Glial cell line-derived neurotrophic factor protects against high-fat diet-induced obesity

Abstract

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.

Glial Cell Line–Derived Neurotrophic Factor Enhances Autophagic Flux in Mouse and Rat Hepatocytes and Protects Against Palmitate Lipotoxicity

“…GDNF transgenic mice overexpress GDNF in cells expressing glial fibrillary acidic proteins, which are found in several tissues including the liver (Supporting Fig. ) . The generation of these mice has been described previously .…”

“…They were fed a regular diet (RD) (2018SX; Teklad Global 18% Protein Extruded Rodent Diet, Harlan Laboratories, Madison, WI) that contained 6.2% fat by weight or a HFD (TD.06414, Harlan Laboratories) that contained 34.3% fat by weight. The complete composition of the diets has been reported previously . All animal studies were approved by the Atlanta Veteran Affairs Medical Center Institutional Animal Care and Use Committee.…”

“…S1). (16) The generation of these mice has been described previously. (17) The mice were used at 5-6 weeks of age and were maintained on a 12-hour light-dark cycle in a temperature-controlled barrier facility with free access to food and water.…”

“…The complete composition of the diets has been reported previously. (16) All animal studies were approved by the Atlanta Veteran Affairs Medical Center Institutional Animal Care and Use Committee.…”

“…To investigate the ability of GDNF to regulate hepatocyte autophagy in response to increased fat load, we first assessed the effects of GDNF overexpression on the liver levels of key components of the autophagy pathway in a dietary mouse model of obesity. GDNF Tg mice fed the HFD for 12 weeks had normal liver triglyceride levels, serum alanine aminotransferase (ALT) levels, and low to moderate hepatic steatosis, whereas control mice fed the HFD had elevated liver triglyceride and serum ALT levels and increased hepatic steatosis (16) S2). We also observed that 12 weeks of HFD feeding resulted in significant increases in liver Atg5, Beclin-1, and LC3A/B-II levels in male and female GDNF Tg mice, and decreases in liver Atg5, Atg7 and LC3A/ B-II levels in female control mice ( Fig.…”