Diet-induced obese mice develop peripheral, but not central, resistance to leptin.

TLDR

Leptin reduces obesity in leptin‑deficient mice, but its efficacy in obese humans with high circulating leptin is unclear. The study aimed to assess whether diet‑induced obesity in mice leads to peripheral and/or central leptin resistance. The authors induced obesity in two mouse strains by feeding them a 45 % fat diet. Serum leptin rose with body weight, and although C57BL/6 and AKR mice initially responded to peripheral leptin, they developed resistance after prolonged high‑fat feeding, whereas central leptin remained effective, indicating peripheral but not central leptin resistance in diet‑induced obesity.

Abstract

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.