Hedgehog signaling via Gli2 prevents obesity induced by high-fat diet in adult mice

Obesity poses a significant risk of developing type II diabetes and other diseases. Hedgehog (Hh) signaling has been shown to inhibit adipose tissue development, but its effect on diet-induced obesity during postnatal life is not known. Here by inducing expression of constitutively active Smoothened (SmoM2) or Gli2 (ΔNGli2) in the adipocyte lineage of postnatal mice, we show that targeted activation of Hh signaling suppresses high-fat-diet-induced obesity and improves whole-body glucose tolerance and insulin sensitivity. Both SmoM2 and ΔNGli2 induce the expression of Wnt6, a known anti-adipogenic factor, in fat depots of the mouse. Hh-Gli2 signaling inhibits not only adipocyte differentiation but also lipogenesis in adipocytes in vitro. Finally, pharmacological inhibition of Porcupine, an acyltransferase essential for Wnt secretion, alleviates both anti-adipogenic and anti-lipogenic effects of Hh in cell culture models. Overall, targeted activation of Hh signaling ameliorates diet-induced obesity and may be explored for pharmaceutical development.

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Tissue-specific expression of Sprouty1 in mice protects against high-fat diet-induced fat accumulation, bone loss and metabolic dysfunction

British Journal Of Nutrition ◽

10.1017/s0007114511006209 ◽

2011 ◽

Vol 108 (6) ◽

pp. 1025-1033 ◽

Cited By ~ 7

Author(s):

Sumithra Urs ◽

Terry Henderson ◽

Phuong Le ◽

Clifford J. Rosen ◽

Lucy Liaw

Keyword(s):

Adipose Tissue ◽

Bone Loss ◽

Bone Mass ◽

Body Fat ◽

High Fat Diet ◽

Conditional Knockout ◽

Whole Body ◽

High Fat ◽

Tissue Specific ◽

Diet Induced Obesity

We recently characterised Sprouty1 (Spry1), a growth factor signalling inhibitor as a regulator of marrow progenitor cells promoting osteoblast differentiation at the expense of adipocytes. Adipose tissue-specific Spry1 expression in mice resulted in increased bone mass and reduced body fat, while conditional knockout of Spry1 had the opposite effect with decreased bone mass and increased body fat. Because Spry1 suppresses normal fat development, we tested the hypothesis that Spry1 expression prevents high-fat diet-induced obesity, bone loss and associated lipid abnormalities, and demonstrate that Spry1 has a long-term protective effect on mice fed a high-energy diet. We studied diet-induced obesity in mice with fatty acid binding promoter-driven expression or conditional knockout of Spry1 in adipocytes. Phenotyping was performed by whole-body dual-energy X-ray absorptiometry, microCT, histology and blood analysis. In conditional Spry1-null mice, a high-fat diet increased body fat by 40 %, impaired glucose regulation and led to liver steatosis. However, overexpression of Spry1 led to 35 % (P < 0·05) lower body fat, reduced bone loss and normal metabolic function compared with single transgenics. This protective phenotype was associated with decreased circulating insulin (70 %) and leptin (54 %; P < 0·005) compared with controls on a high-fat diet. Additionally, Spry1 expression decreased adipose tissue inflammation by 45 %. We show that conditional Spry1 expression in adipose tissue protects against high-fat diet-induced obesity and associated bone loss.

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Glial A2B Adenosine Receptors Modulate Abnormal Tachykininergic Responses and Prevent Enteric Inflammation Associated with High Fat Diet-Induced Obesity

Cells ◽

10.3390/cells9051245 ◽

2020 ◽

Vol 9 (5) ◽

pp. 1245 ◽

Cited By ~ 2

Author(s):

Vanessa D’Antongiovanni ◽

Laura Benvenuti ◽

Matteo Fornai ◽

Carolina Pellegrini ◽

Renè van den Wijngaard ◽

...

Keyword(s):

