Improved glucose and lipid metabolism in genetically obese mice lacking aP2

Adipocyte fatty acid-binding protein, aP2, is a member of the intracellular fatty acid binding protein family. Previously, studies have shown increase d insulin sensitivity in aP2-deficient mice with dietary obesity. Here, we asked whether aP2-related alterations in lipolytic response and insulin pro duction 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 aP 2 null allele (ob/ ob-aP2(-/-)) became more obese than ob/ob mice as indica ted by significantly increased body weight and fat pad size but unaltered b ody length. However, despite their extreme adiposity, ob/ob-aP2(-/-) animal s were more insulin-sensitive compared with ob/ob controls, as demonstrated by significantly lower plasma glucose and insulin levels and better perfor mance in both insulin and glucose tolerance tests. These animals also showe d improvements in dyslipidemia and had lower plasma triglyceride and choles terol levels. Lipolytic response to beta-adrenergic stimulation and lipolys is-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 dat a indicate that in obesity, aP2-deficiency not only improves peripheral ins ulin resistance but also preserves pancreatic beta cell function and has be neficial effects on Lipid metabolism.