Interaction of leptin and amylin in the long-term maintenance of weight loss in diet-induced obese rats.
We have previously shown that combined amylin + leptin agonism elicits synergistic weight loss in diet-induced obese (DIO) rats. Here, we assessed the comparative efficacy of amylin, leptin, or amylin + leptin in the maintenance of amylin + leptin-mediated weight loss. DIO rats pretreated with the combination of rat amylin (50 microg/kg/day) and murine leptin (125 microg/kg/day) for 4 weeks were subsequently infused with either vehicle, amylin, leptin, or amylin + leptin for an additional 4 weeks. Food intake, body weight, body composition, plasma parameters, and the expression of key metabolic genes in liver and white adipose tissue (WAT) were assessed. Amylin + leptin treatment (weeks 0-4) reduced body weight to 87.5% of baseline. Rats subsequently maintained on vehicle or leptin regained all weight (to 104.2 and 101.2% of baseline, respectively), those maintained on amylin had partial weight regain (97.0%). By contrast, weight loss was largely maintained with continued amylin + leptin treatment (91.4%), associated with a 10% decrease in adiposity. Cumulative food intake (weeks 5-8) was reduced by amylin and amylin + leptin, but not by leptin alone. Amylin + leptin, but not amylin or leptin alone, reduced plasma triglycerides (by 55%), total cholesterol (by 19%), and insulin (by 57%) compared to vehicle. Amylin + leptin also reduced hepatic stearoyl-CoA desaturase-1 (Scd1) mRNA, and increased WAT mRNA levels of adiponectin, fatty acid synthase (Fasn), and lipoprotein lipase (Lpl). We conclude that, in DIO rats, maintenance of amylin + leptin-mediated weight loss requires continued treatment with both agonists, and is accompanied by sustained improvements in body composition, and indices of lipid metabolism and insulin sensitivity.
Trevaskis
James L
JL
Amylin Pharmaceuticals, Inc., San Diego, California, USA.
Lei
Chunli
C
Koda
Joy E
JE
Weyer
Christian
C
Parkes
David G
DG
Roth
Jonathan D
JD
D052242:Adiponectin / Q000097:blood; D052436:Adipose Tissue, White / Q000378:metabolism; D000682:Amyloid / Q000097:blood / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D001067:Appetite Depressants / Q000494:pharmacology; D001823:Body Composition / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects*; D004032:Diet; D004347:Drug Interactions; D004435:Eating / Q000187:drug effects; D020869:Gene Expression Profiling; D007328:Insulin / Q000097:blood; D058228:Islet Amyloid Polypeptide; D020738:Leptin / Q000097:blood / Q000494:pharmacology*; D008099:Liver / Q000378:metabolism; D008297:Male; D009765:Obesity / Q000188:drug therapy* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D015431:Weight Loss / Q000187:drug effects*
D052242:Adiponectin; D000682:Amyloid; D001067:Appetite Depressants; D007328:Insulin; D058228:Islet Amyloid Polypeptide; D020738:Leptin; D012333:RNA, Messenger