Central exendin-4 infusion reduces body weight without altering plasma leptin in (fa/fa) Zucker rats.
OBJECTIVE
To investigate whether chronic administration of the long-acting glucagon-like peptide-1 receptor agonist exendin-4 can elicit sustained reductions in food intake and body weight and whether its actions require an intact leptin system.


METHODS
Male lean and obese Zucker (fa/fa) rats were infused intracerebroventricularly with exendin-4 using osmotic minipumps for 8 days.


RESULTS
Exendin-4 reduced body weight in both lean and obese Zucker rats, maximum suppression being reached on Day 5 in obese (8%) and Day 7 in lean (16%) rats. However, epididymal white adipose tissue weight was not reduced, and only in lean rats was there a reduction in plasma leptin concentration. Food intake was maximally suppressed (by 81%) on Day 3 in obese rats but was reduced by only 18% on Day 8. Similarly, in lean rats food intake was maximally reduced (by 93%) on Day 4 of treatment and by 45% on Day 8. Brown adipose tissue temperature was reduced from Days 2 to 4. Plasma corticosterone was elevated by 76% in lean but by only 28% in obese rats.


CONCLUSIONS
Chronic exendin-4 treatment reduced body weight in both obese and lean Zucker rats by reducing food intake: metabolic rate was apparently suppressed. These effects did not require an intact leptin system. Neither does the absence of an intact leptin system sensitize animals to exendin-4. Partial tolerance to the anorectic effect of exendin-4 in lean rats may have been due to elevated plasma corticosterone and depressed plasma leptin levels, but other counter-regulatory mechanisms seem to play a role in obese Zucker rats.
SmithKline Beecham Pharmaceuticals, Department of Vascular Biology, New Frontiers Science Park, Harlow, Essex, United Kingdom. kamal_A_Al-Barazanji@sbphrd.com
K A
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Al-Barazanji
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Arch
R E
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Buckingham
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Tadayyon
D000273:Adipose Tissue / Q000033:anatomy & histology; D002001:Adipose Tissue, Brown / Q000503:physiopathology; D000818:Animals; D001831:Body Temperature; D001835:Body Weight / Q000187:drug effects*; D001921:Brain / Q000187:drug effects*; D003345:Corticosterone / Q000097:blood; D004435:Eating / Q000187:drug effects; D004822:Epididymis; D000077270:Exenatide; D000067757:Glucagon-Like Peptide-1 Receptor; D020738:Leptin / Q000378:metabolism*; D008297:Male; D009765:Obesity / Q000503:physiopathology*; D009929:Organ Size; D010455:Peptides / Q000008:administration & dosage* / Q000494:pharmacology; D051381:Rats; D011924:Rats, Zucker; D018027:Receptors, Glucagon / Q000819:agonists*; D014688:Venoms
C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D020738:Leptin; D010455:Peptides; D018027:Receptors, Glucagon; D014688:Venoms; D000077270:Exenatide; D003345:Corticosterone