Zhen Guo ◽

Yixuan Zhang ◽

Chang Liu ◽

Ji Youn Youn ◽

Hua Linda Cai

Keyword(s):

Endothelial Function ◽

Fat Mass ◽

High Fat Diet ◽

Body Weight Gain ◽

Vascular Dysfunction ◽

Fasting Blood Glucose ◽

Cardiovascular Complications ◽

The Body ◽

High Fat ◽

Enos Uncoupling

We have previously demonstrated a novel role of bone morphogenic protein-4 (BMP4) in inducing NOX1-dependent eNOS uncoupling, endothelial dysfunction, and inflammatory activation in type 2 diabetes mellitus (T2DM). However, it has remained unclear as to how BMP4 activates NOX1 and whether targeting the new mechanistic pathway revealed is effective in preserving endothelial function in T2DM. Here we observed that BMP4 induced marked, time-dependent increase in physiological binding between TLR2 and NOX1 in aortic endothelial cells, as well as increased binding of TLR2 to NOXO1. In high-fat diet fed Tlr2-/- (TLR2 knockout) mice, the body weight gain was significantly less compared to WT (wild-type) mice both in males and females. The high-fat diet induced increases in fasting blood glucose levels, as well as in circulating insulin and leptin levels, were absent in Tlr2-/- mice. High-fat feeding induced increases in overall fat mass, and fat mass of different pockets were abrogated in Tlr2-/- mice. Whereas energy intake was similar in high-fat fed WT and Tlr2-/- mice, TLR2 deficiency resulted in higher energy expenditure attributed to improved physical activity, which was accompanied by restored skeletal muscle mitochondrial function. In addition, TLR2 deficiency recoupled eNOS, reduced total superoxide production, improved H4B and NO bioavailabilities in aortas and restored endothelium-dependent vasorelaxation. Collectively, our data strongly indicate that TLR2 plays important roles in the development of metabolic features of T2DM, and its related endothelial/vascular dysfunction. Therefore, targeting TLR2 may represent a novel therapeutic strategy for T2DM, obesity and cardiovascular complications via specific inhibition of NOX1.

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Extract of Wax Gourd Peel Prevents High-Fat Diet-Induced Hyperlipidemia in C57BL/6 Mice via the Inhibition of the PPARγPathway

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2013/342561 ◽

2013 ◽

Vol 2013 ◽

pp. 1-11 ◽

Cited By ~ 8

Author(s):

Ming Gu ◽

Shengjie Fan ◽

Gaigai Liu ◽

Lu Guo ◽

Xiaobo Ding ◽

...

Keyword(s):

Blood Glucose ◽

High Fat Diet ◽

Target Genes ◽

Metabolic Diseases ◽

Body Weight Gain ◽

Fasting Blood Glucose ◽

Peroxisome Proliferator ◽

Mrna Levels ◽

High Fat ◽

Wax Gourd

Wax gourd is a popular vegetable in East Asia. In traditional Chinese medicine, wax gourd peel is used to prevent and treat metabolic diseases such as hyperlipidemia, hyperglycemia, obesity, and cardiovascular disease. However, there is no experimental evidence to support these applications. Here, we examined the effect of the extract of wax gourd peel (EWGP) on metabolic disorders in diet-induced C57BL/6 obese mice. In the preventive experiment, EWGP blocked body weight gain and lowered serum total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c), liver TG and TC contents, and fasting blood glucose in mice fed with a high-fat diet. In the therapeutic study, we induced obesity in the mice and treated with EWGP for two weeks. We found that EWGP treatment reduced serum and liver triglyceride (TG) contents and fasting blood glucose and improved glucose tolerance in the mice. Reporter assay and gene expression analysis showed that EWGP could inhibit peroxisome proliferator-activated receptorγ(PPARγ) transactivities and could decrease mRNA levels of PPARγand its target genes. We also found that HMG-CoA reductase (HMGCR) was downregulated in the mouse liver by EWGP. Our data suggest that EWGP lowers hyperlipidemia of C57BL/6 mice induced by high-fat diet via the inhibition of PPARγand HMGCR signaling.

