Adipocyte fatty acid-binding protein, aP2, is a member of the
intracellular fatty acid binding protein family. Previously, studies have shown increased
insulin sensitivity in aP2-deficient
mice with dietary
obesity. Here, we asked whether aP2-related alterations in lipolytic response and
insulin production are features of obesity-induced
insulin resistance and investigated the effects of aP2-deficiency on
glucose homeostasis and
lipid metabolism in
ob/ob mice, a model of extreme
obesity.
ob/ob mice homozygous for the aP2
null allele (ob/ ob-aP2-/-) became more
obese than
ob/ob mice as indicated by significantly increased
body weight and fat pad size but unaltered body length. However, despite their extreme
adiposity, ob/ob-aP2-/- animals were more insulin-sensitive compared with ob/ob controls, as demonstrated by significantly lower
plasma glucose and
insulin levels and better performance in both
insulin and
glucose tolerance tests. These animals also showed improvements in
dyslipidemia and had lower plasma
triglyceride and
cholesterol levels. Lipolytic response to beta-adrenergic stimulation and lipolysis-associated
insulin secretion was significantly reduced in ob/ob-aP2-/-
mice. Interestingly, glucose-stimulated
insulin secretion, while virtually abolished in ob/ob controls, was significantly improved in ob/ob-aP2-/- animals. There were no apparent morphological differences in the structure or size of the
pancreatic islets between
genotypes. Taken together, the data indicate that in
obesity, aP2-deficiency not only improves peripheral
insulin resistance but also
preserves pancreatic
beta cell function and has beneficial effects on
lipid metabolism.
