Increased energy expenditure and protection from diet-induced obesity in mice lacking the cGMP-specific phosphodiesterase, PDE9

Ceddia, Ryan P.; Liu, Dianxin; Shi, Fubiao; Mishra, Sumitra; Kass, David A.; Collins, Sheila

doi:10.1101/2021.02.02.429406

Cited by 2 publications

(2 citation statements)

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“…We used PDE9 pharmacological inhibition rather than gene deletion to test its role, as we wanted to generate substantial obesity and CMS before impeding PDE9 activity. Results from a global PDE9 KO mouse subjected to DIO are presented in a separate study and also reveal less weight gain and metabolic improvement over time (58). While our model of obesity-CMS provides insights into HFpEF, it did not recapitulate true HFpEF as the mice did not develop frank heart failure -with fluid retention and increased mortality.…”

Section: Discussionmentioning

confidence: 93%

Inhibition of phosphodiesterase type 9 reduces obesity and cardiometabolic syndrome in mice

Mishra¹,

Sadagopan²,

Dunkerly‐Eyring³

et al. 2021

Journal of Clinical Investigation

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Central obesity with cardiometabolic syndrome (CMS) is a major global contributor to human disease, and effective therapies are needed. Here, we show inhibiting cyclic-GMP selective phosphodiesterase-9A (PDE9-I) in both ovariectomized female or male mice suppresses pre-established severe diet-induced obesity/CMS with or without superimposed mild cardiac pressure-load. PDE9-I reduces total body, inguinal, hepatic, and myocardial fat, stimulating mitochondrial activity in brown and white fat, and improving CMS, without significantly altering activity or food intake. PDE9 localized at mitochondria, and its inhibition in vitro stimulated lipolysis and mitochondrial respiration in adipocytes and myocytes coupled to PPARa-dependent gene regulation.PPARa upregulation was required to achieve the lipolytic, anti-obesity, and metabolic effects of PDE9-I. All these PDE9-I induced changes were not observed in obese/CMS non-ovariectomized females, indicating a strong sexual dimorphism. We found that PPARa chromatin binding was re-oriented away from fat-metabolism regulating genes when stimulated in the presence of co-activated estrogen receptor-a, and this may underly the dimorphism. These findings have translational relevance given that PDE9-I is already being studied in humans for indications including heart failure, and efficacy against obesity/CMS would enhance its therapeutic utility.

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Section: Discussionmentioning

confidence: 93%

Inhibition of phosphodiesterase type 9 reduces obesity and cardiometabolic syndrome in mice

Mishra¹,

Sadagopan²,

Dunkerly‐Eyring³

et al. 2021

Journal of Clinical Investigation

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“…On day 5, iBAT and iWAT were dissected and immediately placed in Trizol (ThermoFisher). Similar CL316,243 treatments in mice have been performed in the lab (Ceddia et al, 2021; Liu et al, 2016b).…”

Section: Methodsmentioning

confidence: 73%

Protein kinase D1 (Prkd1) deletion in brown adipose tissue leads to altered myogenic gene expression after cold exposure, while thermogenesis remains intact

Crowder

Shrestha

Cartailler

et al. 2023

Physiological Reports

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Brown adipose tissue (BAT) has in recent times been rediscovered in adult humans, and together with work from preclinical models, has shown to have the potential of providing a variety of positive metabolic benefits. These include lower plasma glucose, improved insulin sensitivity, and reduced susceptibility to obesity and its comorbidities. As such, its continued study could offer insights to therapeutically modulate this tissue to improve metabolic health. It has been reported that adipose‐specific deletion of the gene for protein kinase D1 (Prkd1) in mice enhances mitochondrial respiration and improves whole‐body glucose homeostasis. We sought to determine whether these effects were mediated specifically through brown adipocytes using a Prkd1 brown adipose tissue (BAT) Ucp1‐Cre‐specific knockout mouse model, Prkd1BKO. We unexpectedly observed that upon both cold exposure and β3‐AR agonist administration, Prkd1 loss in BAT did not alter canonical thermogenic gene expression or adipocyte morphology. We took an unbiased approach to assess whether other signaling pathways were affected. RNA from cold‐exposed mice was subjected to RNA‐Seq analysis. These studies revealed that myogenic gene expression is altered in Prkd1BKO BAT after both acute and extended cold exposure. Given that brown adipocytes and skeletal myocytes share a common precursor cell lineage expressing myogenic factor 5 (Myf5), these data suggest that loss of Prkd1 in BAT may alter the biology of mature brown adipocytes and preadipocytes in this depot. The data presented herein clarify the role of Prkd1 in BAT thermogenesis and present new avenues for the further study of Prkd1 function in BAT.

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Increased energy expenditure and protection from diet-induced obesity in mice lacking the cGMP-specific phosphodiesterase, PDE9

Cited by 2 publications

References 50 publications

Inhibition of phosphodiesterase type 9 reduces obesity and cardiometabolic syndrome in mice

Inhibition of phosphodiesterase type 9 reduces obesity and cardiometabolic syndrome in mice

Protein kinase D1 (Prkd1) deletion in brown adipose tissue leads to altered myogenic gene expression after cold exposure, while thermogenesis remains intact

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