Objective: In a phase II clinical trial in nine obese, insulin-resistant humans, we observed that treatment with KDT501, a novel isohumulone drug, increased total and high-molecular weight (HMW) adiponectin in plasma. The objective was to determine whether KDT501 increased adiponectin secretion from subcutaneous white adipose tissue (SC WAT) and the underlying mechanism(s). Methods: Nine obese participants with either prediabetes or with normal glucose tolerance plus three features of metabolic syndrome were part of the study. SC WAT biopsies were performed before and after 28 days of KDT501 treatment in a clinical research setting. In addition, a cold stimulus was used to induce thermogenic gene expression. Adiponectin secretion was measured, and gene expression of 130 genes involved in adipose tissue function was determined. The effect of KDT501 on adipocyte mitochondrial function was analyzed in vitro. Results: SC WAT explants secreted more total and HMW adiponectin after KDT501 treatment (P < 0.05). After KDT501 treatment, a number of genes involved in thermogenesis and lipolysis were induced by cold (P < 0.05). KDT501 also potentiated β-adrenergic signaling (P < 0.001) and enhanced mitochondrial function in adipocytes (P < 0.001). Conclusion: KDT501 induced adiponectin secretion posttranscriptionally and increased gene expression of thermogenic and lipolytic genes in response to cold stimulation. These beneficial effects on SC WAT may be explained by the ability of KDT501 to potentiate β-adrenergic signaling and enhance mitochondrial function in adipocytes.
|Frontiers in Endocrinology
|Published - Sep 29 2017
Bibliographical noteFunding Information:
The authors wish to thank the staffof the University of Kentucky Clinical Research Unit for the assistance with this study, especially Dr. Jen Moylan for the adiponectin ELISAs, Donna Wall for technical assistance with the nanostring assays, and Dorothy Ross for coordinating the recruitment of the participants. This work was supported by Kindex Pharmaceuticals, National Institute of Diabetes and Digestive and Kidney Diseases (DK107646), National Institute of General Medical Sciences (P20GM103527), NIH Office of the Director (1S10OD16357), and National Center for Advancing Translational Sciences (CTSA grant UL1TR001998).
© 2017 Finlin, Zhu, Kok, Godio, Westgate, Grayson, Sims, Bland, Saez and Kern.
- Adipocyte secretion
- Adipose tissue biology
- Gene expression profiling
- Metabolic syndrome
ASJC Scopus subject areas
- Endocrinology, Diabetes and Metabolism