Glial Cell ◽

High Fat Diet ◽

Enzyme Linked Immunosorbent Assay ◽

Standard Diet ◽

Tlr4 Expression ◽

High Fat ◽

Toll Like Receptor 4 ◽

Diet Induced Obesity ◽

Adenosine A2b

The role played by adenosine A2B receptors (A2BRs) in the regulation of enteric glial cell (EGC) functions remains unclear. This study was aimed at investigating the involvement of A2BRs in the control of EGC functions in a model of obesity. C57BL/6 mice were fed with standard diet (SD) or high fat diet (HFD) for eight weeks. Colonic tachykininergic contractions were recorded in the presence of BAY60-6583 (A2BRs agonist), MRS1754 (A2BRs antagonist), and the gliotoxin fluorocitrate. Immunofluorescence distribution of HuC/D, S100β, and A2BRs was assessed in whole mount preparations of colonic myenteric plexus. To mimic HFD, EGCs were incubated in vitro with palmitate (PA) and lipopolysaccharide (LPS), in the absence or in the presence of A2BR ligands. Toll-like receptor 4 (TLR4) expression was assessed by Western blot analysis. Interleukin-1β (IL-1β), substance P (SP), and glial cell derived neurotrophic factor (GDNF) release were determined by enzyme-linked immunosorbent assay (ELISA) assays. MRS1754 enhanced electrically evoked tachykininergic contractions of colonic preparations from HFD mice. BAY60-6583 decreased the evoked tachykininergic contractions, with higher efficacy in HFD mice. Such effects were blunted upon incubation with fluorocitrate. In in vitro experiments on EGCs, PA and LPS increased TLR4 expression as well as IL-1β, GDNF, and SP release. Incubation with BAY60-6583 reduced TLR4 expression as well as IL-1β, GDNF, and SP release. Such effects were blunted by MRS1754. The present results suggest that A2BRs, expressed on EGCs, participate in the modulation of enteric inflammation and altered tachykininergic responses associated with obesity, thus representing a potential therapeutic target.

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Urtica dioica Whole Vegetable as a Functional Food Targeting Fat Accumulation and Insulin Resistance-a Preliminary Study in a Mouse Pre-Diabetic Model

Nutrients ◽

10.3390/nu12041059 ◽

2020 ◽

Vol 12 (4) ◽

pp. 1059

Author(s):

Si Fan ◽

Samnhita Raychaudhuri ◽

Olivia Kraus ◽

Md Shahinozzaman ◽

Leila Lofti ◽

...

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Adipose Tissue ◽

Glucose Metabolism ◽

High Fat Diet ◽

Urtica Dioica ◽

Whole Body ◽

High Fat ◽

Fat Accumulation ◽

Diet Induced Obesity

The shoot of Urtica dioica is used in several cultures as a vegetable or herb. However, not much has been studied about the potential of this plant when consumed as a whole food/vegetable rather than an extract for dietary supplements. In a 12-week dietary intervention study, we tested the effect of U. dioica vegetable on high fat diet induced obesity and insulin resistance in C57BL/6J mice. Mice were fed ad libitum with isocaloric diets containing 10% fat or 45% fat with or without U. dioica. The diet supplemented with U. dioica attenuated high fat diet induced weight gain (p < 0.005; n = 9), fat accumulation in adipose tissue (p < 0.005; n = 9), and whole-body insulin resistance (HOMA-IR index) (p < 0.001; n = 9). Analysis of gene expression in skeletal muscle showed no effect on the constituents of the insulin signaling pathway (AKT, IRS proteins, PI3K, GLUT4, and insulin receptor). Notable genes that impact lipid or glucose metabolism and whose expression was changed by U. dioica include fasting induced adipocyte factor (FIAF) in adipose and skeletal muscle, peroxisome proliferator-activated receptor-α (Ppar-α) and forkhead box protein (FOXO1) in muscle and liver, and Carnitine palmitoyltransferase I (Cpt1) in liver (p < 0.01). We conclude that U. dioica vegetable protects against diet induced obesity through mechanisms involving lipid accumulation and glucose metabolism in skeletal muscle, liver, and adipose tissue.

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The Resin fromProtium heptaphyllumPrevents High-Fat Diet-Induced Obesity in Mice: Scientific Evidence and Potential Mechanisms

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2015/106157 ◽

2015 ◽

Vol 2015 ◽

pp. 1-13 ◽

Cited By ~ 6

Author(s):

Karine Maria Martins Bezerra Carvalho ◽

José Delano Barreto Marinho Filho ◽

Tiago Sousa de Melo ◽

Ana Jérsia Araújo ◽

Josiane da Silva Quetz ◽

...

Keyword(s):

High Fat Diet ◽

Scientific Evidence ◽

Net Energy ◽

High Fat ◽

Beneficial Effects ◽

Proinflammatory Mediators ◽

Glucose And Lipid Metabolism ◽

Diet Induced Obesity ◽

Obesity In Mice

Herbal compounds rich in triterpenes are well known to regulate glucose and lipid metabolism and to have beneficial effects on metabolic disorders. The present study investigated the antiobesity properties of resin fromProtium heptaphyllum(RPH) and the possible mechanisms in mice fed a high-fat diet (HFD) for 15 weeks. Mice treated with RPH showed decreases in body weight, net energy intake, abdominal fat accumulation, plasma glucose, amylase, lipase, triglycerides, and total cholesterol relative to their respective controls, which were RPH unfed. Additionally, RPH treatment, while significantly elevating the plasma level of ghrelin hormone, decreased the levels of insulin, leptin, and resistin. Besides, HFD-induced increases in plasma levels of proinflammatory mediators TNF-α, IL-6, and MCP-1 were significantly lowered by RPH. Furthermore,in vitrostudies revealed that RPH could significantly inhibit the lipid accumulation in 3T3-L1 adipocytes (measured by Oil-Red O staining) at concentrations up to 50 μg/mL. These findings suggest that the antiobese potential of RPH is largely due to its modulatory effects on various hormonal and enzymatic secretions related to fat and carbohydrate metabolism and to the regulation of obesity-associated inflammation.

