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

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 Ͻ 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 Ͻ 0.00001) and body weight ( P Ͻ 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. ( J. Clin. Invest. 1997. 99:385-390.) Key words: leptin resistance • high fat diet • food intake • C57BL/6 • AKR

Severe pulmonary metastasis in obese and diabetic mice

“…21 Also, the serum leptin concentration rises in proportion to the amount of body fat in obese human subjects. 29,30 The notion of leptin resistance, a state of reduced responsiveness to leptin in various tissues, has recently come to be accepted, 31,32 and may explain why obesity causes immune dysregulation including tumor immunity. Although Dovio et al reported that the activity of NK cells did not differ between obese and nonobese humans, 33 it is not clear whether leptin resistance reflects the NK cell activity in obese individuals.…”

Leptin resistance exacerbates diet-induced obesity and is associated with diminished maximal leptin signalling capacity in rats

“…Diet-induced obesity in rodents is associated with elevated leptin levels [16] and such rats have apparent leptin resistance [3,4,17]. Identifying whether leptin resistance contributes to or is simply secondary to obesity is important in understanding the mechanisms underlying obesity.…”

“…Treatment by central rAAV-leptin delivery, which leads to both reduced signalling capacity and leptin resistance, exacerbates diet-induced obesity. Leptin resistance is the trademark of diet-induced obesity in rodents [3,4,17] and is generally considered a consequence rather than a cause of obesity. This simple view seems to be at odds with a recent study in transgenic mice overexpressing leptin [26].…”

Effects of leptin on adipose tissue lipoprotein lipase in the obese ob/ob mouse

“…Although circulating leptin levels have not been measured in the present study, because of a lack of plasma, Trayhurn 44 suggested that such a lack of effect of exogenous leptin may be partly due to a suppression of endogenous leptin production. An alternative possibility is the development of resistance to peripherally, but not centrally, administered leptin in lean animals, 11,45 perhaps at the level of its transport into the brain. 46 For example, AKR lean mice fed a 10% fat diet were found to be sensitive to peripheral leptin until the day 56 of treatment, after which they were only sensitive to centrally administered leptin.…”