Mice lacking dipeptidyl peptidase IV are protected against obesity and insulin resistance.
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 beta 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.
Conarello
Stacey L
SL
Department of Metabolic Disorders and Molecular Endocrinology, Merck Research Laboratories, Rahway, NJ 07065, USA.
Li
Zhihua
Z
Ronan
John
J
Roy
Ranabir Sinha
RS
Zhu
Lan
L
Jiang
Guoqiang
G
Liu
Franklin
F
Woods
John
J
Zycband
Emanuel
E
Moller
David E
DE
Thornberry
Nancy A
NA
Zhang
Bei B
BB
D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D018819:Dipeptidyl Peptidase 4 / Q000235:genetics / Q000378:metabolism*; D020022:Genetic Predisposition to Disease; D006943:Hyperglycemia / Q000139:chemically induced; D007150:Immunohistochemistry; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D009765:Obesity / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013311:Streptozocin
D017931:DNA Primers; D013311:Streptozocin; D018819:Dipeptidyl Peptidase 4