684 Glial Cell Line Derived Neurotrophic Factor Protects Against High Fat Diet-Induced Obesity by Stimulating Increased Energy Expenditure and β-Adrenergic Signaling

Obesity is a growing epidemic with limited effective treatments. The neurotrophic factor glial cell line-derived neurotrophic factor (GDNF) was recently shown to enhance β-cell mass and improve glucose control in rodents. Its role in obesity is, however, not well characterized. In this study, we investigated the ability of GDNF to protect against high-fat diet (HFD)-induced obesity. GDNF transgenic (Tg) mice that overexpress GDNF under the control of the glial fibrillary acidic protein promoter and wild-type (WT) littermates were maintained on a HFD or regular rodent diet for 11 wk, and weight gain, energy expenditure, and insulin sensitivity were monitored. Differentiated mouse brown adipocytes and 3T3-L1 white adipocytes were used to study the effects of GDNF in vitro. Tg mice resisted the HFD-induced weight gain, insulin resistance, dyslipidemia, hyperleptinemia, and hepatic steatosis seen in WT mice despite similar food intake and activity levels. They exhibited significantly ( P < 0.001) higher energy expenditure than WT mice and increased expression in skeletal muscle and brown adipose tissue of peroxisome proliferator activated receptor-α and β1- and β3-adrenergic receptor genes, which are associated with increased lipolysis and enhanced lipid β-oxidation. In vitro, GDNF enhanced β-adrenergic-mediated cAMP release in brown adipocytes and suppressed lipid accumulation in differentiated 3T3L-1 cells through a p38MAPK signaling pathway. Our studies demonstrate a novel role for GDNF in the regulation of high-fat diet-induced obesity through increased energy expenditure. They show that GDNF and its receptor agonists may be potential targets for the treatment or prevention of obesity.

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Glial Cell Line Derived Neurotrophic Factor Prevents High Fat Diet Induced Obesity

Gastroenterology ◽

10.1016/s0016-5085(11)60177-7 ◽

2011 ◽

Vol 140 (5) ◽

pp. S-44

Author(s):

Simon M. Mwangi ◽

Smitha Marri ◽

Behtash G. Nezami ◽

Ping P. Fu ◽

Javelin C. Cheng ◽

...

Keyword(s):

Cell Line ◽

Glial Cell ◽

Neurotrophic Factor ◽

High Fat Diet ◽

High Fat ◽

Diet Induced Obesity

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Glial Cell Line Derived Neurotrophic Factor Reverses High Fat Diet-Induced Suppression of Hepatic Autophagy and Enhances Hepatocyte Mitochondrial Fatty Acid Oxidation and Survival

Gastroenterology ◽

10.1016/s0016-5085(17)33609-0 ◽

2017 ◽

Vol 152 (5) ◽

pp. S1069

Author(s):

Simon M. Mwangi ◽

Ge Li ◽

Francois Reichardt ◽

C. Michael Hart ◽

Mark J. Czaja ◽

...

Keyword(s):

Fatty Acid ◽

Cell Line ◽

Glial Cell ◽

Fatty Acid Oxidation ◽

Neurotrophic Factor ◽

High Fat Diet ◽

Acid Oxidation ◽

High Fat ◽

Mitochondrial Fatty Acid Oxidation ◽

Mitochondrial Fatty Acid

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Su1492 - Glial Cell Line Derived Neurotrophic Factor Prevents High Fat Diet-Induced Hepatic Fibrosis

Gastroenterology ◽

10.1016/s0016-5085(18)33833-2 ◽

2018 ◽

Vol 154 (6) ◽

pp. S-1157

Author(s):

Simon M. Mwangi ◽

Ali Ahmad ◽

Ge Li ◽

Shanthi Srinivasan

Keyword(s):

Cell Line ◽

Glial Cell ◽

Hepatic Fibrosis ◽

Neurotrophic Factor ◽

High Fat Diet ◽

High Fat

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Glial cell line-derived neurotrophic factor protects against high-fat diet-induced hepatic steatosis by suppressing hepatic PPAR-γ expression

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00196.2015 ◽

2016 ◽

Vol 310 (2) ◽

pp. G103-G116 ◽

Cited By ~ 4

Author(s):

Simon Musyoka Mwangi ◽

Sophia Peng ◽

Behtash Ghazi Nezami ◽

Natalie Thorn ◽

Alton B. Farris ◽

...

