[DP-IV inhibition -- Merck]
>>Published online before print May 14, 2003
Proc. Natl. Acad. Sci. USA, 10.1073/pnas.0631828100
Physiology
Mice lacking dipeptidyl peptidase IV are protected against obesity and insulin resistance
Stacey L. Conarello *, Zhihua Li *, John Ronan , Ranabir Sinha Roy *, Lan Zhu *, Guoqiang Jiang *, Franklin Liu *, John Woods , Emanuel Zycband , David E. Moller *, Nancy A. Thornberry *, and Bei B. Zhang *
Departments of *Metabolic Disorders and Molecular Endocrinology, Comparative Medicine, and Immunology and Inflammation, Merck Research Laboratories, Rahway, NJ 07065
Communicated by Roger H. Unger, University of Texas Southwestern Medical Center, Dallas, TX, March 29, 2003 (received for review December 9, 2002)
Dipeptidyl peptidase IV (DP-IV), a member of the prolyl oligopeptidase family of peptidases, is involved in the metabolic inactivation of a glucose-dependent insulinotropic hormone, glucagon-like peptide 1 (GLP-1), and other incretin hormones. Here, we investigated the impact of DP-IV deficiency on body weight control and insulin sensitivity in mice. Whereas WT mice displayed accelerated weight gain and hyperinsulinemia when fed a high-fat diet (HFD), mice lacking the gene encoding DP-IV (DP-IV-/-) are refractory to the development of obesity and hyperinsulinemia. Pair-feeding and indirect calorimetry studies indicate that reduced food intake and increased energy expenditure accounted for the resistance to HFD-induced obesity in the DP-IV-/- mice. Ablation of DP-IV also is associated with elevated GLP-1 levels and improved metabolic control in these animals, resulting in improved insulin sensitivity, reduced pancreatic islet hypertrophy, and protection against streptozotocin-induced loss of cell mass and hyperglycemia. Together, these observations suggest that chronic deletion of DP-IV gene has significant impact on body weight control and energy homeostasis, providing validation of DP-IV inhibition as a viable therapeutic option for the treatment of metabolic disorders related to diabetes and obesity.<<
Cheers, Tuck |
