Prostaglandin PGE2 receptor EP4 regulates microglial phagocytosis and increases susceptibility to diet-induced obesity

Background: In rodents, susceptibility to diet-induced obesity requires microglial activation, but the molecular components of this pathway remain incompletely defined. Prostaglandin E2 (PGE2) levels increase in the mediobasal hypothalamus during high fat diet (HFD) feeding, and the PGE2 receptor EP4 regulates microglial activation state and phagocytic activity, suggesting a potential role for microglial EP4 signaling in obesity pathogenesis. Method: Metabolic phenotyping, as assessed by body weight, energy expenditure, glucose, and insulin tolerance, was performed in microglia-specific EP4 knockout (MG-EP4 KO) mice and littermate controls on HFD. Morphological and gene expression analysis of microglia, and a histological survey of microglia-neuron interactions in the arcuate nucleus was performed. Phagocytosis was assessed using in vivo and in vitro pharmacological techniques. Results: Microglial EP4 deletion markedly reduced weight gain and food intake in response to HFD feeding. In correspondence with this lean phenotype, insulin sensitivity was also improved in the HFD-fed MG-EP4 KO mice though glucose tolerance remained surprisingly unaffected. Mechanistically, EP4-deficient microglia showed an attenuated phagocytic state marked by reduced CD68 expression and fewer contacts with POMC neuron soma and processes. These cellular changes observed in the microglial EP4 knockout mice corresponded with an increased density of POMC neurites extending into the paraventricular nucleus. Conclusion: These findings reveal that microglial EP4 signaling promotes body weight gain and insulin resistance during HFD feeding. Furthermore, the data suggest that curbing microglial phagocytic function may preserve POMC cytoarchitecture and PVN input to limit overconsumption during diet-induced obesity.

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Bauhiniastatin-1 alleviates diet induced obesity and lipid accumulation through modulating PPAR-γ/AMPK expressions: In-vitro, in-vivo and in-silico studies.

10.21203/rs.3.rs-302339/v1 ◽

2021 ◽

Author(s):

Karunakaran Reddy Sankaran ◽

Lokanatha Oruganti ◽

Muni Swamy Ganjayi ◽

Venkataramaiah Chintha ◽

Muni Kesavulu Muppuru ◽

...

Keyword(s):

Body Weight ◽

Weight Gain ◽

Western Blot ◽

Blot Analysis ◽

Body Weight Gain ◽

Liver Lipid ◽

Ppar Γ ◽

Diet Induced Obesity

Abstract Background: Consumption of energy dense foods and sedentary lifestyles have led to high prevalence of obesity and associated disorders. Intensive research efforts have focussed to develop effective alternative therapeutics from plant sources. Bauhiniastatins have been reported to possess antineoplastic activity. In the present study, Bauhiniastatin-1 (BSTN1) was isolated and purified from Bauhinia purpurea and evaluated for its therapeutic efficacy against adipogenesis and obesity using high fat diet (HFD)-induced obese rodent model and 3T3-L1 cells.Methods: We performed in-vitro experiments like MTT assay, Oil Red O (ORO) stain, cellular lipid content, glycerol release and RT-PCR analysis in 3T3-L1 cells. In-vivo parameters like body weight gain, body composition, plasma adipokines, serum & liver lipid profiles, liver marker enzymes, western blot analysis and histopathological examination were conducted in rat model. In addition, molecular docking studies were also performed to understand interaction of BSTN1 with peroxisome proliferator-activated gamma receptor (PPAR-γ) and AMP-activated protein kinase (AMPK) which supported our experimental results.Results: BSTN1 at 20 μM significantly (p<0.001) inhibited cell differentiation and lipid accumulation of 3T3-L1 adipocytes. Mechanistic studies showed that mRNA expression of key adipogenic markers, PPAR-γ, fatty acid synthase (FAS) and sterol-regulatory element-binding protein-1 (SREBP1) were down-regulated while AMPK was up-regulated by BSTN1. Oral administration of BSTN1 (5 mg/kg. b.wt.) to HFD-induced obese rats substantially decreased body weight gain, fat mass, serum and liver lipid levels and promoted integrity of hepatic and adipose tissue architecture compared to HFD-control rats. In BSTN1 administered groups, decreased serum aspartate transaminase (AST) and alanine aminotransferase (ALT) levels, decreased plasma leptin but increased adiponectin levels were noted. Western blot analysis of adipose and hepatic tissues collected from BSTN1 treated rats showed decreased expression level of PPAR-γ but increase in AMPK expression relative to the untreated group. In-silico studies showed strong binding interactions of BSTN1 against PPAR-γ and AMPK, the key molecules of adipogenesis and obesity.Conclusions: Taken together, the results suggest that BSTN1 could be promising molecule for the treatment of diet-induced obesity and non-alcoholic fatty liver disease (NAFLD).

