Mice lacking dipeptidyl peptidase IV are protected against obesity and insulin resistance

Abstract

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.

Fig. 1.

Disruption of DP-IV prevents HFD-induced obesity. (A) Body weight gain in WT and DP-IV^-/- mice on 10% FD or 45% FD (n = 17). (B) Histological analyses of epididymal white adipose tissues. (C) Histological analyses of intrascapular BAT. P < 0.05, comparing WT with DP-IV^-/- mice on 45% FD (*) or 10% FD (#).

Fig. 2.

Energy homeostasis in DP-IV^-/- mice. (A) Pair-feeding of WT mice on reduced food intake equal to the amount consumed by DP-IV^-/- mice. Shown are body weights of mice in each group [P < 0.05, comparing WT ad libitum group (#) or WT pair-fed group (*) with DP-IV^-/- mice fed ad libitum, n = 14]. Metabolic rate and oxygen consumption were measured over light and dark phases (B) and expressed as total oxygen consumption over a 23-h period (C). (D) Expression of uncoupling protein 1 and β-3 adrenergic receptor in BAT. *, P < 0.05, n = 8.

Fig. 3.

DP-IV^-/- mice are protected from high fat-induced insulin resistance. (A) DP-IV^-/- mice have reduced circulating plasma insulin levels on 10% and 45% FD for 20 weeks (n = 17). (B) Histological analyses of pancreatic islets. (C) Glucose levels during insulin tolerance test in WT and DP-IV^-/- mice on HFD (n = 10). Insulin was dosed i.p. at 1 unit/kg. P < 0.05, comparing WT with DP-IV^-/- mice on HFD (*) or LFD (#).

Fig. 4.

Deletion of DP-IV confers resistance to high fat-induced hepatic lipid accumulation. (A) Hepatic lipid content in WT and DP-IV^-/- mice. (B and C) Expression levels of PPARα and SREBP-1c genes in liver of WT and DP-IV^-/- mice (n = 10). *, P < 0.05, comparing WT with DP-IV^-/- mice on HFD.

Fig. 5.

DP-IV^-/- mice are resistant to STZ-induced hyperglycemia and loss of β cell mass. (A) Glucose levels in WT and DP-IV^-/- mice after STZ injection (n = 8–12). (B) Plasma insulin levels at 3 weeks post-STZ injection (n = 8–12). (C) Immunohistochemical analyses of islets from DP-IV^-/- (Upper) and WT (Lower) mice. Insulin-positive cells are shown in green, and glucagon-positive cells are shown in red. *, P < 0.05, comparing WT with DP-IV^-/- mice.