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Semen Cuscutae Administration Improves Hepatic Lipid Metabolism and Adiposity in High Fat Diet-Induced Obese Mice

Nutrients ◽

10.3390/nu11123035 ◽

2019 ◽

Vol 11 (12) ◽

pp. 3035

Author(s):

Jiyoung Moon ◽

Min Jin Ha ◽

Min-Jeong Shin ◽

Oh Yoen Kim ◽

Eun Hye Yoo ◽

...

Keyword(s):

High Fat Diet ◽

Fatty Acid Synthase ◽

Regulatory Element ◽

Whole Body ◽

No Production ◽

Peroxisome Proliferator ◽

Obese Mice ◽

High Fat ◽

Hepatic Lipid

Since arginase has been shown to compete with nitric oxide (NO) synthase, emerging evidence has reported that arginase inhibition improves obesity by increasing NO production. Semen cuscutae (SC), which is a well-known Chinese medicine, has multiple biological functions such as anti-oxidant function and immune regulation. In this study, we investigated whether the SC as a natural arginase inhibitor influences hepatic lipid abnormalities and whole-body adiposity in high-fat diet (HFD)-induced obese mice. The lipid accumulation was significantly reduced by SC treatment in oleic acid-induced hepatic steatosis in vitro. Additionally, SC supplementation substantially lowered HFD-induced increases in arginase activity and weights of liver and visceral fat tissue, while increasing hepatic NO. Furthermore, elevated mRNA expressions of sterol regulatory element-binding transcription factor 1 (SREBP-1c), fatty-acid synthase (FAS), peroxisome proliferator-activated receptor-gamma (PPAR-γ)1, and PPAR-γ2 in HFD-fed mice were significantly attenuated by SC supplementation. Taken together, SC, as a novel natural arginase inhibitor, showed anti-obesity properties by modulating hepatic arginase and NO production and metabolic pathways related to hepatic triglyceride (TG) metabolism.

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Lactococcus chungangensis CAU 28 alleviates diet-induced obesity and adipose tissue metabolism in vitro and in mice fed a high-fat diet

Journal of Dairy Science ◽

10.3168/jds.2020-18681 ◽

2020 ◽

Vol 103 (11) ◽

pp. 9803-9814

Author(s):

Qi Zhang ◽

Jong-Hwa Kim ◽

Yena Kim ◽

Wonyong Kim

Keyword(s):

Adipose Tissue ◽

High Fat Diet ◽

High Fat ◽

Adipose Tissue Metabolism ◽

Tissue Metabolism ◽

Diet Induced Obesity

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Time course of changes in in vitro lipolysis of intra-abdominal fat depots in relation to high-fat diet-induced hepatic steatosis in rats

British Journal Of Nutrition ◽

10.1079/bjn20061775 ◽

2006 ◽

Vol 96 (2) ◽

pp. 268-275 ◽

Cited By ~ 9

Author(s):

Pascal Collin ◽

Natalie Chapados ◽

Elise Dufresne ◽

Pierre Corriveau ◽

Pascal Imbeault ◽

...

Keyword(s):

Hepatic Steatosis ◽

High Fat Diet ◽

Time Course ◽

Liver Lipid ◽

Abdominal Fat ◽

Standard Diet ◽

High Fat ◽

Fat Depots ◽

Fat Accretion

The purpose of the present study was to determine the time course of changes in in vitro lipolysis and in perilipin content (Western blot) in the mesenteric and/or the retroperitoneal fat depots in relation to the development of hepatic steatosis in high-fat diet-fed rats. Female Sprague-Dawley rats were submitted to a high-fat diet (HF diet; 42% as kJ) or a standard diet (SD diet) for 1, 2, 3 or 8 weeks. Fat accretion in the mesenteric and retroperitoneal tissues was higher (P<0·01) in HF diet-fed than in SD diet-fed rats as soon as 1 week after the beginning of the diet. Liver triacylglycerol concentrations were significantly (P<0·01) higher in HF diet-fed than in SD diet-fed rats throughout the experiment, the highest values being reached at week 2 of the diet. Basal and stimulated lipolysis (10−4 to 10−7m-isoproterienol) in the mesenteric and retroperitoneal fat depots was not changed during the first 3 weeks, regardless of the diet. Lipolysis in the mesenteric adipose tissue in the basal and stimulated states was, however, higher (P<0·01) in HF diet-fed than in SD diet-fed rats after 8 weeks of the diets. There were no significant (P>0·05) effects of diet and time on perilipin content of mesenteric tissue. In spite of a rapid fat accretion, the present results do not provide any evidence of a rapid (3 weeks) increase in in vitro lipolysis in intra-abdominal fat depots upon the undertaking of an HF diet at a time where liver lipid infiltration is the most significant.

