A low-protein diet as a model of leptin resistance

Most obese humans are characterized by elevated concentrations of circulating leptin. Despite this, body fat and food intake remain elevated. This suggests most obese humans are resistant to the effects of leptin. Young rats fed a low-protein (10% casein) diet quickly become hyperphagic and accumulate body fat even with increased plasma leptin levels, again suggesting these animals are resistant to leptin. The objectives of this research were to determine if rats fed a low-protein diet have a: (1) decreased response to exogenous leptin as demonstrated by an attenuation of the leptin-induced decrease in food intake and body weight, (2) change in expression of hypothalamic mediators of leptin signaling, and (3) different pattern of hyperphagia than that generated by a high-fat diet. To examine the effects of chronic leptin administration, 3–5 male rats weighing about 150 g were given 5 μg of leptin intracerebroventricularly (ICV) twice per day for 6 or 8 days while fed a diet containing either 10% casein (low-protein) or 20% casein (control). In one study, food intake, expressed as a percent of intake of the vehicle-injected animals receiving the same diet, was greater for rats fed the low-protein diet only 24 h after leptin injection. In a separate study, of the two leptin-treated groups, the low-protein fed animals ate significantly more than the animals fed the control diet only on the 3rd day after injection. To examine the effects of an acute dose of leptin, 28 male rats weighing about 125 g were given one of three doses of leptin (0.03, 0.3, or 3.0 μg) or the vehicle ICV while being fed low-protein or control diet. After 24 h, the low-protein group was returned to control diet, and after a 4 d washout period, the experiment was repeated for four injections. Basomedial hypothalamus (BMEH) was removed 24 h after the fourth injection, and neuropeptide Y (NPY), pro-opiomelanocortin (POMC), and leptin receptor (OB-Rb) gene expression was determined by ribonuclease protection assay. All leptin doses equally suppressed food intake. The leptin-induced decrease in food intake was attenuated in rats fed the low-protein diet compared to the control diet at 24 and 72 h after the injection, indicating that low dietary protein leads to leptin resistance. At 24 h after the last injection, no differences were found for NPY and POMC mRNA, but OB-Rb mRNA was significantly elevated in the vehicle-treated low-protein group compared to other groups. To determine the pattern of food intake in rats fed a low-protein diet as compared to a high-fat diet, 20 male rats weighing about 250 g were fed one of four diets: (1) low-protein (5% casein), (2) high-fat (20% corn oil), (3) low-protein/high-fat, or (4) control (20% casein, 10% corn oil) for 4 d. Diets 1 and 3 induced hyperphagia by 2 d regardless of the fat content. Consumption of diet 2 steadily increased to equal that of diets 1 and 3 on the 4th day of feeding. No significant effect was found for NPY, POMC, or OB-Rb mRNA in the BMH, though an interaction for dietary fat and protein was found for NPY mRNA. These studies suggest that a low-protein diet in young rats leads to leptin resistance that is mechanistically different from that of a high-fat diet.