@article{f2c1af44e5f349a0a06f45c690e813a3,
title = "Increased Energy Expenditure and Protection From Diet-Induced Obesity in Mice Lacking the cGMP-Specific Phosphodiesterase PDE9",
abstract = "Cyclic nucleotides cAMP and cGMP are important second messengers for the regulation of adaptive thermogenesis. Their levels are controlled not only by their synthesis, but also their degradation. Since pharmacological inhibitors of cGMP-specific phosphodiesterase 9 (PDE9) can increase cGMP-dependent protein kinase signaling and uncoupling protein 1 expression in adipocytes, we sought to elucidate the role of PDE9 on energy balance and glucose homeostasis in vivo. Mice with targeted disruption of the PDE9 gene, Pde9a, were fed nutrient-matched high-fat (HFD) or low-fat diets. Pde9a−/− mice were resistant to HFD-induced obesity, exhibiting a global increase in energy expenditure, while brown adipose tissue (AT) had increased respiratory capacity and elevated expression of Ucp1 and other thermogenic genes. Reduced adiposity of HFD-fed Pde9a−/− mice was associated with improvements in glucose handling and hepatic steatosis. Cold exposure or treatment with β-adrenergic receptor agonists markedly decreased Pde9a expression in brown AT and cultured brown adipocytes, while Pde9a−/− mice exhibited a greater increase in AT browning, together suggesting that the PDE9-cGMP pathway augments classical cold-induced β-adrenergic/cAMP AT browning and energy expenditure. These findings suggest PDE9 is a previously unrecognized regulator of energy metabolism and that its inhibition may be a valuable avenue to explore for combating metabolic disease.",
author = "Ceddia, {Ryan P.} and Dianxin Liu and Fubiao Shi and Crowder, {Mark K.} and Sumita Mishra and Kass, {David A.} and Sheila Collins",
note = "Funding Information: This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases grant R01 DK103056 (to S.C.), National Heart, Lung, and Blood InstituteR35-HL135827 (to D.A.K.), and American Heart Association grant 16SFRN28620000 (to D.A.K. and S.C.). R.P.C. was supported by National Institute of Diabetes and Digestive and Kidney Diseases grant F32 DK116520. F.S. was supported by American Diabetes Association grant 1-18-PDF-110. The Vanderbilt Mouse Metabolic Phenotyping Center is supported in part by National Institute of Diabetes and Digestive and Kidney Diseases grant DK059637 and National Institutes of Health grants S10RR028101 and S10OD025199. The Vanderbilt Translational Pathology Shared Resource is supported by National Cancer Institute/NIH Cancer Center support grants 2P30 CA068485-14, 5P30 CA68485-19, 5U24DK059637-13, and S10 OD023475-01A1. The Lipid Core is supported by National Institute of Diabetes and Digestive and Kidney Diseases grant DK020593. Funding Information: Acknowledgments. The authors thank Bruce Spiegelman (Dana-Farber Cancer Institute, Harvard Medical School) for the IngJ6 and Bat8 cells and Ez-Zoubir Amri (Institut de Biologie Valrose, Universit{\'e}C{\^o}te d{\textquoteright}Azur) for the hMADS. Funding. This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases grant R01 DK103056 (to S.C.), National Heart, Lung, and Blood Institute R35-HL135827 (to D.A.K.), and American Heart Association grant 16SFRN28620000 (to D.A.K. and S.C.). R.P.C. was supported by National Institute of Diabetes and Digestive and Kidney Diseases grant F32 DK116520. F.S. was supported by American Diabetes Association grant 1-18-PDF-110. The Vanderbilt Mouse Metabolic Phenotyping Center is supported in part by National Institute of Diabetes and Digestive and Kidney Diseases grant DK059637 and National Institutes of Health grants S10RR028101 and S10OD025199. The Vanderbilt Translational Pathology Shared Resource is supported by National Cancer Institute/NIH Cancer Center support grants 2P30 CA068485-14, 5P30 CA68485-19, 5U24DK059637-13, and S10 OD023475-01A1. The Lipid Core is supported by National Institute of Diabetes and Digestive and Kidney Diseases grant DK020593. Duality of Interest. D.A.K. is a co-inventor on a patent filed by Johns Hopkins University regarding uses of PDE9 inhibitors for the treatment of car-diometabolic disorders and obesity. No other potential conflicts of interest relevant to this article were reported. Author Contributions. R.P.C., D.A.K., and S.C. conceived and designed the study. R.P.C., D.L., F.S., M.K.C., and S.M. performed experiments. R.P.C. analyzed the data and wrote the manuscript. D.A.K. and S.C. reviewed and edited the manuscript. S.C. is the guarantor of this work and, as such, had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Prior Presentation. This study was presented at EMBO Workshop: Organ crosstalk in energy balance and metabolic disease, C{\'a}diz, Spain, 8–11 April 2019. Publisher Copyright: {\textcopyright} 2021 by the American Diabetes Association.",
year = "2021",
month = dec,
doi = "10.2337/db21-0100",
language = "English (US)",
volume = "70",
pages = "2823--2836",
journal = "Diabetes",
issn = "0012-1797",
publisher = "American Diabetes Association Inc.",
number = "12",
}