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ively resistant to age-related weight gain and insulin resistance. These studies tested whether Ostalpha(-/-) mice are also protected from weight gain, lipid changes, and insulin resistance which are normally observed with a western-style diet high in both fat and cholesterol (WD). Wild-type and Ostalpha(-/-) mice were fed a WD, a control defined low-fat diet (LF) or standard laboratory chow (CH). Surprisingly, although the Ostalpha(-/-) mice remained lighter on LF and CH diets, they weighed the same as wild-type mice after 12 weeks on the WD even though bile acid pool levels remained low and fecal lipid excretion remained elevated. Mice of both genotypes excreted relatively less lipid when switched from CH to LF or WD. WD caused slightly greater changes in expression of genes involved in lipid transport in the small intestines of Ostalpha(-/-) mice than wild-type, but the largest differences were between CH and defined diets. After WD feeding, Ostalpha(-/-) mice had lower serum cholesterol and hepatic lipids, but Ostalpha(-/-) and wild-type mice had equivalent levels of muscle lipids and similar responses in glucose and insulin tolerance tests. Taken together, the results show that Ostalpha(-/-) mice are able to adapt to a western-style diet despite low bile acid levels.