The peroxisomal 3-ketoacyl-CoA thiolase B (ThB) catalyzes the thiolytic cleavage of straight chain 3-ketoacyl-CoAs. Up to now, the ability of ThB to interfere with lipid metabolism was studied in mice fed a laboratory chow enriched or not with the synthetic agonist
Wy14,643, a pharmacological activator of the
nuclear hormone receptor PPARĪ±. The aim of the present study was therefore to determine whether ThB could play a role in
obesity and lipid metabolism when mice are chronically fed a synthetic High Fat Diet (HFD) or a
Low Fat Diet (LFD) as a control diet. To investigate this possibility, wild-type (WT) mice and mice deficient for Thb (Thb(-/-)) were subjected to either a synthetic LFD or a HFD for 25 weeks, and their responses were compared. First, when fed a normal regulatory laboratory chow, Thb(-/-) mice displayed growth retardation as well as a severe reduction in the plasma level of
Growth Hormone (GH) and
Insulin Growth Factor-I (
IGF-I), suggesting alterations in the GH/IGF-1 pathway. When fed the synthetic diets, the corrected energy intake to body mass was significantly higher in Thb(-/-) mice, yet those mice were protected from HFD-induced adiposity. Importantly, Thb(-/-) mice also suffered from
hypoglycemia, exhibited reduction in
liver glycogen stores and circulating
insulin levels under the LFD and the HFD. Thb deficiency was also associated with higher levels of plasma HDL (
High Density Lipoproteins)
cholesterol and increased liver content of
cholesterol under both the LFD and the HFD. As shown by the plasma
lathosterol to
cholesterol ratio, a
surrogate marker for
cholesterol biosynthesis, whole body
cholesterol de novo synthesis was increased in Thb(-/-) mice. By comparing liver
RNA from WT mice and Thb(-/-) mice using
oligonucleotide microarray and RT-qPCR, a coordinated decrease in the expression of critical
cholesterol synthesizing genes and an increased expression of genes involved in
bile acid synthesis (Cyp7a1, Cyp17a1, Akr1d1) were observed in Thb(-/-) mice. In parallel, the elevation of the
lathosterol to
cholesterol ratio as well as the increased expression of
cholesterol synthesizing genes were observed in the kidney of Thb(-/-) mice fed the LFD and the HFD. Overall, the data indicate that ThB is not fully interchangeable with the thiolase A
isoform. The present study also reveals that modulating the expression of the peroxisomal ThB
enzyme can largely reverberate not only throughout
fatty acid metabolism but also
cholesterol,
bile acid and
glucose metabolism.