Diet-induced obese mice develop peripheral, but not central, resistance to leptin.
Leptin administration reduces obesity in leptin-deficient ob/ob mice; its effects in obese humans, who have high circulating leptin levels, remain to be determined. This longitudinal study was designed to determine whether diet-induced obesity in mice produces resistance to peripheral and/or central leptin treatment. Obesity was induced in two strains of mice by exposure to a 45% fat diet. Serum leptin increased in proportion to body weight (P < 0.00001). Whereas C57BL/6 mice initially responded to peripherally administered leptin with a marked decrease in food intake, leptin resistance developed after 16 d on high fat diet; mice on 10% fat diet retained leptin sensitivity. In AKR mice, peripheral leptin significantly decreased food intake in both 10 and 45% fat-fed mice after 16 d of dietary treatment. However, after 56 d, both groups became resistant to peripherally administered leptin. Central administration of leptin to peripherally leptin-resistant AKR mice on 45% fat diet resulted in a robust response to leptin, with a dose-dependent decrease in food intake (P < 0.00001) and body weight (P < 0.0001) after a single intracerebroventricular infusion. These data demonstrate that, in a diet-induced obesity model, mice exhibit resistance to peripherally administered leptin, while retaining sensitivity to centrally administered leptin.
Van Heek
M
M
Department of CNS and Cardiovascular Research, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA. margaret.van.heek@spcorp.com
Compton
D S
DS
France
C F
CF
Tedesco
R P
RP
Fawzi
A B
AB
Graziano
M P
MP
Sybertz
E J
EJ
Strader
C D
CD
Davis
H R
HR
D000818:Animals; D001069:Appetite Regulation / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D004041:Dietary Fats / Q000008:administration & dosage / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D004435:Eating / Q000187:drug effects; D005247:Feeding Behavior / Q000187:drug effects; D020738:Leptin; D008137:Longitudinal Studies; D008297:Male; D051379:Mice; D008806:Mice, Inbred AKR; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000097:blood / Q000188:drug therapy*; D011506:Proteins / Q000008:administration & dosage* / Q000032:analysis / Q000627:therapeutic use*; D013997:Time Factors
D004041:Dietary Fats; D020738:Leptin; D011506:Proteins