The
hormone FGF21 regulates
carbohydrate and
lipid homeostasis as well as
body weight, and increasing
FGF21 improves metabolic abnormalities associated with
obesity and diabetes.
FGF21 is thought to act on its target tissues, including liver and adipose tissue, to improve
insulin sensitivity and reduce adiposity. Here, we used mice with selective hepatic inactivation of the IR (LIRKO) to determine whether
insulin sensitization in liver mediates
FGF21 metabolic actions. Remarkably,
hyperglycemia was completely normalized following
FGF21 treatment in LIRKO mice, even though
FGF21 did not reduce gluconeogenesis in these animals. Improvements in
blood sugar were due in part to increased
glucose uptake in brown fat, browning of white fat, and overall increased energy expenditure. These effects were preserved even after removal of the main interscapular brown fat pad. In contrast to its retained effects on reducing
glucose levels, the effects of
FGF21 on reducing circulating
cholesterol and hepatic
triglycerides and regulating the expression of key genes involved in
cholesterol and lipid metabolism in liver were disrupted in LIRKO mice. Thus,
FGF21 corrects
hyperglycemia in diabetic mice independently of
insulin action in the liver by increasing energy metabolism via activation of brown fat and browning of white fat, but intact liver
insulin action is required for
FGF21 to control hepatic lipid metabolism.