DPP-IV inhibition enhances the antilipolytic action of NPY in human adipose tissue.
BACKGROUND
Dipeptidyl peptidase IV (DPP-IV) inactivates the incretin hormone glucagon-like peptide. It can also affect the orexigenic hormone neuropeptide Y (NPY(1-36)) which is truncated by DPP-IV to NPY(3-36), as a consequence NPY's affinity changes from receptor Y1, which mediates the antilipolytic function of NPY, to other NPY receptors. Little is known whether DPP-IV inhibitors for the treatment of type 2 diabetic (T2DM) patients could influence these pathways.


OBJECTIVE
To investigate the in vitro effects of NPY with DPP-IV inhibition in isolated abdominal subcutaneous (AbdSc) adipocytes on fat metabolism, and assessment of NPY receptor and DPP-IV expression in adipose tissue (AT).


METHODS
Ex vivo human AT was taken from women undergoing elective surgery (body mass index: 27.5 (mean +/- s.d.) +/- 5 kg/m2, age: 43.7 +/- 10 years, n = 36). Isolated AbdSc adipocytes were treated with human recombinant (rh)NPY (1-100 nM) with and without DPP-IV inhibitor (1 M); glycerol release and tissue distribution of DPP-IV, Y1 and Y5 messenger RNA (mRNA) were measured and compared between lean and obese subjects.


CONCLUSIONS
rhNPY reduced glycerol release, an effect that was further enhanced by co-incubation with a DPP-IV inhibitor [control: 224 (mean +/- s.e.) +/- 37 micromol/l; NPY, 100 nM: 161 +/- 27 micromol/l**; NPY 100 nM/DPP-IV inhibitor, 1 M: 127 +/- 14 micromol/l**; **p < 0.01, n = 14]. DPP-IV was expressed in AbdSc AT and omental AT with relative DPP-IV mRNA expression lower in AbdSc AT taken from obese [77 +/- 6 signal units (SU)] vs. lean subjects (186 +/- 29 SU*, n = 10). Y1 was predominantly expressed in fat and present in all fat depots but higher in obese subjects, particularly the AbdSc AT-depot (obese: 1944 +/- 111 SU vs. lean: 711 +/- 112 SU**, n = 10). NPY appears to be regulated by AT-derived DPP-IV. DPP-IV inhibitors augment the antilipolytic effect of NPY in AT. Further studies are required to show whether this explains the lack of weight loss in T2DM patients treated with DPP-IV inhibitors.
Kos
K
K
Unit for Diabetes and Metabolism, Clinical Sciences Research Institute (CSRI), Warwick Medical School, Coventry, UK.
Baker
A R
AR
Jernas
M
M
Harte
A L
AL
Clapham
J C
JC
O'Hare
J P
JP
Carlsson
L
L
Kumar
S
S
McTernan
P G
PG
D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism; D000328:Adult; D002478:Cells, Cultured; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism / Q000502:physiology; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D005260:Female; D005990:Glycerol / Q000378:metabolism; D006801:Humans; D008066:Lipolysis / Q000187:drug effects; D008875:Middle Aged; D009478:Neuropeptide Y / Q000494:pharmacology*; D009765:Obesity / Q000378:metabolism / Q000473:pathology; D011994:Recombinant Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D050507:Subcutaneous Fat, Abdominal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology
D054873:Dipeptidyl-Peptidase IV Inhibitors; D009478:Neuropeptide Y; D011994:Recombinant Proteins; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4; D005990:Glycerol