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

Am J Physiol Gastrointest Liver Physiol. 2014 Mar;306(6):G515-25. doi: 10.1152/ajpgi.00364.2013. Epub 2014 Jan 23.


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.

Keywords: beta-oxidation; energy expenditure; hepatic steatosis; neurotrophic; β-adrenergic signaling.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • 3T3-L1 Cells
  • Animals
  • Diet, High-Fat*
  • Energy Metabolism
  • Fatty Liver / prevention & control
  • Glial Cell Line-Derived Neurotrophic Factor / physiology*
  • Insulin Resistance
  • Male
  • Mice
  • Mice, Transgenic
  • Obesity / prevention & control*
  • Triglycerides / metabolism


  • Gdnf protein, mouse
  • Glial Cell Line-Derived Neurotrophic Factor
  • Triglycerides