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The autumn wind is getting tighter, are the friends holding the nth cup of milk tea in autumn while worrying about how to lose weight? Nearly one-fifth of the people in the world suffer from obesity
.
In addition to appearance and body anxiety, obesity also brings a series of health threats, including cardiometabolic syndrome (CMS) such as diabetes, abnormal lipid metabolism, non-alcoholic fatty liver and hypertension [1]
.
In the face of this global epidemic, scientists continue to explore effective methods to promote fat breakdown and control weight
.
Recently, a research team led by Professor David A.
Kass of the Johns Hopkins University School of Medicine published important research results in the Journal of Clinical Investigation.
Their research found that the cGMP phosphodiesterase PDE-9A, a close relative of Viagra, was selected Sex inhibitors (PDE9-I) can promote fat cell mitochondrial metabolism and lipolysis, thereby treating diet-induced obesity and cardiometabolic syndrome (CMS) [2]
.
Their research shows that the old drug PDE9-I has a potential therapeutic effect on central obesity and its related cardiometabolic syndrome in addition to the treatment of heart failure
.
The team of Professor David A.
Kass revealed that the fat-reducing effect of PDE9-I is activated by natriuretic peptide (NP) or nitric oxide (NO).
The cGMP-PKG pathway is one of the important pathways for endogenous lipolysis
.
Previous studies have shown that activating the cGMP-PKG pathway can up-regulate the expression levels of hormone-sensitive lipase (HSL) and perilipin, promote mitochondrial oxidative metabolism and insulin pathway activity, thereby inhibiting diet-induced obesity [3]
.
Accordingly, promoting the synthesis of cGMP or inhibiting the hydrolysis of cGMP may be an effective treatment for promoting lipolysis and thus weight loss
.
However, synthetic recombinant natriuretic peptides, () nitrates and other soluble cGMP agonists have limitations such as short half-life and potential hypotensive effects [4]
.
So, from the perspective of inhibiting the hydrolysis of cGMP, can we achieve our goal of fat loss? PDE5 and PDE9 are classic phosphodiesterases that specifically degrade cGMP
.
Among them, PDE5 inhibitors (PDE5-I) can expand blood vessels by activating the NO-cGMP pathway, and are used to treat erectile dysfunction, pulmonary hypertension, and heart failure [5]
.
Unfortunately, in an ovariectomized mouse model that mimics the physiological conditions of menopausal women, scientists found that the cardiovascular protective effect of PDE5-I no longer exists [6]
.
As we all know, the incidence of central obesity and cardiometabolic syndrome in postmenopausal women is much higher than that of premenopausal young and middle-aged women [7]; and the cardiovascular protective effect of PDE5-I obviously cannot cover this high-risk group
.
Different from PDE5-I, previous studies have confirmed that PDE9-I exerts cardiovascular protection by activating the NP-cGMP pathway (rather than NO-cGMP) [5]
.
David's team guessed that different treatment mechanisms may make PDE9-I have a therapeutic effect on obesity-related cardiovascular diseases in postmenopausal women
.
In order to explore the therapeutic effects of PDE9-I on obesity and cardiometabolic syndrome, Professor David A.
Kass's team first established a diet-induced obesity model (DIO/mTAC) with cardiovascular disease
.
Male, female, and OVX female experimental mice were fed with a high-fat diet (HFD) for 6 consecutive months
.
One group of mice underwent aortic clipping (mTAC) surgery two months after a high-fat diet to cause a mild cardiac pressure load as an obesity model with cardiometabolic syndrome; the other group only Make a high-fat diet treatment to induce obesity model
.
Diet-induced obesity model combined with cardiovascular disease.
Subsequently, the researchers observed the therapeutic effect of oral PDE9-I on the above two model mice
.
They found that PDE9-I can not only significantly reduce the body weight and visceral fat content of obese mice, but also significantly improve the performance of metabolic syndromes such as hyperglycemia, hyperlipidemia, and fatty liver
.
Based on the cardiovascular protective effects of PDE9-I reported in previous studies [5], David's team further explored whether PDF9-I can improve the cardiac structure and function abnormalities of obese mice with cardiometabolic syndrome
.
