The liver secretes
triglyceride-rich VLDLs, and the
triglycerides in these particles are taken up by peripheral tissues, mainly heart, skeletal muscle, and adipose tissue. Blocking hepatic VLDL secretion interferes with the delivery of liver-derived
triglycerides to peripheral tissues and results in an accumulation of
triglycerides in the liver. However, it is unclear how interfering with hepatic
triglyceride secretion affects adiposity, muscle
triglyceride stores, and
insulin sensitivity. To explore these issues, we examined mice that cannot secrete VLDL [due to the absence of
microsomal triglyceride transfer protein (
Mttp) in the liver]. These mice exhibit markedly reduced levels of
apolipoprotein B-100 in the plasma, along with reduced levels of
triglycerides in the plasma. Despite the low plasma
triglyceride levels,
triglyceride levels in skeletal muscle were unaffected. Adiposity and adipose tissue
triglyceride synthesis rates were also normal, and
body weight curves were unaffected. Even though the blockade of VLDL secretion caused hepatic steatosis accompanied by increased
ceramides and
diacylglycerols in the liver, the mice exhibited normal
glucose tolerance and were sensitive to
insulin at the whole-body level, as judged by hyperinsulinemic euglycemic clamp studies. Normal hepatic
glucose production and
insulin signaling were also maintained in the
fatty liver induced by
Mttp deletion. Thus, blocking VLDL secretion causes hepatic steatosis without
insulin resistance, and there is little effect on muscle
triglyceride stores or adiposity.