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GIP receptor antagonist treatment causes weight loss in ovariectomized high fat diet-fed mice

10.22541/au.162303461.16209224/v1 ◽

2021 ◽

Author(s):

Geke Aline Boer ◽

Jenna Hunt ◽

Maria Gabe ◽

Johanne Windeløv ◽

Alexander Sparre-Ulricht ◽

...

Keyword(s):

Body Weight ◽

Weight Gain ◽

High Fat Diet ◽

Body Weight Gain ◽

Pharmacokinetic Profile ◽

High Fat ◽

Ovariectomized Mice ◽

Gip Receptor

Background and purpose The incretin hormone, glucose-dependent insulinotropic polypeptide (GIP), secreted by the enteroendocrine K-cells in the proximal intestine, may regulate lipid metabolism and adiposity but its exact role in these processes is unclear. Experimental approach We characterized in vitro and in vivo antagonistic properties of a novel GIP analogue, mGIPAnt-1. We further assessed the in vivo pharmacokinetic profile of this antagonist, as well as its ability to affect high-fat diet (HFD)-induced body weight gain in ovariectomized mice during an 8-week treatment period. Key results mGIPAnt-1 showed competitive antagonistic properties to the GIP receptor (GIPR) in vitro as it inhibited GIP-induced cAMP accumulation in COS-7 cells. Furthermore, mGIPAnt-1 was capable of inhibiting GIP-induced glucoregulatory and insulinotropic effects in vivo and has a favourable pharmacokinetic profile with a half-life of 7.2 hours in C57Bl6 female mice. Finally, sub-chronic treatment with mGIPAnt-1 in ovariectomized HFD mice resulted in a reduction of body weight and fat mass. Conclusion and Implications mGIPAnt-1 successfully inhibited acute GIP-induced effects in vitro and in vivo and sub-chronically induces resistance to HFD-induced weight gain in ovariectomized mice. Our results support the development of GIP antagonists for the therapy of obesity.

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Metabolic features of diet-induced obesity without hyperphagia in young rats

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1986.251.3.r433 ◽

1986 ◽

Vol 251 (3) ◽

pp. R433-R440 ◽

Cited By ~ 9

Author(s):

B. E. Levin ◽

J. Triscari ◽

A. C. Sullivan

Keyword(s):

Body Weight ◽

Weight Gain ◽

Food Intake ◽

Body Weight Gain ◽

Brown Adipocyte ◽

Metabolic Efficiency ◽

Interscapular Brown Adipose Tissue ◽

Diet Induced Obesity ◽

Brown Adipose

Diet-induced obesity (DIO) developed in 1-mo-old male Sprague-Dawley rats over an 8-wk period on a relatively high-fat (16%) high-calorie (4.6 kcal/g) diet (DIO diet). Percent carcass lipid (56%) and body weight gain (15%) were greater, whereas food intake was decreased over the first 3-5 wk in DIO diet-compared with chow-fed controls. Overall, 8-wk body weight gain (15%), percent carcass lipid (26%), and feed efficiency (15%) were greater, but food intake was not increased. Norepinephrine (NE) turnover rate, indicative of organ sympathetic activity, increased in interscapular brown adipose tissue (IBAT; 57-218%), heart (21-44%), and pancreas (25%) during the first 3 wk and remained elevated for the entire 8 wk. IBAT weight (51%) and in vitro lipolytic capacity (68%) increased by 1 wk and brown adipocyte size (43%) by 3 wk; IBAT thermogenic capacity (maximal NE-stimulated in vitro O2 consumption) increased by 5 wk (39%). Plasma insulin levels were similar in both diet groups over the entire 8-wk period. Why DIO diet-fed rats had increased metabolic efficiency is unknown, but activation of IBAT metabolism and thermogenesis failed to prevent the development of DIO.

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N-acetylcysteine+nimesulide: An association strategy aiming to prevent nimesulide-induced hepatotoxicity

Brazilian Journal of Health and Biomedical Sciences ◽

10.12957/bjhbs.2020.59709 ◽

2021 ◽

Vol 19 (2) ◽

pp. 91-99

Author(s):

Amanda G. Elias ◽

Julia S. da Silva ◽

Rafaela L. Klein ◽

Francieli U. I. Amaral ◽

Marcelo D. Arbo ◽

...

