title: Pioglitazone treatment increases food intake and decreases energy expenditure partially via hypothalamic adiponectin/adipoR1/AMPK pathway.
abstract: BACKGROUND
  Thiazolidinediones (TZDs) enhanced body weight (BW) partially by increased adipogenesis and hyperphagia. Neuronal PPARγ knockout mice on high-fat diet (HFD) are leaner because of enhanced leptin response, although it could be secondary to their leanness. Thus, it still is an open question how TZDs may alter energy balance. Multiple factors regulate food intake (FI) and energy expenditure (EE), including anorexigenic hormones as insulin and leptin. Nonetheless, elevated hypothalamic AMPK activity increases FI and TZDs increase AMPK activity in muscle cells. Thus, the aim of the present study was to investigate whether Pioglitazone (PIO) treatment alters hypothalamic insulin and leptin action/signaling, AMPK phosphorylation, and whether these alterations may be implicated in the regulation of FI and EE.
  
  
  METHODS
  Swiss mice on HFD (2 months) received PIO (25 mg kg(-1) per day-gavage) or vehicle for 14 days. AMPK and AdipoR1 were inhibited via Intracerebroventricular injections using Compound C (CompC) and small interference RNA (siRNA), respectively. Western blot, real-time PCR and CLAMS were done.
  
  
  RESULTS
  PIO treatment increased BW, adiposity, FI, NPY mRNA and decreased POMC mRNA expression and EE in HFD mice. Despite higher adiposity, PIO treatment improved insulin sensitivity, glucose tolerance, decreased insulin and increased adiponectin serum levels. This result was associated with, improved insulin and leptin action/signaling, decreased α2AMPK(Ser491) phosphorylation and elevated Acetyl-CoA carboxylase and AMPK(Thr172) phosphorylation in hypothalamus. The inhibition of hypothalamic AMPK with CompC was associated with decreased adiposity, FI, NPY mRNA and EE in PIO-treated mice. The reduced expression of hypothalamic AdipoR1 with siRNA concomitantly with PIO treatment reverted PIO induced obesity development, suggesting that adiponectin may be involved in this effect.
  
  
  CONCLUSIONS
  These results demonstrated that PIO, despite improving insulin/leptin action in hypothalamus, increases FI and decreases EE, partially, by activating hypothalamic adiponectin/AdipoR1/AMPK axis. Suggesting a novel mechanism in the hypothalamus by which TZDs increase BW.
authors.affiliation: Department of Internal Medicine, State University of Campinas (UNICAMP), Campinas, SP, Brazil.
authors.forename: P G F
authors.initials: PG
authors.lastname: Quaresma
authors.affiliation: School of Applied Sciences, State University of Campinas (UNICAMP), Limeira, SP, Brazil.
authors.forename: N
authors.initials: N
authors.lastname: Reencober
authors.affiliation: Department of Internal Medicine, State University of Campinas (UNICAMP), Campinas, SP, Brazil.
authors.forename: T M
authors.initials: TM
authors.lastname: Zanotto
authors.affiliation: Department of Internal Medicine, State University of Campinas (UNICAMP), Campinas, SP, Brazil.
authors.forename: A C
authors.initials: AC
authors.lastname: Santos
authors.affiliation: Department of Internal Medicine, State University of Campinas (UNICAMP), Campinas, SP, Brazil.
authors.forename: L
authors.initials: L
authors.lastname: Weissmann
authors.affiliation: Department of Medical Genetics, School of Medical Sciences, University of Campinas (UNICAMP), Campinas, SP, Brazil.
authors.forename: A H B
authors.initials: AH
authors.lastname: de Matos
authors.affiliation: Department of Medical Genetics, School of Medical Sciences, University of Campinas (UNICAMP), Campinas, SP, Brazil.
authors.forename: I
authors.initials: I
authors.lastname: Lopes-Cendes
authors.affiliation: Department of Medicine, Division of Diabetes, University of Texas Health Science Center at San Antonio, Texas, USA.|Departament of Medical Clinics, Obesity and Comorbidities Research Center (O.C.R.C.), State University of Campinas (UNICAMP), Campinas, SP, Brazil.
authors.forename: F
authors.initials: F
authors.lastname: Folli
authors.affiliation: Department of Internal Medicine, State University of Campinas (UNICAMP), Campinas, SP, Brazil.
authors.forename: M J A
authors.initials: MJ
authors.lastname: Saad
authors.affiliation: Department of Internal Medicine, State University of Campinas (UNICAMP), Campinas, SP, Brazil.|School of Applied Sciences, State University of Campinas (UNICAMP), Limeira, SP, Brazil.
authors.forename: P O
authors.initials: PO
authors.lastname: Prada
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D052242:Adiponectin / Q000378:metabolism*; D000818:Animals; D059305:Diet, High-Fat; D004435:Eating; D004734:Energy Metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007031:Hypothalamus / Q000378:metabolism*; D008297:Male; D051379:Mice; D000077205:Pioglitazone; D012333:RNA, Messenger; D045162:Thiazolidinediones / Q000494:pharmacology*
chemical_list: D052242:Adiponectin; D007004:Hypoglycemic Agents; D012333:RNA, Messenger; D045162:Thiazolidinediones; D055372:AMP-Activated Protein Kinases; D000077205:Pioglitazone