Retinol
Binding Protein 4 An
Adipokine potential contribution to pathophysiology
of obesity
Serum retinol binding protein 4 contributes to insulin
resistance in obesity and type 2 diabetes.
In obesity and type 2 diabetes,
expression of the GLUT4 glucose transporter is decreased
selectively in adipocytes. Adipose-specific Glut4
(also known as Slc2a4) knockout (adipose-Glut4(-/-))
mice show insulin resistance secondarily in muscle
and liver. Here we show, using DNA arrays, that expression
of retinol binding protein-4 (RBP4) is elevated in
adipose tissue of adipose-Glut4(-/-) mice. We show
that serum RBP4 levels are elevated in insulin-resistant
mice and humans with obesity and type 2 diabetes.
RBP4 levels are normalized by rosiglitazone, an insulin-sensitizing
drug. Transgenic overexpression of human RBP4 or injection
of recombinant RBP4 in normal mice causes insulin
resistance. Conversely, genetic deletion of Rbp4 enhances
insulin sensitivity. Fenretinide, a synthetic retinoid
that increases urinary excretion of RBP4, normalizes
serum RBP4 levels and improves insulin resistance
and glucose intolerance in mice with obesity induced
by a high-fat diet. Increasing serum RBP4 induces
hepatic expression of the gluconeogenic enzyme phosphoenolpyruvate
carboxykinase (PEPCK) and impairs insulin signalling
in muscle. Thus, RBP4 is an adipocyte-derived 'signal'
that may contribute to the pathogenesis of type 2
diabetes. Lowering RBP4 could be a new strategy for
treating type 2 diabetes.
Yang Q, et al. Nature. 2005 Jul 21;436(7049):356-62.
Metabolism: A is for adipokine
Adipokines are hormones that
signal changes in fatty-tissue mass and energy status
so as to control fuel usage. A fat-derived adipokine
that binds to vitamin A provides a new link between
obesity and insulin resistance. Clearly, the study
by Yang et al.2 moves the adipocyte and its secreted
factors closer to the epicentre of the diabetes and
obesity epidemic.
Deborah M. Muoio1 and Christopher
B. Newgard1. Nature. 2005 Jul 21;436(7049):337-8.
In normal individuals, binding
of insulin to its receptor on the cell membrane stimulates
glucose uptake into muscle and fat cells through the
GLUT4 transporter. It also inhibits glucose production
in liver, thereby maintaining normal glucose levels
in the blood. In adipose tissue, glucose provides
fuel for the synthesis of fat stores, which serve
as the body's main energy reservoir. Yang et al.2
found that the decrease in GLUT4 expression that occurs
in the fatty tissue of obese animals is accompanied
by increased expression and secretion of the fat-derived
factor RBP4. This factor, possibly working in concert
with retinol (vitamin A), impairs insulin signalling
in muscle, inhibiting glucose uptake, and interferes
with insulin-mediated suppression of glucose production
in the liver, causing blood glucose levels to rise.
Deborah M. Muoio1 and Christopher
B. Newgard1. Metabolism: A is for adipokine. Nature
436, 337-338 (21 July 2005) | doi: 10.1038/436337a