Keyword(s):

Body Weight ◽

Weight Gain ◽

Cell Model ◽

Body Weight Gain ◽

The Body ◽

Relative Mass ◽

Male Wistar Rats ◽

Control Body

Introduction: Nimesulide is a potent anti-inflammatorywith rapid and long-lasting effects, but also with a high riskof hepatotoxicity. Objective: This work aimed to preventnimesulide-induced hepatotoxicity through the associationof nimesulide with a hepatoprotective agent. Materials andMethods: First, we tested three hepatoprotective agents:N-acetylcysteine, L-carnitine, and Gingko biloba extract inan in vitro hepatic cell model. Both N-acetylcysteine and G.biloba showed promisor results. We selected N-acetylcysteineto continue the studies in an animal model. In vivo study wasperformed using male Wistar rats divided in 4 groups: control,nimesulide (100mg/kg/day), nimesulide (100mg/kg/day) +N-acetylcysteine (100mg/kg/day) and N-acetylcysteine alone(100mg/kg/day). Treatments were given by gavage, daily, for15 days. Results: Animals receiving nimesulide alone showedlower body weight gain compared to control. Body weightgain in the nimesulide + N-acetylcysteine group was higherthan nimesulide alone, evidencing lower toxicity. However,the body weight gain of the nimesulide + N-acetylcysteinegroup was still lower than the control animals. Animals treatedwith nimesulide alone presented an increased relative mass ofheart, liver, and spleen and significant hepatic damage seen inmicroscopy when compared to other groups. N-acetylcysteineco-administered with nimesulide prevented the increasedheart mass, but the same was not true with liver and spleen.Conclusions: This work evidence partial protection elicitedby the association of N-acetylcysteine and nimesulide againstnimesulide-induced hepatotoxicity.

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Caralluma Acutangula Prevents Body Weight Gain in Rats Feed on Hyperlipidic Diet

Bulletin of University of Agricultural Sciences and Veterinary Medicine Cluj-Napoca Veterinary Medicine ◽

10.15835/buasvmcn-vm:006617 ◽

2018 ◽

Vol 75 (2) ◽

pp. 168

Author(s):

Pare DRAMANE ◽

Hilou ADAMA ◽

Adrian POTÂRNICHE ◽

Mabozou KPEMISSI ◽

Orsolya SÁRPATAKI ◽

...

Keyword(s):

Body Weight ◽

Weight Gain ◽

Body Weight Gain ◽

Body Weight Loss ◽

Treated Group ◽

Total Phenolic ◽

Control Group ◽

Hyperlipidic Diet

Caralluma acutangula (Decne.) (CA) (Asclepiadaceae) is a medicinal plant traditionally used in Burkina Faso for the management of weight. The aim of this study was to evaluate the effect of extract of CA on body weight, food intake, blood biochemistry parameters on experimental obesity rat model. One group received CA 400 mg/kg b.w. per day and was fed on hyperlipidic diet (HD), while the control group received HD only for three weeks long. The phytochemical investigation of extract showed a high total phenolic content (36.21±1.36 mg GAE/100mg of extract) and total flavonoids (4.98 ±0.31 QE/100 mg of extract). In the end, CA-HD treated group had a body weight loss of 2%, compared to HD group who presented a body weight gain of 15%. The CA-HD treated group showed also a lower levels of plasma triglyceride (136.57±13.82 mg/dL) and glycemia (187.74±31.16 mg/dL) compared to HD (206.02±23.82 and respectively 230.96±79.07 mg/dL) (p<0.05). CA extract also showed a good anti-oxidant activity in vivo (effect on antioxydant enzyme (MDA, GPX, SOD) and in vitro (inhibition of DPPH radical, ferric ion reduction). This study showed that CA is a potential natural remedy for the control of body weight and alleviation of obesity related disease.

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Genistein and daidzein decrease food intake and body weight gain in mice, and alter LXR signaling in vivo and in vitro

Food & Function ◽

10.1039/c8fo01718b ◽

2018 ◽

Vol 9 (12) ◽

pp. 6257-6267 ◽

Cited By ~ 8

Author(s):

Ting Luo ◽

Omar Miranda-Garcia ◽

Geoff Sasaki ◽

Jinling Wang ◽

Neil F. Shay

Keyword(s):

Metabolic Syndrome ◽

Body Weight ◽

Weight Gain ◽

Food Intake ◽

Glucose Metabolism ◽

Body Weight Gain ◽

Differential Effects ◽

Decrease Food Intake

Genistein and daidzein decrease mice food intake, ameliorate symptoms of metabolic syndrome, including decreasing body weight gain, and improving glucose metabolism, and appear to produce differential effects, possibly via the regulation of LXR-mediated pathways.

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Chronic glucose-dependent insulinotropic polypeptide receptor (GIPR) agonism desensitizes adipocyte GIPR activity mimicking functional GIPR antagonism

Nature Communications ◽

10.1038/s41467-020-18751-8 ◽

2020 ◽

Vol 11 (1) ◽

Cited By ~ 2

Author(s):

Elizabeth A. Killion ◽

Michelle Chen ◽

James R. Falsey ◽

Glenn Sivits ◽

Todd Hager ◽

...

