title: Insulin-sensitizing action of rosiglitazone is enhanced by preventing hyperphagia.
abstract: OBJECTIVE
  We investigated whether pair-feeding to prevent hyperphagia would potentiate the insulin-sensitizing effect of rosiglitazone in chow-fed and insulin-resistant dietary obese rats, and studied the role of leptin and hypothalamic neuropeptide Y as mediators of weight gain during treatment.
  
  
  METHODS
  Dietary obese and chow-fed rats (575 +/- 10 vs. 536 +/- 7 g; p < 0.01) were given rosiglitazone (30 mg/kg p.o.) or vehicle daily for 14 days.
  
  
  RESULTS
  Energy intake and weight gain were greater in rosiglitazone-treated ad-lib-fed rats (body weight: chow + 24 +/- 2 g, rosiglitazone-treated + 55 +/- 2 g, p < 0.001; dietary obese + 34 +/- 2 g, rosiglitazone-treated + 74 +/- 7 g, p < 0.001). Half of each rosiglitazone-treated group were pair-fed to vehicle-treated controls. Rosiglitazone normalized circulating free fatty acids (FFAs) and insulin sensitivity in dietary obese rats (homeostasis model assessment (HOMA): chow-fed controls, 3.9 +/- 0.3; dietary obese controls, 6.7 +/- 0.7; rosiglitazone-treated, ad lib-fed dietary obese, 4.2 +/- 0.5; both p < 0.01). Insulin sensitivity improved further with pair-feeding (HOMA: 2.9 +/- 0.4; p < 0.05 vs. rosiglitazone-treated, ad lib-fed dietary obese), despite unchanged FFAs. Qualitatively similar findings were made in chow-fed rats. Pair-feeding prevented rosiglitazone-related weight gain in chow-fed, but not dietary obese rats (body weight: + 49 +/- 5 g, p < 0.001 vs. untreated dietary obese controls). Adipose tissue OB mRNA was elevated in dietary obese rats, reduced 49% (p < 0.01) by rosiglitazone treatment, and further (by 16%) with pair-feeding (p < 0.0001). Plasma leptin, however, only fell in the pair-fed group. Hypothalamic neuropeptide Y mRNA was unchanged throughout, suggesting that weight gain associated with high-dose rosiglitazone treatment is independent of hypothalamic neuropeptide Y.
  
  
  CONCLUSIONS
  Food restriction potentiates the insulin-sensitizing effect of rosiglitazone in rats, and this effect is independent of a fall in FFAs.
authors: Department of Medicine, University of Liverpool, Liverpool, UK.
authors: L C
authors: LC
authors: Pickavance
authors: R E
authors: RE
authors: Buckingham
authors: J P
authors: JP
authors: Wilding
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002352:Carrier Proteins / Q000378:metabolism; D004435:Eating / Q000187:drug effects; D005508:Food Deprivation; D006963:Hyperphagia / Q000378:metabolism / Q000517:prevention & control*; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use; D007031:Hypothalamus / Q000737:chemistry / Q000187:drug effects; D007333:Insulin Resistance / Q000502:physiology*; D007473:Ion Channels; D020738:Leptin / Q000097:blood / Q000235:genetics; D008297:Male; D024101:Mitochondrial Proteins; D009478:Neuropeptide Y / Q000235:genetics / Q000378:metabolism; D009765:Obesity / Q000209:etiology / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D000077154:Rosiglitazone; D013844:Thiazoles / Q000494:pharmacology* / Q000627:therapeutic use; D045162:Thiazolidinediones; D000071247:Uncoupling Protein 3
chemical_list: D002352:Carrier Proteins; D007004:Hypoglycemic Agents; D007473:Ion Channels; D020738:Leptin; D024101:Mitochondrial Proteins; D009478:Neuropeptide Y; D012333:RNA, Messenger; D013844:Thiazoles; D045162:Thiazolidinediones; D000071247:Uncoupling Protein 3; D000077154:Rosiglitazone