Antiobesity effects of the beta-cell hormone amylin in combination with phentermine or sibutramine in diet-induced obese rats.
OBJECTIVE
To characterize the interactive effects of amylin with phentermine or sibutramine on food intake, body weight/composition and gene expression in diet-induced obese (DIO) rats.


METHODS
DIO rats were intraperitoneally injected with a single dose of amylin (10 microg kg(-1)) and/or phentermine (1 mg kg(-1)) or chronically infused with amylin (100 microg kg(-1) d(-1)) or vehicle with or without phentermine (0.5-10 mg kg(-1) d(-1)) or sibutramine (3 mg kg(-1) d(-1)) using two surgically implanted subcutaneous osmotic mini-pumps.


METHODS
Twenty-four hour food intake, locomotor activity and components of meal microstructure (meal size, latency, duration and intermeal interval) were measured following acute administration (amylin, phentermine or amylin+phentermine). Body weight and composition (for amylin and/or sibutramine or phentermine) and metabolism-related gene mRNA expression in the liver (fatty acid synthase, stearoyl-CoA desaturase-1 and carnitine palmitoyltransferase-1) and brown fat (beta-adrenergic receptors and uncoupling protein-1) were measured (for amylin and/or phentermine) after sustained infusion (2 weeks).


RESULTS
Acute co-administration of amylin (10 microg kg(-1)) and phentermine (1 mg kg(-1)) reduced acute food intake (up to 19 h) more than either monotherapy. In two studies, sustained subcutaneous infusion of amylin for 2 weeks decreased cumulative food intake (22%) and vehicle-corrected body weight gain ( approximately 4-8%). Phentermine's anorexigenic (10-17%) and weight-reducing effects ( approximately 0-5%) were only evident at the highest dose tested (10 mg kg(-1) d(-1)). Combination of amylin (100 microg kg(-1) d(-1)) and phentermine reduced food intake (30-43%), body weight (8-12%) and adiposity to a greater extent than either monotherapy. Amylin prevented phentermine-induced reductions in UCP-1 mRNA in brown adipose tissue. When amylin+sibutramine were infused, mathematically additive decreases in food intake (up to 45%) and body weight (up to 12%) were evident. Similar to amylin+phentermine treatment, amylin+sibutramine mediated weight loss was attributable to significant reductions in fat mass.


CONCLUSIONS
Combined treatment of DIO rats with the pancreatic beta-cell hormone amylin and phentermine or sibutramine resulted in additive anorexigenic, weight- and fat-reducing effects.
Roth
J D
JD
Amylin Pharmaceuticals, Inc, San Diego, CA 92121, USA. Jonathan.Roth@amylin.com
Trevaskis
J L
JL
Wilson
J
J
Lei
C
C
Athanacio
J
J
Mack
C
C
Kesty
N C
NC
Coffey
T
T
Weyer
C
C
Parkes
D G
DG
D000682:Amyloid / Q000627:therapeutic use*; D000818:Animals; D019440:Anti-Obesity Agents / Q000627:therapeutic use*; D001823:Body Composition / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D003503:Cyclobutanes / Q000627:therapeutic use*; D004032:Diet / Q000009:adverse effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004359:Drug Therapy, Combination; D004435:Eating / Q000187:drug effects; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects; D058228:Islet Amyloid Polypeptide; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009765:Obesity / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D010645:Phentermine / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000682:Amyloid; D019440:Anti-Obesity Agents; D003503:Cyclobutanes; D058228:Islet Amyloid Polypeptide; D010645:Phentermine; C058254:sibutramine