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 progressive development of high fat diet-induced obesity. Secondly, we examined peripheral and central exogenous leptin sensitivity in mice fed high-or low-fat diets for 1, 8 or 19 weeks.

SUBJECTS: A total of 168 C57BL/6J mice (3 weeks old) were used in this study.

MEASUREMENTS: In the first experiment, we measured the body weight, energy intake, adipose tissue mass, tibia bone length, and plasma leptin in mice fed 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 at 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 development of high fat diet-induced obesity in mice could be divided into early, middle and late stages. Compared with the mice fed a low-fat diet, the mice fed a high-fat diet showed a gradually increased body weight (+ 5.2%), fat storage (epididymal plus perirenal;+ 6.7%) and plasma leptin (+ 18%) 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 began to increase gradually after 8 weeks of high-fat diet feeding and then increased dramatically from 15 weeks to be 14% higher than that of controls after 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 μg/g (body weight) intraperitoneal (ip) injection of leptin, with no differences 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 μg/g (body weight) ip leptin, but were sensitive to a 0.1 μg intracerebroventricular (icv) injection of leptin;(3) after 19 weeks of feeding, the mice fed a high-fat diet were insensitive to 0.1 μg icv leptin, but were sensitive to a high dose of 2 μg icv leptin.

CONCLUSIONS: The present study demonstrated that the development of high fat diet-induced obesity (19 weeks) in C57 B1/6J mice could be divided into three 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 had an increase in leptin production and still retained central leptin sensitivity; and (3) an increased food intake stage, accompanied by a reduction of central leptin sensitivity.