The results showed that PDE9-I not only significantly improved the left ventricular ejection fraction, isovolumic delay time (IVRT) and other cardiac function indicators in DIO/mTAC mice, but also down-regulated the expression of a series of genes that promote myocardial hypertrophy and fibrosis, effectively controlling Myocardial hypertrophy progresses
.
It is worth noting that the fat reduction and cardioprotection of PDE9-I are more consistent in male and surgically removed ovariectomized (OVX) female mice, but it has no significant effect on obese female mice
.
PDE9-I improves cardiac dysfunction and inhibits myocardial hypertrophy.
So, how does PDE9-I play a therapeutic role in reducing fat and weight and protecting the heart? David's team found through transcriptome sequencing that the PDE9-I treatment group had a higher expression of the transcription factor PPARα than the control group's cardiomyocytes
.
Not only that, the expression levels of multiple downstream fatty acid oxidation (FAO) genes regulated by PPARα were also significantly up-regulated after receiving PDE9-I treatment
.
Considering that fatty acid oxidation is one of the important ways of fat decomposition [1]
.
David's team wanted to know whether PDE9-I up-regulated the expression of genes related to fatty acid oxidation downstream of PPARα, and whether it promoted lipolysis
.
David's team added fatty acids to the cardiomyocytes in vitro culture system to simulate the toxic effect of high-fat diet on cardiomyocytes
.
They found that the deposition of lipid droplets in cardiomyocytes treated with PDE9-I was significantly reduced, accompanied by an increase in the number of mitochondria, and an increase in the level of glycerol, a lipolysis product
.
These experimental results indicate that PDE9-I may reduce the toxic effect of high fat on cardiomyocytes by promoting the oxidation of mitochondrial fatty acids
.
PDE9-I promotes the breakdown of fat by cardiomyocytes.
Subsequently, David's team found that using a small molecule inhibitor of PPARα (GW6471) to inhibit PPARα activity would block the fat-reducing effect of PDE9-I on obese mice
.
This result once again confirmed that activation of PPARα is the core mechanism of PDE9-I to promote lipolysis
.
But there is still an unsolved question: Why does PDE9-I have no obvious fat-reducing effect in high-fat-fed female mice? Previous studies have also found similar findings that endogenous estrogen can inhibit PPARα activity and reduce its downstream fatty acid oxidation-related gene expression levels, but the mechanism is still unclear [8]
.
David's team found that in high-fat-fed female mice, although PDE9-I treatment still up-regulated the expression level of PPARα, there was no significant change in the expression of fatty acid oxidation-related genes regulated downstream
.
They suspected that this may be the estrogen receptor (ER) pathway blocking the binding of the transcription factor PPARα to its downstream regulatory genes
.
In order to confirm this conjecture, David's team used chromatin immunoprecipitation-sequencing (ChIP-seq) experiments and found that when only PPARα agonists were added, about 17,500 DNA binding sites were regulated by the transcription factor PPARα; and When the estrogen receptor ERα is activated at the same time, this number is almost halved; when the estrogen receptor ERβ is co-activated, only about 1/3 of the above-mentioned DNA binding sites are still regulated by PPARα
.
Not only that, KEGG gene enrichment analysis showed that most of the PPARα target genes inhibited by activation of estrogen receptors are related to cell metabolism, especially fatty acid oxidation metabolism
.
This shows that the estrogen receptor pathway does inhibit the regulation of the transcription factor PPARα on fatty acid oxidation-related genes; it also further explains why PDE9-I cannot effectively promote lipolysis and oxidative metabolism in obese female mice
.
In obese female mice, PDE9-I has no obvious regulatory effect on the expression of PPARα fatty acid oxidation genes.
In general, the research of Professor David A.
Kass’s team clarified that PDE9-I, a vasodilator, can activate the transcription factor PPARα Promote fat oxidation metabolism, and then treat obesity-related cardiometabolic syndrome
.
It is worth noting that the fat reduction effect of PDE9-I on premenopausal young and middle-aged women may not be ideal
.
