Neurogenin 3-specific dipeptidyl peptidase-2 deficiency causes impaired glucose tolerance, insulin resistance, and visceral obesity.
The control of glucose metabolism is a complex process, and dysregulation at any level can cause impaired glucose tolerance and insulin resistance. These two defects are well-known characteristics associated with obesity and onset of type 2 diabetes. Here we introduce the N-terminal dipeptidase, DPP2, as a novel regulator of the glucose metabolism. We generated mice with a neurogenin 3 (NGN3)-specific DPP2 knockdown (kd) to explore a possible role of DPP2 in maintaining metabolic homeostasis. These mice spontaneously developed hyperinsulinemia, glucose intolerance, and insulin resistance by 4 months of age. In addition, we observed an increase in food intake in DPP2 kd mice, which was associated with a significant increase in adipose tissue mass and enhanced liver steatosis but no difference in body weight. In accordance with these findings, the mutant mice had a higher rate of respiratory exchange than the control littermates. This phenotype was exacerbated with age and when challenged with a high-fat diet. We report, for the first time, that DPP2 enzyme activity is essential for preventing hyperinsulinemia and maintaining glucose homeostasis. Interestingly, the phenotype of NGN3-DPP2 kd mice is opposite that of DPP4 knockout mice with regard to glucose metabolism, namely the former have normal glucagon-like peptide 1 levels but present with glucose intolerance, whereas the latter have increased glucagon-like peptide 1, which is accompanied by augmented glucose tolerance.
Danilova
Olga V
OV
Department of Pathology, Tufts University School of Medicine, Boston, Massachusetts 02111, USA.
Tai
Albert K
AK
Mele
Deanna A
DA
Beinborn
Martin
M
Leiter
Andrew B
AB
Greenberg
Andrew S
AS
Perfield
James W
JW
Defuria
Jason
J
Singru
Praful S
PS
Lechan
Ronald M
RM
Huber
Brigitte T
BT
D000273:Adipose Tissue / Q000378:metabolism / Q000473:pathology; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D001786:Blood Glucose / Q000378:metabolism; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000235:genetics / Q000378:metabolism*; D004435:Eating; D005215:Fasting / Q000097:blood; D005234:Fatty Liver / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005260:Female; D005455:Fluorescent Antibody Technique; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D018149:Glucose Intolerance / Q000097:blood / Q000378:metabolism*; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism*
D051792:Basic Helix-Loop-Helix Proteins; D001786:Blood Glucose; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; D052216:Glucagon-Like Peptide 1; D007328:Insulin; D009419:Nerve Tissue Proteins; C407737:Neurog3 protein, mouse; C100151:dipeptidyl peptidase II