title: Limiting glucocorticoid secretion increases the anorexigenic property of Exendin-4.
abstract: OBJECTIVE
  Glucagon-like peptide-1 (GLP-1) analogs are attractive options for the treatment of type II diabetes and obesity because of their incretin and anorexigenic effects. Peripheral administration of the GLP-1R agonist Exendin-4 (Ex-4) also increases glucocorticoid secretion in rodents and humans, but whether the released glucocorticoids interact with Ex-4's anorexigenic effect remains unclear.
  
  
  METHODS
  To test this, we used two experimental approaches that suppress corticosterone secretion and then assessed Ex-4 effects on eating in adult male rats. First, we combined acute and chronic low dose dexamethasone treatment with Ex-4. Second, we ablated hindbrain catecholamine neurons projecting to the hypothalamus with anti-dopamine-β-hydroxylase-saporin (DSAP) to block Ex-4-induced corticosterone secretion.
  
  
  RESULTS
  Combining dexamethasone and Ex-4 produced a larger acute anorexigenic effect than Ex-4 alone. Likewise, chronic dexamethasone and Ex-4 co-treatment produced a synergistic effect on eating and greater body weight loss in diet-induced obese rats than Ex-4 alone. DSAP lesions not only blunted Ex-4's ability to increase corticosterone secretion, but potentiated the anorexigenic effect of Ex-4, indicating that Ex-4-dependent corticosterone secretion opposes Ex-4's actions. Consistent with the enhancement of Ex-4's anorexigenic effect, DSAP lesion altered Ex-4-dependent changes in neuropeptide Y, preproglucagon, and corticotropin releasing hormone gene expression involved in glucocorticoid feedback.
  
  
  CONCLUSIONS
  Our findings demonstrate that limiting glucocorticoid secretion and actions with low dose dexamethasone or DSAP lesion increases Ex-4's ability to reduce food intake and body weight. Novel glucocorticoid receptor based mechanisms, therefore, may help enhance GLP-1-based obesity therapies.
authors.affiliation: Physiology and Behavior Laboratory, ETH Zürich, 8603 Schwerzenbach, Switzerland. Electronic address: shin-lee@ethz.ch.
authors.forename: Shin J
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Physiology and Behavior Laboratory, ETH Zürich, 8603 Schwerzenbach, Switzerland.
authors.forename: Katharina
authors.initials: K
authors.lastname: Diener
authors.affiliation: Physiology and Behavior Laboratory, ETH Zürich, 8603 Schwerzenbach, Switzerland.
authors.forename: Sharon
authors.initials: S
authors.lastname: Kaufman
authors.affiliation: Physiology and Behavior Laboratory, ETH Zürich, 8603 Schwerzenbach, Switzerland.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Krieger
authors.affiliation: Physiology and Behavior Laboratory, ETH Zürich, 8603 Schwerzenbach, Switzerland.
authors.forename: Klaus G
authors.initials: KG
authors.lastname: Pettersen
authors.affiliation: Physiology and Behavior Laboratory, ETH Zürich, 8603 Schwerzenbach, Switzerland.
authors.forename: Nino
authors.initials: N
authors.lastname: Jejelava
authors.affiliation: Physiology and Behavior Laboratory, ETH Zürich, 8603 Schwerzenbach, Switzerland.
authors.forename: Myrtha
authors.initials: M
authors.lastname: Arnold
authors.affiliation: Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Alan G
authors.initials: AG
authors.lastname: Watts
authors.affiliation: Physiology and Behavior Laboratory, ETH Zürich, 8603 Schwerzenbach, Switzerland.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Langhans
keywords: Anti-dopamine-β-hydroxylase-saporin; Corticosterone; Exendin-4; GLP-1; Hypothalamus; Neuropeptide Y