Editors' ChoiceObesity

DPP4 Joins Weight Watchers

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Science Translational Medicine  01 Jun 2011:
Vol. 3, Issue 85, pp. 85ec80
DOI: 10.1126/scitranslmed.3002685

Not simply a storage depot, fat is now appreciated as a dynamic endocrine organ. Leptin and several other proteins are adipose-derived hormones known as adipokines. As sensors of adipose tissue mass and energy status, adipokines are intimately tied to metabolic and inflammatory processes that underlie chronic obesity and its health consequences. Now, Lamers et al. introduce dipeptidyl peptidase 4 (DPP4) as a newly described adipokine that further defines these ties.

DPP4 is a ubiquitously expressed glycoprotein enzyme with both transmembrane and soluble forms that cleaves numerous growth factor, chemokine, and neuropeptide substrates. DPP4 inactivates glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP), two incretins that control postprandial insulin secretion. Inhibition of this activity has formed the basis for a number of new therapies for type 2 diabetes.

In searching for new adipokines, the investigators identified DPP4 by proteomic profiling of conditioned media derived from primary cultures of human adipocytes. They found that DPP4 was expressed and released by differentiating adipocytes in vitro and was stimulated by regulators of adipocyte secretion, tumor necrosis factor–α and insulin. To establish a role for DPP4 as an adipokine, the authors examined its effect on insulin signaling in tissue targets of insulin resistance. In this key experiment, soluble DPP4 impaired insulin signaling in primary cultures of human adipocytes and smooth muscle cells in a dose-dependent manner, an effect that was reversible by addition of a DPP4 inhibitor. To pursue this provocative result, Lamers and colleagues asked whether circulating DPP4 was associated with obesity or other metabolic changes in humans. In two small cohorts of Caucasian patients, they found that levels of DPP4 in both serum and adipose tissue were increased with obesity and correlated with increasing adipocyte cell volume and body-mass index (BMI). In obese patients, visceral fat showed greater DPP4 expression than that of subcutaneous fat. Most striking, several clinical features of the metabolic syndrome (including high triglycerides, low high-density lipoprotein cholesterol, increased BMI, and waist measurements) and insulin resistance were associated with enhanced DPP4 release from adipose tissue explanted from the patients.

Although in the early stages, this study is notable for its translational approach to understanding obesity and the metabolic syndrome. The results suggest that DPP4 may mediate or be a biomarker for the linked conditions of obesity, insulin resistance, and the metabolic syndrome. Future studies will show whether current DPP4 inhibitors can be useful in the treatment of obesity.

D. Lamers et al., Dipeptidyl peptidase 4 is a novel adipokine potentially linking obesity to the metabolic syndrome, Diabetes 18 May 2011 (10.2337/db10-1707). [Abstract]

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