Development of high fat diet-induced obesity and leptin resistance in C57BI/6J mice

OBJECTIVE: To investigate the development of high fat diet-induced obesity and leptin resistance. DESIGN: Two experiments were carried out in this study. Firstly, we fed the mice with a high- or low-fat diet for up to 19 weeks to examine a progress ive development of high fat diet-induced obesity. Secondly, we examined per ipheral and central exogenous leptin sensitivity in mice fed high- or low-f at diets for 1, 8 or 19 weeks. SUBJECTS: A total of 168 C57BL/6J mice (3 weeks old) were used in this stud y. MEASUREMENTS: In the first experiment, we measured the body weight, energy intake, adipose tissue mass, tibia bone length, and plasma leptin in mice f ed either a high- or low-fat diet for 1, 8, 15 and 19 weeks. In the second experiment, body weight change and cumulative energy intake were measured a t 6 h intervals for 72 h after leptin injection in mice fed a high- or low- fat diet for 1, 8 or 19 weeks. RESULTS: The results from the first experiment suggested that the developme nt of high fat diet-induced obesity in mice could be divided into early, mi ddle and late stages. Compared with the mice fed a low-fat diet, the mice f ed a high-fat diet showed a gradually increased body weight ( + 5.2%), fat storage (epididymal plus perirenal; + 6.7%) and plasma leptin ( + 48%) at 1 week; + 11.4%, + 68.1%, and + 223%, respectively, at 8 weeks; and + 30.5%, + 141 %, and + 458%, respectively, at 19 weeks. Energy intake of high fat diet-fed mice was equal to that of low fat diet-fed controls for the first 3 weeks; it fell below control levels over the next 5 week period, but bega n to increase gradually after 8 weeks of high-fat diet feeding and then inc reased dramatically from 15 weeks to be 14% higher than that of controls af ter 19 weeks. The results from our second experiment showed that: (1) after 1 week of feeding, the mice fed a high-fat diet were sensitive to a 2 mu g /g (body weight) intraperitoneal (i.p.) injection of leptin, with no differ ences in body weight change or cumulative energy intake post-injection; (2) after 8 weeks of feeding, the mice fed a high-fat diet were insensitive to 2 mu g/g (body weight) i.p, leptin, but were sensitive to a 0.1 mu g intra cerebroventricular (i.c.v.) injection of leptin; (3) after 19 weeks of feed ing, the mice fed a high-fat diet were insensitive to 0.1 mu g i.c.v. lepti n, but were sensitive to a high dose of 2 mu g i.c.v, leptin. CONCLUSIONS: The present study demonstrated that the development of high fa t diet-induced obesity (19 weeks) in C57 B1/6J mice could be divided into t hree stages: (1) an early stage in response to high-fat diet that mice were sensitive to exogenous leptin; (2) a reduced food intake stage when mice h ad an increase in leptin production and still retained central leptin sensi tivity; and (3) an increased food intake stage, accompanied by a reduction of central leptin sensitivity.