Multi-hormonal weight loss combinations in diet-induced obese rats: therapeutic potential of cholecystokinin?
Cholecystokinin (CCK) acutely synergizes with amylin to suppress food intake in lean mice. To extend on these findings, the present studies sought to identify neural correlates for the interaction of amylin and CCK, as well as further understand the therapeutic potential of CCK-based combinations in obesity. First, c-Fos activation was assessed in various brain nuclei after a single intraperitoneal injection of amylin (5microg/kg) and/or CCK (5microg/kg). Amylin and CCK additively increased c-Fos within the area postrema (AP), predominantly in noradrenergic (e.g., dopamine-beta-hydroxylase-containing) cells. Next, amylin (100 or 300microg/kg/d) and/or CCK (100 or 300microg/kg/d) were subcutaneously infused for 7days in diet-induced obese (DIO) rats. Amylin treatment of DIO rats for 7days induced significant body weight loss. CCK, while ineffective alone, significantly enhanced body weight loss when co-administered with the higher dose of amylin. Finally, the addition of CCK (300microg/kg/d) to leptin (125microg/kg/d), and to the combination of amylin (50microg/kg/d) and leptin (125microg/kg/d), was also explored in DIO rats via sustained subcutaneous infusion for 14days. Infusion of amylin/leptin/CCK for 14days exerted significantly greater body weight loss, inhibition of food intake, and reduction in adiposity compared to amylin/leptin treatment alone in DIO rats. However, co-infusion of CCK and leptin was an ineffective weight loss regimen in this model. Whereas CCK agonism alone is ineffective at eliciting or maintaining weight loss, it durably augmented the food intake and body weight-lowering effects of amylin and amylin/leptin in a relevant disease model, and when combined with amylin, cooperatively activated neurons within the caudal brainstem.
Trevaskis
James L
JL
Amylin Pharmaceuticals, Inc., 9360 Towne Centre Drive, San Diego, CA 92121, United States.
Turek
Victoria F
VF
Griffin
Peter S
PS
Wittmer
Carrie
C
Parkes
David G
DG
Roth
Jonathan D
JD
D000682:Amyloid / Q000494:pharmacology / Q000627:therapeutic use; D000704:Analysis of Variance; D000818:Animals; D001067:Appetite Depressants / Q000494:pharmacology / Q000627:therapeutic use; D031608:Area Postrema / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001835:Body Weight / Q000187:drug effects; D002766:Cholecystokinin / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004299:Dopamine beta-Hydroxylase / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination / Q000379:methods; D004435:Eating / Q000187:drug effects; D058228:Islet Amyloid Polypeptide; D020738:Leptin / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D009474:Neurons / Q000378:metabolism; D009765:Obesity / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015431:Weight Loss / Q000187:drug effects
D000682:Amyloid; D001067:Appetite Depressants; D058228:Islet Amyloid Polypeptide; D020738:Leptin; D016760:Proto-Oncogene Proteins c-fos; D002766:Cholecystokinin; D004299:Dopamine beta-Hydroxylase