Post-transcriptional stimulation of the assembly and secretion of triglyceride-rich apolipoprotein B lipoproteins in a mouse with selective deficiency of brown adipose tissue, obesity, and insulin resistance

A mouse model of insulin resistance and its associated dyslipidemia was gen erated by crossing mice expressing human apolipoprotein B (apoB) with mice lacking only brown adipose tissue (BATless). On a high fat diet, male apoB/ BATless mice became obese, hypercholesterolemic, hypertriglyceridemic, and hyperinsulinemic compared with control apoB mice. Fast performance liquid c hromatography revealed increased triglyceride concentrations in intermediat e density lipoprotein/low density lipoprotein (LDL) and reduced high densit y lipoprotein cholesterol concentrations. Inhibition of lipolysis by the dr ug, tetrahydrolipostatin, demonstrated that very low density lipoprotein-si zed particles were initially secreted. Metabolic studies employing Triton W R-1339 and either [H-3]glycerol or [H-3]palmitate showed that the hypertrig lyceridemia in apoB/BATless mice was due to the increased synthesis and sec retion of triglyceride. Furthermore, lipoprotein lipase and hepatic lipase activities were not defective. ApoB was also secreted at increased rates in the apoB/BATless mice. Similar levels of apoB mRNA in apoB and apoB/BATles s mice indicated that apoB secretion was regulated posttranscriptionally. L DL receptor mRNA was increased in the apoB/BATless mice, indicating that th e observed increase in apoB-lipoprotein secretion was not due to their decr eased reuptake. Finally, mRNA levels of the large subunit of microsomal tri glyceride transfer protein, a required component for very low density prote in assembly, were not different between apoB and apoB/ BATless mice. This r odent model should prove useful in exploring mechanisms underlying the regu lation of apoB secretion in the context of insulin resistance.