It has been hypothesized that the increase in body weight is associated with an increase in the capacity of the microbiota to extract nutrients from the diet and in inducing metabolic changes necessary in the host, such as increased fatty acid oxidation in muscle and increased triglyceride storage in the liver (4, 39). However, other mechanisms such as changes in gut function, altered activity in the peripheral and central nervous system, and/or induction of hyperphagia have not been fully explored. Obesity and associated metabolic disorders are characterized by chronic or ��low-grade�� inflammation (22). Changes in the composition of the gut microbiota and epithelial functions may play a role in inflammation associated with obesity.

Diet-induced obese mice exhibit a low but constant increase in plasma endotoxin (lipopolysaccharide, LPS), a breakdown product of the outer membrane of Gram-negative staining bacteria, termed ��metabolic endotoxemia�� (10�C11). LPS acts via toll-like receptor-4 (TLR4) to initiate downstream inflammatory events, such as secretion of proinflammatory cytokines like interleukin-6 or tumor necrosis factor (TNF)-�� (16, 37), and may be responsible for some of the downstream inflammatory processes associated with obesity, such as insulin resistance (10, 13). Mice lacking the TLR4 adapter protein CD14 do not develop diet-induced obesity (10). Moreover, hyperphagia and the increase in adiposity and metabolic changes seen with ingestion of HF diets were recapitulated by chronic (4 wk) continuous administration of LPS in mice (10�C11).

These data suggest that the effects of a HF diet on the gut can influence the controls of food intake and result in or contribute to the diet-induced obese phenotype (4�C5, 13). It has previously been established that Sprague-Dawley rats, which are an outbred strain, vary in their propensity to HF diet-induced obesity; some individuals are prone (DIO-P) to the obesigenic effects of the HF diet, while others are resistant (DIO-R) (27). This propensity for hyperphagia and weight gain and adiposity when ingesting a HF diet is associated with elevated plasma leptin and alteration in activation of the vagal afferent pathway in response to intestinal lipid (34). This observation provides an interesting and potentially useful model in which to investigate the role of the gut in generating the obese phenotype in response to a HF diet and potentially gain insight into whether changes in the gut microbiota GSK-3 are driven by the HF diet or by the ensuing obesity. In the present study, the hypothesis to be tested was that ingestion of a HF diet alters the gut microbiota, induces gut inflammation and elevated LPS, and that this only occurs in obese-prone rats.