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

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 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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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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