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Antiobesity Effect of a Novel Herbal Formulation LI85008F in High-Fat Diet-Induced Obese Mice

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2021/6612996 ◽

2021 ◽

Vol 2021 ◽

pp. 1-8

Author(s):

Hak Joo Choi ◽

Hwa Young Kim ◽

Kyoung Sik Park

Keyword(s):

Weight Gain ◽

Body Fat ◽

Fat Mass ◽

High Fat Diet ◽

Body Weight Gain ◽

Whole Body ◽

Body Fat Mass ◽

Obese Mice ◽

High Fat ◽

Herbal Formulation

A variety of natural products have been explored for their antiobesity potential and widely used to develop dietary supplements for the prevention of weight gain from excess body fat. In an attempt to find a natural antiobesity agent, this study was designed to evaluate the antiobesity activity of a novel herbal formulation LI85008F composed of extracts from three medicinal plants in high-fat diet- (HFD-) induced obese mice. After the thirteen-week oral administration of the test materials to mice, the body weight gain, whole-body fat mass, adipose tissue weight, and the expression levels of obesity-related proteins were measured. Our results indicated that LI85008F can suppress body weight gain and lower whole-body fat mass in HFD-induced obese mice. Significant decreases in epididymal and retroperitoneal fat mass were observed in LI85008F-treated groups compared with the HFD-fed control group ( p < 0.05 ). Furthermore, the oral administration of LI85008F caused significant decreases in the expression level of adipogenic (C/EBPα and PPARγ) and lipogenic (ACC) markers and notable increases in the production level of thermogenetic (AMPKα, PGC1α and UCP1) and lipolytic (HSL) proteins. These findings suggest that LI85008F holds great promise for a novel herbal formulation with antiobesity activities, preventing body fat accumulation and altering lipid metabolism.

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The Role of Berberine in the Prevention of HIF-1α Activation to Alleviate Adipose Tissue Fibrosis in High-Fat-Diet-Induced Obese Mice

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2018/4395137 ◽

2018 ◽

Vol 2018 ◽

pp. 1-12 ◽

Cited By ~ 2

Author(s):

Meilin Hu ◽

Fan Wu ◽

Jinlong Luo ◽

Jing Gong ◽

Ke Fang ◽

...

Keyword(s):

Adipose Tissue ◽

High Fat Diet ◽

Body Weight Gain ◽

Chinese Herb ◽

Underlying Mechanism ◽

The Body ◽

Epididymal Adipose Tissue ◽

Metabolic Dysfunction ◽

High Fat ◽

Tissue Fibrosis

Berberine (BBR) is the main active ingredient of a traditional Chinese herb Coptis chinensis. It has been reported to exhibit beneficial effects in treating diabetes and obesity. However, the underlying mechanism has not been fully elucidated. Adipose tissue fibrosis is a hallmark of obesity-associated adipose tissue dysfunction. HIF-1α plays a key role in adipose tissue fibrosis, which closely linked to metabolic dysfunction in obese state. We hypothesized that BBR may alleviate obesity-induced adipose tissue fibrosis and associated metabolic dysfunction through inhibition of HIF-1α. To test this hypothesis, we treated high fat diet (HFD) feeding mice with different dose of BBR (100 mg/kg, 200 mg/kg, and 300 mg/kg) for 8 weeks. We found that BBR treatment greatly decreased the body weight gain and reduced insulin resistance induced by HFD. Data also revealed that BBR improved histologic fibrous of epididymal white adipose tissue (eWAT) and was accompanied with inhibition of the abnormal synthesis and deposition of extracellular matrix (ECM) proteins, such as collagen and fibronectin. We also found that BBR treatment suppressed the expression of HIF-1α and decreased the mRNA expression of LOX in epididymal adipose tissue, which plays a key role in fibrosis development. Taken together, these results suggest that BBR can regulate metabolic homeostasis and suppress adipose tissue fibrosis through inhibiting the expression of HIF-1α.

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Anti-obesity Effect of (8-E)-Nüzhenide, a Secoiridoid from Ligustrum lucidum, in High-fat Diet-induced Obese Mice

Natural Product Communications ◽

10.1177/1934578x1400901001 ◽

2014 ◽

Vol 9 (10) ◽

pp. 1934578X1400901 ◽

Cited By ~ 4

Author(s):

Qing Liu ◽

Sang Hyun Kim ◽

Seon Beom Kim ◽

Yang Hee Jo ◽

Eun Sil Kim ◽

...

Keyword(s):

