Antiobesity action of peripheral exenatide (exendin-4) in rodents: effects on food intake, body weight, metabolic status and side-effect measures.
BACKGROUND
Exenatide (exendin-4) is an incretin mimetic currently marketed as an antidiabetic agent for patients with type 2 diabetes. In preclinical models, a reduction in body weight has also been shown in low-fat-fed, leptin receptor-deficient rodents.


OBJECTIVE
To more closely model the polygenic and environmental state of human obesity, we characterized the effect of exenatide on food intake and body weight in high-fat-fed, normal (those with an intact leptin signaling system) rodents. As glucagon-like peptide-1 receptor agonism has been found to elicit behaviors associated with visceral illness in rodents, we also examined the effect of peripheral exenatide on kaolin consumption and locomotor activity.


RESULTS
High-fat-fed C57BL/6 mice and Sprague-Dawley rats were treated with exenatide (3, 10 and 30 microg/kg/day) for 4 weeks via subcutaneously implanted osmotic pumps. Food intake and body weight were assessed weekly. At 4 weeks, body composition and plasma metabolic profiles were measured. Kaolin consumption and locomotor activity were measured in fasted Sprague-Dawley rats following a single intraperitoneal injection of exenatide (0.1-10 microg/kg). Exenatide treatment in mice and rats dose-dependently decreased food intake and body weight; significant reductions in body weight gain were observed throughout treatment at 10 and 30 microg/kg/day (P<0.05). Decreased body weight gain was associated with a significant decrease in fat mass (P<0.05) with sparing of lean tissue. Plasma cholesterol, triglycerides and insulin were also significantly reduced (P<0.05). Exenatide at 10 microg/kg significantly reduced food intake (P<0.05) but failed to induce kaolin intake. In general, locomotor activity was reduced at doses of exenatide that decreased food intake, although a slightly higher dose was required to produce significant changes in activity.


CONCLUSIONS
Systemic exenatide reduces body weight gain in normal, high-fat-fed rodents, a model that parallels human genetic variation and food consumption patterns, and may play a role in metabolic pathways mediating food intake.
Amylin Pharmaceuticals Inc., San Diego, CA 92121, USA. christine.mack@amylin.com
C M
CM
Mack
C X
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Moore
C M
CM
Jodka
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Bhavsar
J K
JK
Wilson
J A
JA
Hoyt
J L
JL
Roan
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Vu
K D
KD
Laugero
D G
DG
Parkes
A A
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Young
D000818:Animals; D001823:Body Composition; D001835:Body Weight / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004435:Eating / Q000187:drug effects; D000077270:Exenatide; D005260:Female; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D007616:Kaolin / Q000008:administration & dosage; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D009765:Obesity / Q000517:prevention & control*; D010455:Peptides / Q000008:administration & dosage* / Q000009:adverse effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D014688:Venoms / Q000008:administration & dosage* / Q000009:adverse effects
D007004:Hypoglycemic Agents; D010455:Peptides; D014688:Venoms; D007616:Kaolin; D000077270:Exenatide