Keyword(s):

Body Weight ◽

Weight Gain ◽

Body Weight Gain ◽

Preclinical Models ◽

Prevent Weight Gain ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

Abstract Antagonism or agonism of the glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) prevents weight gain and leads to dramatic weight loss in combination with glucagon-like peptide-1 receptor agonists in preclinical models. Based on the genetic evidence supporting GIPR antagonism, we previously developed a mouse anti-murine GIPR antibody (muGIPR-Ab) that protected diet-induced obese (DIO) mice against body weight gain and improved multiple metabolic parameters. This work reconciles the similar preclinical body weight effects of GIPR antagonists and agonists in vivo, and here we show that chronic GIPR agonism desensitizes GIPR activity in primary adipocytes, both differentiated in vitro and adipose tissue in vivo, and functions like a GIPR antagonist. Additionally, GIPR activity in adipocytes is partially responsible for muGIPR-Ab to prevent weight gain in DIO mice, demonstrating a role of adipocyte GIPR in the regulation of adiposity in vivo.

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Development and Validation of in Vitro Induction Assays for Toxic Halogenated Aromatic Mixtures: A Review

Toxicology and Industrial Health ◽

10.1177/074823378900500513 ◽

1989 ◽

Vol 5 (5) ◽

pp. 757-775 ◽

Cited By ~ 28

Author(s):

Stephen Safe ◽

Grant Mason ◽

Thomas Sawyer ◽

Tim Zacharewski ◽

Mark Harris ◽

...

Keyword(s):

Body Weight ◽

Weight Gain ◽

Flame Retardants ◽

Body Weight Gain ◽

Complex Mixture ◽

Aryl Hydrocarbon ◽

Ecosystem Risk ◽

Rat Hepatoma

Halogenated aromatic industrial compounds, typified by the polychlorinated dibenzo-p-dioxins (PCDDs), dibenzofurans (PCDFs) and biphenyls (PCBs) have been identified as residues in almost every component of the global ecosystem. Risk assessment of the complex mixtures of halogenated aromatics found in envi ronmental samples is complicated by analytical problems and the lack of toxicological information on individual compounds and mixtures. Research in our laboratory has focused on the develop ment and vadidation of the in vitro aryl hydrocarbon hydroxylase (AHH) induction assay in rat hepatoma H-4-II E cells in culture for quantitating individual toxic halogenated aryl hydrocarbons and their mixtures. For several PCB, PCDD, PCDF congeners, their mixed bromo/chloro analogs and reconstituted mixtures there was an excellent linear correlation between their -log ED50 values for AHH induction in rat hepatoma cells and their -log ED50 values for in vivo hepatic microsomal AHH induction, inhibi tion of body weight gain and thymic atrophy in the rat. It has also been shown for selected compounds that there was a good correla tion between their in vitro AHH induction potencies and their effects in guinea pigs (AHH induction, inhibition of body weight gain) and mice (immunotoxicity). This assay system has been uti lized to quantitate the "2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) equivalents "present in extracts from diverse sources including fly ash from a municipal incinerator and pyrolyzed brom inated flame retardants which contain a complex mixture of halo genated dibenzo-p-dioxins and dibenzofurans.

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Identification of the Active Ingredient and Beneficial Effects of Vitex rotundifolia Fruits on Menopausal Symptoms in Ovariectomized Rats

Biomolecules ◽

10.3390/biom11071033 ◽

2021 ◽

Vol 11 (7) ◽

pp. 1033

Author(s):

Ji Hwan Lee ◽

Sullim Lee ◽

Quynh Nhu Nguyen ◽

Hung Manh Phung ◽

Myoung-Sook Shin ◽

...

Keyword(s):

Weight Gain ◽

Body Weight Gain ◽

Animal Experiments ◽

Ovariectomized Rats ◽

Biological Functions ◽

Menopausal Syndrome ◽

Active Constituents ◽

Mcf 7

Estrogen replacement therapy is a treatment to relieve the symptoms of menopause. Many studies suggest that natural bioactive ingredients from plants resemble estrogen in structure and biological functions and can relieve symptoms of menopause. The fruit of V. rotundifolia, called “Man HyungJa” in Korean, is a traditional medicine used to treat headache, migraine, eye pain, neuralgia, and premenstrual syndrome in Korea and China. The aim of the present study was to confirm that V. rotundifolia fruit extract (VFE) exerts biological functions similar to those of estrogen in menopausal syndrome. We investigated its in vitro effects on MCF-7 cells and in vivo estrogen-like effects on weight gain and uterine contraction in ovariectomized rats. Using the polar extract, the active constituents of VFE (artemetin, vitexicarpin, hesperidin, luteolin, vitexin, and vanillic acid) with estrogen-like activity were identified in MCF-7 cells. In animal experiments, the efficacy of VFE in ameliorating body weight gain was similar to that of estrogen, as evidenced from improvements in uterine atrophy. Vitexin and vitexicarpin are suggested as the active constituents of V. rotundifolia fruits.

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