Body Weight ◽

High Fat Diet ◽

Body Weight Gain ◽

Treated Group ◽

The Body ◽

Metabolic Parameters ◽

Obese Mice ◽

High Fat ◽

Ligustrum Lucidum ◽

Epididymal Fat

The effect of the extract of Ligustrum lucidum fruits (LFE) and its major secoiridoid (LFS), (8- E)-nüzhenide, on obesity was investigated using high fat-diet (HFD)-induced C58BL/6J obese mice. LFE and LFS were administered at the doses of 300 mg/kg and 30 mg/kg, respectively, for 6 weeks. The anti-obesity activity was evaluated by measuring body weight, epididymal fat and metabolic plasma parameters. On Day 42, the body weight of the LFS-treated group was significantly lower compared with the HFD-treated group. Body weight gain was also reduced by 23.2% and 32.0% in the LFE- and LFS-treated groups, respectively, compared with the HFD group. In addition, the weight of the epididymal fat in the mice was significantly decreased in the HFD+LFS group. The food efficiency ratios (FERs) of the HFD+LFE and HFD+LFS groups were also lower compared with the HFD group with the same food intake. Metabolic parameters that had increased in the HFD group were decreased in the HFD+LFE and HFD+LFS groups. In particular, the increased triglyceride values were significantly reduced in the HFD+LFS group. These results show that treatment with LFE and LFS decreased HFD-induced obesity, mainly by improving metabolic parameters, such as fats and triglycerides. Therefore, LFE and LFS have potential benefits in regulation of obesity.

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Obesity is the major contributor to vascular dysfunction and inflammation in high-fat diet hypertensive rats

Clinical Science ◽

10.1042/cs20090395 ◽

2009 ◽

Vol 118 (4) ◽

pp. 291-301 ◽

Cited By ~ 57

Author(s):

Ahmed A. Elmarakby ◽

John D. Imig

Keyword(s):

Oxidative Stress ◽

High Fat Diet ◽

Body Weight Gain ◽

Vascular Dysfunction ◽

Normal Diet ◽

Sprague Dawley ◽

High Fat ◽

Hypertensive Rats ◽

Induced Hypertension ◽

Cox 2

Obesity and hypertension are the two major risk factors that contribute to the progression of end-stage renal disease. To examine whether hypertension further exacerbates oxidative stress and vascular dysfunction and inflammation in obese rats, four groups of male Sprague–Dawley rats were fed either a normal (7% fat) or high-fat (36% fat) diet for 6 weeks and osmotic pumps were implanted to deliver ANG (angiotensin II) or vehicle for an additional 4 weeks. Treatment with the high-fat diet did not alter ANG-induced hypertension compared with the normal diet (174±6 compared with 170±5 mmHg respectively). Treatment with the high-fat diet increased body weight gain and plasma leptin levels and induced insulin resistance in normotensive and ANG-induced hypertensive rats. Plasma TBARS (thiobarbituric acid-reacting substances), a measure of oxidative stress, were elevated in high-fat diet-fed rats compared with controls (11.2±1 compared with 8.4±1 nmol/ml respectively) and was increased further in ANG-induced hypertensive rats fed a high-fat diet (18.8±2.2 nmol/ml). Urinary nitrite excretion was also decreased in rats fed a high-fat diet without or with ANG infusion compared with controls. Afferent arteriolar relaxation to acetylcholine was impaired in rats fed the high-fat diet without or with ANG infusion. Renal cortical TNF-α (tumour necrosis factor-α), COX-2 (cyclo-oxygenase-2) and phospho-IKK (inhibitor of nuclear factor κB kinase) expression increased in high-fat diet-fed rats compared with normal diet-fed rats. The increases in phospho-IKK and COX-2 expression were elevated further in ANG-induced hypertensive rats fed the high-fat diet. These results suggest that ANG-induced hypertension exacerbates oxidative stress and renal inflammation without further impairment in vascular dysfunction in high-fat diet-induced obesity.

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The Effects of Triacylglycerol Structures on the Food Intake and Body Weight of Mice in a High-Fat Diet Setting

Current Developments in Nutrition ◽

10.1093/cdn/nzab055_026 ◽

2021 ◽

Vol 5 (Supplement_2) ◽

pp. 1216-1216

Author(s):

Xinge Hu

Keyword(s):

Body Weight ◽

Food Intake ◽

High Fat Diet ◽

Tissue Sample ◽

Body Weight Gain ◽

Diet Group ◽

The Body ◽

Lower Percentage ◽

Chow Diet ◽

High Fat

Abstract Objectives The dietary fat content plays an important role in the regulation of chronic metabolic diseases such as obesity and type 2 diabetes. Here, we tested the impacts of triacylglycerol structure on the body weight gain and food intake of mice in a high-fat diet (HFD) setting. Methods Male C57/BL6J mice at 6 weeks old were fed one of the following three diets for 6 weeks, Teklad Rodent Diet chow diet (number 8640), the chow diet containing 36% (w/w) 1,2-Dipalmitoyl-3-oleoylglycerol (PPO), or the chow diet containing 36% (w/w) 1,3-Dipalmitoyl-2-oleoylglycerol (POP). Each group contained 9 mice, and their food intake and BW were measured daily. The mice were euthanized after 6 weeks (12 weeks old) for tissue sample collection. Results Both high HFD groups had significantly higher BW gain and caloric intakes than the chow diet group. Mice fed the POP diet had a lower percentage of BW gain and consumed less accumulated calories than those fed the PPO diet, as well as a significantly lower liver to BW ratio. Since week 4, the body BW rate of the POP group started to be lower than that of the PPO diet group. Conclusions TAG structures in an HFD setting affect the BW gain rate and obesity in mice. The different structures of fat added to affect the food intake and BW gain differently in an HFD setting. In the future, we would like to compare the changes of the hepatic lipogenesis enzyme in these mice. This will help us to understand how the triacylglycerol structures in the diet affect lipid metabolism in mice. Funding Sources Internal.

