Effects of chronic murine and human leptin infusion on plasma leptin and corticosterone levels and energy balance in lean Zucker rats.
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.
Al-Barazanji
K A
KA
Department of Vascular Biology, SmithKline Beecham Pharmaceuticals, New Frontiers Science Park, Harlow, Essex, UK. Kamal_A_Al-Barazanji@sbphrd.com
Buckingham
R E
RE
Arch
J R
JR
Briscoe
C
C
Jenkins
O
O
Tadayyon
M
M
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
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