title: Hypothalamic Phosphodiesterase 3B Pathway Mediates Anorectic and Body Weight-Reducing Effects of Insulin in Male Mice.
abstract: BACKGROUND
  Insulin action in the hypothalamus plays a critical role in the regulation of energy homeostasis, yet the intracellular signaling mechanisms mediating insulin action are incompletely understood. Although phosphodiesterase 3B (PDE3B) mediates insulin action in the adipose tissue and it is highly expressed in the hypothalamic areas implicated in energy homeostasis, its role, if any, in mediating insulin action in the hypothalamus is unknown. We tested the hypothesis that insulin action in the hypothalamus is mediated by PDE3B.
  
  
  METHODS
  Using enzymatic assay, we examined the effects of peripheral or central administration of insulin on hypothalamic PDE3B activity in adult mice. Western blotting and immunohistochemistry also examined p-Akt and p-STAT3 levels in the hypothalamus. Effects of leptin on these parameters were also compared. We injected cilostamide, a PDE3 inhibitor, prior to central injection of insulin and examined the 12- to 24-hour food intake and 24-hour body weight. Finally, we examined the effect of cilostamide on insulin-induced proopiomelanocortin (Pomc), neurotensin (Nt), neuropeptide Y (Npy) and agouti-related peptide (Agrp) gene expression in the hypothalamus by qPCR.
  
  
  RESULTS
  Peripheral or central injection of insulin significantly increased PDE3B activity in the hypothalamus in association with increased p-Akt levels but without any change in p-STAT3 levels. However, leptin-induced increase in PDE3B activity was associated with an increase in both p-Akt and p-STAT3 levels in the hypothalamus. Prior administration of cilostamide reversed the anorectic and body weight-reducing effects as well as stimulatory effect of insulin on hypothalamic Pomc mRNA levels. Insulin did not alter Nt, Npy and Agrp mRNA levels.
  
  
  CONCLUSIONS
  Insulin induction of hypothalamic PDE3B activity and the reversal of the anorectic and body weight-reducing effects and stimulatory effect of insulin on hypothalamic Pomc gene expression by cilostamide suggest that activation of PDE3B is a novel mechanism of insulin signaling in the hypothalamus.
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Magee-Womens Research Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pa., USA.
authors.forename: Maitrayee
authors.initials: M
authors.lastname: Sahu
authors.forename: Prashanth
authors.initials: P
authors.lastname: Anamthathmakula
authors.forename: Abhiram
authors.initials: A
authors.lastname: Sahu
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3 / Q000008:administration & dosage / Q000378:metabolism*; D004435:Eating / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D007031:Hypothalamus / Q000187:drug effects / Q000201:enzymology*; D007328:Insulin / Q000008:administration & dosage / Q000378:metabolism*; D020738:Leptin / Q000008:administration & dosage / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage; D010766:Phosphorylation; D011333:Pro-Opiomelanocortin / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015363:Quinolones / Q000008:administration & dosage; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D015431:Weight Loss / Q000187:drug effects
chemical_list: D007328:Insulin; D020738:Leptin; D010726:Phosphodiesterase Inhibitors; D015363:Quinolones; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C021294:cilostamide; D011333:Pro-Opiomelanocortin; D051057:Proto-Oncogene Proteins c-akt; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3