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Anti-obesity effect of Tamarindus indicus seed extract against a high-fat diet-induced obese model in rats

International Journal of Research in Pharmaceutical Sciences ◽

10.26452/ijrps.v11i2.2149 ◽

2020 ◽

Vol 11 (2) ◽

pp. 2083-2089

Author(s):

Nabeel K ◽

Asra Fathima ◽

Farhath Khanum ◽

Manjula S N ◽

Mruthunjaya K ◽

...

Keyword(s):

Body Weight ◽

High Fat Diet ◽

Body Weight Gain ◽

Seed Extract ◽

The Body ◽

High Fat ◽

Cell Viability Assay ◽

Serum Triglycerides

The present study was aimed to evaluate the anti-obesity property of Tamarindus indica seed extract (TSE) on high fat-fed obese rats. TSE was prepared by cold maceration method and qualitative phytochemical studies had been carried out. In vitro cell viability assay (MTT assay) was and oil red staining for evaluating the lipid accumulation in cells was carried out using 3T3-L1 cells, and leptin levels was evaluated by ELISA. In-vivo Obesity was induced in experimental rats by administration of a high-fat diet for 04 weeks. The anti-obesity effect was screened by oral administration of TSE at two different dose levels i.e., 250 and 500mg/kg b. Wt. Along with a high-fat diet for a period of 04 weeks. The anti-obesity activity is estimated in terms of body weight gain, serum triglycerides (TG), Total cholesterol (TC). In -vitro studies revealed that the TSE has no cytotoxic effect, Administration of a high-fat diet for 04 weeks significantly increased the body weight, serum triglycerides, cholesterol. Upon treatment with TSE, a significant dose-dependent alteration in body weight, triglycerides, cholesterol levels were observed, inferring the anti-obesity property of Tamarindus seed extract.

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Anti-obesity effect of milk fermented by Lactobacillus plantarum NCDC 625 alone and in combination with herbs on high fat diet fed C57BL/6J mice

Beneficial Microbes ◽

10.3920/bm2015.0083 ◽

2016 ◽

Vol 7 (3) ◽

pp. 375-385 ◽

Cited By ~ 17

Author(s):

R. Pothuraju ◽

R.K. Sharma ◽

P.K. Kavadi ◽

J. Chagalamarri ◽

S. Jangra ◽

...

Keyword(s):

Lactobacillus Plantarum ◽

High Fat Diet ◽

Fasting Blood Glucose ◽

Fold Change ◽

The Body ◽

Gymnema Sylvestre ◽

High Fat ◽

Final Body Weight ◽

Epididymal Fat ◽

Significant Difference

The effect of dietary supplementation of milk fermented with indigenous probiotic Lactobacillus plantarum (LP625) alone and in combination with herbs (Aloe vera and Gymnema sylvestre) was investigated on high fat diet (HFD, 60 kcal% fat) fed mice for 12 weeks. Administration of LP625 alone or in combination with both herbs lowered the final body weight, however, a significant difference was observed with LP625 supplemented Gymnema sylvestre only as compared to the HFD fed group (25.06±0.18 vs 27.29±0.72 g, P<0.05). Similarly, the epididymal fat mass, fasting blood glucose and serum insulin levels were significantly (P<0.05) decreased by all treatment groups. In addition, a protective effect against the rise in serum and liver triglycerides, and in liver total cholesterol levels was found with the consumption of LP625 alone or in combination with herbs. Furthermore, the HFD fed mice showed a remarkable increase in the epididymal fat cell size, whereas administration of LP625 alone or in combination with herbs exhibited a significant decrease in the size. Finally, a significant increase in the relative mRNA expression of thermogenic proteins, i.e. uncoupling protein-2 (UCP-2, 1.16±0.25 fold change, P<0.05) and a decrease in pro-inflammatory markers, such as tumour necrosis factor-α and interleukin-6 (1.55±0.18 and 3.10±0.58 fold change, respectively, P<0.05) were due to LP625 supplementation in the HFD fed group. This shows that LP625 alone or supplemented with herbs seems to protect against diet induced obesity by decreasing the body and epididymal fat weight through upregulation of UCP-2 expression and reduced expression of pro-inflammatory cytokines.

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