Keyword(s):

Cell Line ◽

Hepatic Steatosis ◽

Glial Cell ◽

Neurotrophic Factor ◽

High Fat Diet ◽

De Novo ◽

De Novo Lipogenesis ◽

High Fat ◽

Protein Levels ◽

Ppar Γ

Glial cell line-derived neurotrophic factor (GDNF) protects against high-fat diet (HFD)-induced hepatic steatosis in mice, however, the mechanisms involved are not known. In this study we investigated the effects of GDNF overexpression and nanoparticle delivery of GDNF in mice on hepatic steatosis and fibrosis and the expression of genes involved in the regulation of hepatic lipid uptake and de novo lipogenesis. Transgenic overexpression of GDNF in liver and other metabolically active tissues was protective against HFD-induced hepatic steatosis. Mice overexpressing GDNF had significantly reduced P62/sequestosome 1 protein levels suggestive of accelerated autophagic clearance. They also had significantly reduced peroxisome proliferator-activated receptor-γ (PPAR-γ) and CD36 gene expression and protein levels, and lower expression of mRNA coding for enzymes involved in de novo lipogenesis. GDNF-loaded nanoparticles were protective against short-term HFD-induced hepatic steatosis and attenuated liver fibrosis in mice with long-standing HFD-induced hepatic steatosis. They also suppressed the liver expression of steatosis-associated genes. In vitro, GDNF suppressed triglyceride accumulation in Hep G2 cells through enhanced p38 mitogen-activated protein kinase-dependent signaling and inhibition of PPAR-γ gene promoter activity. These results show that GDNF acts directly in the liver to protect against HFD-induced cellular stress and that GDNF may have a role in the treatment of nonalcoholic fatty liver disease.

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Dietary Isoliquiritigenin at a Low Dose Ameliorates Insulin Resistance and NAFLD in Diet-Induced Obesity in C57BL/6J Mice

International Journal of Molecular Sciences ◽

10.3390/ijms19103281 ◽

2018 ◽

Vol 19 (10) ◽

pp. 3281 ◽

Cited By ~ 4

Author(s):

Youngmi Lee ◽

Eun-Young Kwon ◽

Myung-Sook Choi

Keyword(s):

Insulin Resistance ◽

Energy Expenditure ◽

Body Fat ◽

Fat Mass ◽

High Fat Diet ◽

Plasma Cholesterol ◽

Cellular Respiration ◽

Body Fat Mass ◽

High Fat ◽

Diet Induced Obesity

Isoliquiritigenin (ILG) is a flavonoid constituent of Glycyrrhizae plants. The current study investigated the effects of ILG on diet-induced obesity and metabolic diseases. C57BL/6J mice were fed a normal diet (AIN-76 purified diet), high-fat diet (40 kcal% fat), and high-fat diet +0.02% (w/w) ILG for 16 weeks. Supplementation of ILG resulted in decreased body fat mass and plasma cholesterol level. ILG ameliorated hepatic steatosis by suppressing the expression of hepatic lipogenesis genes and hepatic triglyceride and fatty acid contents, while enhancing β-oxidation in the liver. ILG improved insulin resistance by lowering plasma glucose and insulin levels. This was also demonstrated by the intraperitoneal glucose tolerance test (IPGTT). Additionally, ILG upregulated the expression of insulin signaling-related genes in the liver and muscle. Interestingly, ILG elevated energy expenditure by increasing the expression of thermogenesis genes, which is linked to stimulated mitochondrial biogenesis and uncoupled cellular respiration in brown adipose tissue. ILG also suppressed proinflammatory cytokine levels in the plasma. These results suggest that ILG supplemented at 0.02% in the diet can ameliorate body fat mass, plasma cholesterol, non-alcoholic fatty liver disease, and insulin resistance; these effects were partly mediated by increasing energy expenditure in high-fat fed mice.

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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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SIM1 Overexpression Partially Rescues Agouti Yellow and Diet-Induced Obesity by Normalizing Food Intake

Endocrinology ◽

10.1210/en.2006-0453 ◽

2006 ◽

Vol 147 (10) ◽

pp. 4542-4549 ◽

Cited By ~ 54

Author(s):

Bassil M. Kublaoui ◽

J. Lloyd Holder ◽

Kristen P. Tolson ◽

Terry Gemelli ◽

Andrew R. Zinn

Keyword(s):

Food Intake ◽

Energy Expenditure ◽

Transgenic Mice ◽

High Fat Diet ◽

Chow Diet ◽

High Fat ◽

Enhanced Sensitivity ◽

Diet Induced Obesity ◽

Melanocortin 4 Receptor ◽

Obesity In Mice

Single-minded 1 (SIM1) mutations are associated with obesity in mice and humans. Haploinsufficiency of mouse Sim1 causes hyperphagic obesity with increased linear growth and enhanced sensitivity to a high-fat diet, a phenotype similar to that of agouti yellow and melanocortin 4 receptor knockout mice. To investigate the effects of increased Sim1 dosage, we generated transgenic mice that overexpress human SIM1 and examined their phenotype. Compared with wild-type mice, SIM1 transgenic mice had no obvious phenotype on a low-fat chow diet but were resistant to diet-induced obesity on a high-fat diet due to reduced food intake with no change in energy expenditure. The SIM1 transgene also completely rescued the hyperphagia and partially rescued the obesity of agouti yellow mice, in which melanocortin signaling is abrogated. Our results indicate that the melanocortin 4 receptor signals through Sim1 or its transcriptional targets in controlling food intake but not energy expenditure.

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