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Leanness and Low Plasma Leptin in GPR17 Knockout Mice Are Dependent on Strain and Associated With Increased Energy Intake That Is Not Suppressed by Exogenous Leptin

Frontiers in Endocrinology ◽

10.3389/fendo.2021.698115 ◽

2021 ◽

Vol 12 ◽

Author(s):

Edward T. Wargent ◽

Suhaib J. S. Ahmad ◽

Qing Richard Lu ◽

Evi Kostenis ◽

Jonathan R. S. Arch ◽

...

Keyword(s):

Body Weight ◽

Food Intake ◽

Energy Intake ◽

High Fat Diet ◽

Sympathetic Activity ◽

The Body ◽

Whole Body ◽

High Fat ◽

Diet Induced Obesity ◽

Plasma Leptin

Previous studies have shown that agonists of GPR17 stimulate, while antagonists inhibit feeding. However, whole body knockout of GPR17 in mice of the C57Bl/6 strain did not affect energy balance, whereas selective knockout in oligodendrocytes or pro-opiomelanocortin neurons provided protection from high fat diet-induced obesity and impaired glucose homeostasis. We reasoned that whole body knockout of GPR17 in mice of the 129 strain might elicit more marked effects because the 129 strain is more susceptible than the C57Bl/6 strain to increased sympathetic activity and less susceptible to high fat diet-induced obesity. Consistent with this hypothesis, compared to wild-type mice, and when fed on either a chow or a high fat diet, GPR17 -/- mice of the 129 strain displayed increased expression of uncoupling protein-1 in white adipose tissue, lower body weight and fat content, reduced plasma leptin, non-esterified fatty acids and triglycerides, and resistance to high fat diet-induced glucose intolerance. Not only energy expenditure, but also energy intake was raised. Administration of leptin did not suppress the increased food intake in GPR17 -/- mice of the 129 strain, whereas it did suppress food intake in GPR17 +/+ mice. The only difference between GPR17 +/- and GPR17 +/+ mice of the C57Bl/6 strain was that the body weight of the GPR17 -/- mice was lower than that of the GPR17 +/+ mice when the mice were fed on a standard chow diet. We propose that the absence of GPR17 raises sympathetic activity in mice of the 129 strain in response to a low plasma fuel supply, and that the consequent loss of body fat is partly mitigated by increased energy intake.

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RGC32 deficiency protects against high-fat diet-induced obesity and insulin resistance in mice

Journal of Endocrinology ◽

10.1530/joe-14-0548 ◽

2014 ◽

Vol 224 (2) ◽

pp. 127-137 ◽

Cited By ~ 21

Author(s):

Xiao-Bing Cui ◽

Jun-Na Luan ◽

Jianping Ye ◽

Shi-You Chen

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Adipose Tissue ◽

High Fat Diet ◽

Tolerance Test ◽

High Fat ◽

Diet Induced Obesity

Obesity is an important independent risk factor for type 2 diabetes, cardiovascular diseases and many other chronic diseases. Adipose tissue inflammation is a critical link between obesity and insulin resistance and type 2 diabetes and a contributor to disease susceptibility and progression. The objective of this study was to determine the role of response gene to complement 32 (RGC32) in the development of obesity and insulin resistance. WT and RGC32 knockout (Rgc32−/− (Rgcc)) mice were fed normal chow or high-fat diet (HFD) for 12 weeks. Metabolic, biochemical, and histologic analyses were performed. 3T3-L1 preadipocytes were used to study the role of RGC32 in adipocytes in vitro. Rgc32−/− mice fed with HFD exhibited a lean phenotype with reduced epididymal fat weight compared with WT controls. Blood biochemical analysis and insulin tolerance test showed that RGC32 deficiency improved HFD-induced dyslipidemia and insulin resistance. Although it had no effect on adipocyte differentiation, RGC32 deficiency ameliorated adipose tissue and systemic inflammation. Moreover, Rgc32−/− induced browning of adipose tissues and increased energy expenditure. Our data indicated that RGC32 plays an important role in diet-induced obesity and insulin resistance, and thus it may serve as a potential novel drug target for developing therapeutics to treat obesity and metabolic disorders.

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