title: Effects of chronic murine and human leptin infusion on plasma leptin and corticosterone levels and energy balance in lean Zucker rats.
abstract: OBJECTIVE
  To clarify whether centrally delivered leptin can access the circulation and to determine to what extent the effects of i.c.v. h-leptin and m-leptin on body weight and plasma corticosterone are due to reduced food intake.
  
  
  METHODS
  Male lean Zucker rats were infused i.c.v. with recombinant m-leptin or h-leptin (42 microg/day) for 7 days. Terminal plasma leptin levels were measured using selective r-leptin, m-leptin and h-leptin RIA. Plasma h-leptin and corticosterone levels were determined on days 0, 2, 4 and 6 of h-leptin infusion. Interscapular brown adipose tissue weight and UCP-1 mRNA expression (an indicator of thermogenic capacity) were also measured.
  
  
  RESULTS
  The terminal plasma leptin level was elevated (from 2.2 +/- 0.4 to 42.7 +/- 20.2 ng/ml) in the h-leptin-treated lean rats to levels similar to those in vehicle i.c.v. infused fa/fa rats (72.2 +/- 4.7 ng/ml), but this was only detectable when the h-leptin radioimmunoabsorbent assay (RIA) was used. Further, both m-leptin and h-leptin infusions in lean rats elevated terminal plasma corticosterone (352 +/- 37 and 389 +/- 55 ng/ml, respectively) to levels similar to those in i.c.v. rats (386 +/- 62 ng/ml), whereas diet-restriction by pair-feeding, with the h-leptin group, in lean rats had no effect (207 +/- 45 ng/ml). The increase in plasma corticosterone level coincided with the maximum hypophagic effects of leptin and preceded the appearance and sustained elevation of exogenous human leptin in the circulation. Both m-leptin and h-leptin i.c.v. infusion reduced body weight gain (3% and 4%, respectively, compared to pair-fed group) and increased UCP-1 expression (11-fold and 16-fold, respectively) in lean rats. However, h-leptin elicited an earlier effect than m-leptin on body weight, manifested as an earlier reduction in food intake and greater increase in UCP-1 expression. h-Leptin also elicited a greater reduction in body weight gain than did pair-feeding.
  
  
  CONCLUSIONS
  Intracerebroventricular-infused m-leptin or h-leptin was detected in the circulation. Furthermore, m-leptin and h-leptin elevated plasma corticosterone levels and h-leptin caused some weight loss in lean rats independently of its suppression of food intake. The elevation of corticosterone levels in the lean rats may be a mechanism whereby they resist excessive weight loss in response to leptin.
authors.affiliation: Department of Vascular Biology, SmithKline Beecham Pharmaceuticals, New Frontiers Science Park, Harlow, Essex, UK. Kamal_A_Al-Barazanji@sbphrd.com
authors.forename: K A
authors.initials: KA
authors.lastname: Al-Barazanji
authors.forename: R E
authors.initials: RE
authors.lastname: Buckingham
authors.forename: J R
authors.initials: JR
authors.lastname: Arch
authors.forename: C
authors.initials: C
authors.lastname: Briscoe
authors.forename: O
authors.initials: O
authors.lastname: Jenkins
authors.forename: M
authors.initials: M
authors.lastname: Tadayyon
mesh_terms: D002001:Adipose Tissue, Brown / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics; D003345:Corticosterone / Q000097:blood*; D004734:Energy Metabolism / Q000187:drug effects*; D004822:Epididymis; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007262:Infusions, Intravenous; D007473:Ion Channels; D020738:Leptin / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D024101:Mitochondrial Proteins; D009765:Obesity / Q000097:blood / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D011924:Rats, Zucker; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology; D013851:Thinness; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects; D000071256:Uncoupling Protein 1
chemical_list: D002352:Carrier Proteins; D007473:Ion Channels; D020738:Leptin; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D012333:RNA, Messenger; D011994:Recombinant Proteins; C000604371:UCP1 protein, human; C000604372:Ucp1 protein, mouse; C000604373:Ucp1 protein, rat; D000071256:Uncoupling Protein 1; D003345:Corticosterone