Effects of exendin-4 alone and with peptide YY(3-36) on food intake and body weight in diet-induced obese rats.
Significant weight loss following Roux-en-Y gastric bypass surgery (RYGB) in obese humans correlates with enhanced secretion of anorexigenic gut hormones glucagon-like peptide-1 (GLP-1) and peptide YY(3-36) (PYY(3-36)). Our aim here was to identify a dosing strategy for intraperitoneal (IP) infusion of GLP-1 homologue exendin-4 alone and with PYY(3-36) that produces a sustained reduction in daily food intake and body weight in diet-induced obese (DIO) rats. We tested 12 exendin-4 strategies over 10 weeks. Exendin-4 infused during the first and last 3 h of the dark period at 15-20 pmol/h (0.15 nmol/kg/day) produced a sustained 24 ± 1% reduction in daily food intake for 17 days, and decreased body weight by 7%. In a separate group of DIO rats, none of seven dosing strategies combining exendin-4 and PYY(3-36) produced a similar reduction in daily food intake for >10 days. The subsequent decline in efficacies of exendin-4 alone and with PYY(3-36) on food intake and body weight in each experiment suggested possible receptor downregulation and tolerance to treatments. However, when treatments were discontinued for 1 day following losses in efficacies, daily food intake significantly increased. Together, these results demonstrate that (i) intermittent IP infusion of a low dose of exendin-4 can produce a relatively prolonged reduction in daily food intake and body weight in DIO rats, (ii) co-infusion of exendin-4 and PYY(3-36) does not further prolong this response, and (iii) activation of an orexigenic mechanism gradually occurs to counteract the inhibitory effects of exendin-4 alone and with PYY(3-36) on food intake and body weight.
Reidelberger
Roger D
RD
Department of Veterans Affairs, Nebraska Western Iowa Health Care System, Omaha, Nebraska, USA. roger.reidelberger@va.gov
Haver
Alvin C
AC
Apenteng
Bettye A
BA
Anders
Krista L
KL
Steenson
Sharalyn M
SM
D000818:Animals; D001835:Body Weight / Q000187:drug effects* / Q000502:physiology; D004032:Diet / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004353:Drug Evaluation, Preclinical; D004435:Eating / Q000187:drug effects* / Q000502:physiology; D000077270:Exenatide; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D009765:Obesity / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology*; D010446:Peptide Fragments; D019894:Peptide YY / Q000008:administration & dosage* / Q000494:pharmacology; D010455:Peptides / Q000008:administration & dosage* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014688:Venoms / Q000008:administration & dosage* / Q000494:pharmacology*; D015431:Weight Loss / Q000187:drug effects
D004338:Drug Combinations; D007004:Hypoglycemic Agents; D010446:Peptide Fragments; D010455:Peptides; D014688:Venoms; D019894:Peptide YY; C061785:peptide YY (3-36); D000077270:Exenatide