Development of high fat diet-induced obesity and leptin resistance in C57Bl/6J mice

Abstract

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 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 C57BLa6J mice (3 weeks old) were used in this study. MEASUREMENTS: In the ®rst 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 ®rst 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 ®rst 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 highfat diet were sensitive to a 2 mgag (body weight) intraperitoneal (i.p.) 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 mgag (body weight) i.p. leptin, but were sensitive to a 0.1 mg intracerebroventricular (i.c.v.) injection of leptin; (3) after 19 weeks of feeding, the mice fed a high-fat diet were insensitive to 0.1 mg i.c.v. leptin, but were sensitive to a high dose of 2 mg i.c.v. leptin. CONCLUSIONS: The present study demonstrated that the development of high fat diet-induced obesity (19 weeks) in C57 B1a6J 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.

High-fat diet-induced obesity in animal models

“…A more recent study showed that adult male SpragueDawley rats fed a high-fat diet (60 % of energy) for 2 weeks were hypersensitive to the food intake-lowering effect of ICV administration of leptin (3 mg); however, after 5 weeks on the high-fat diet, rats became insensitive to this effect of injected leptin (185) . Another study in weanling C57BL/6J mice led to similar conclusions (186) . The researchers suggested that early in high-fat feeding, animals are sensitive to the food-lowering effect of leptin but despite the reduction in food intake animals become fat as a result of the increase in food efficiency, leading to an increase in plasma leptin levels that is followed by insensitivity to its action (186) .…”

Metabolic and behavioral responses to high-fat feeding in mice selectively bred for high wheel-running activity

“…[3][4][5][6] This study investigated whether and how such an effect may be influenced by physical activity. For this Mean and s.e.m.…”

“…[3][4][5][6][7] In particular, the use of selectively bred and genetically for example, previously reported that spontaneous wheel running behavior was able to treat DIO. In addition, Patterson et al 14 observed that 3 weeks of wheel running behavior at the juvenile stage delays DIO in selectively bred DIO-prone rats, probably by favorably altering hypothalamic pathways controlling energy balance.…”

“…[3][4][5][6][7] In particular, the use of selectively bred and genetically engineered rodents that display diet-induced obesity (DIO) or obesity resistance has provided considerable insight about underlying mechanisms (for reviews, see Caroll et al 8 and Tschop and Heiman 9 ) Reports on whether and how physical activity could be involved in preventing dietary fat-induced obesity and associated metabolic derangements are less abundant. In part, this is attributable to the methodological problems that can arise when animals are 'forced' to be active.…”

Effect of Cheonggukjang supplementation upon hepatic acyl-CoA synthase, carnitine palmitoyltransferase I, acyl-CoA oxidase and uncoupling protein 2 mRNA levels in C57BL/6J mice fed with high fat diet

“…Therefore, we demonstrated that Cheonggukjang supplementation reduces body fat stores in mice fed high fat diets. The increased plasma triglyceride levels associated with dietary fat might be due to increased secretion of triglyceride from the liver or decreased triglyceride removal from plasma [10]. There was a report that elevated plasma TG level may be major cause of coronary artery disease because of lower levels of HDLcholesterol and increased chylomicron levels [4].…”