The reason, David's team, pointed out that the estrogen receptor pathway inhibited the regulation of PPARα on fatty acid oxidation-related genes, and even caused the gender difference in the fat-reducing effect of PDE9-I (pig and pig girl cry for a second in the storm.
.
.
)
.
There is a long way to go to reduce fat, and we look forward to scientists developing new weight loss drugs that can also be used by the milk tea fairies! References: [1] Koliaki C, Liatis S, Kokkinos A.
Obesity and cardiovascular disease: revisiting an old relationship.
Metabolism.
2019;92:98-107.
doi:10.
1016/j.
metabol.
2018.
10.
011[2] Mishra S, Sadagopan N, Dunkerly-Eyring B, et al.
Inhibition of phosphodiesterase type 9 reduces obesity and cardiometabolic syndrome in mice [published online ahead of print, 2021 Oct 7].
J Clin Invest.
2021;e148798.
doi:10.
1172/JCI148798 [3] Collins S.
A heart-adipose tissue connection in the regulation of energy metabolism.
Nat Rev Endocrinol.
2014;10(3):157-163.
doi:10.
1038/nrendo.
2013.
234[4] Hoffmann LS, Etzrodt J, Willkomm L, et al.
Stimulation of soluble guanylyl cyclase protects against obesity by recruiting brown adipose tissue.
Nat Commun.
2015;6:7235.
Published 2015 May 26.
doi:10.
1038/ncomms8235[5] Lee DI, Zhu G, Sasaki T , et al.
.
In addition to appearance and body anxiety, obesity also brings a series of health threats, including cardiometabolic syndrome (CMS) such as diabetes, abnormal lipid metabolism, non-alcoholic fatty liver and hypertension [1]
.
In the face of this global epidemic, scientists continue to explore effective methods to promote fat breakdown and control weight
.
Recently, a research team led by Professor David A.
Kass of the Johns Hopkins University School of Medicine published important research results in the Journal of Clinical Investigation.
Their research found that the cGMP phosphodiesterase PDE-9A, a close relative of Viagra, was selected Sex inhibitors (PDE9-I) can promote fat cell mitochondrial metabolism and lipolysis, thereby treating diet-induced obesity and cardiometabolic syndrome (CMS) [2]
.
Their research shows that the old drug PDE9-I has a potential therapeutic effect on central obesity and its related cardiometabolic syndrome in addition to the treatment of heart failure
.
The team of Professor David A.
Kass revealed that the fat-reducing effect of PDE9-I is activated by natriuretic peptide (NP) or nitric oxide (NO).
The cGMP-PKG pathway is one of the important pathways for endogenous lipolysis
.
Previous studies have shown that activating the cGMP-PKG pathway can up-regulate the expression levels of hormone-sensitive lipase (HSL) and perilipin, promote mitochondrial oxidative metabolism and insulin pathway activity, thereby inhibiting diet-induced obesity [3]
.
Accordingly, promoting the synthesis of cGMP or inhibiting the hydrolysis of cGMP may be an effective treatment for promoting lipolysis and thus weight loss
.
However, synthetic recombinant natriuretic peptides, () nitrates and other soluble cGMP agonists have limitations such as short half-life and potential hypotensive effects [4]
.
So, from the perspective of inhibiting the hydrolysis of cGMP, can we achieve our goal of fat loss? PDE5 and PDE9 are classic phosphodiesterases that specifically degrade cGMP
.
Among them, PDE5 inhibitors (PDE5-I) can expand blood vessels by activating the NO-cGMP pathway, and are used to treat erectile dysfunction, pulmonary hypertension, and heart failure [5]
.
Unfortunately, in an ovariectomized mouse model that mimics the physiological conditions of menopausal women, scientists found that the cardiovascular protective effect of PDE5-I no longer exists [6]
.
As we all know, the incidence of central obesity and cardiometabolic syndrome in postmenopausal women is much higher than that of premenopausal young and middle-aged women [7]; and the cardiovascular protective effect of PDE5-I obviously cannot cover this high-risk group
.
Different from PDE5-I, previous studies have confirmed that PDE9-I exerts cardiovascular protection by activating the NP-cGMP pathway (rather than NO-cGMP) [5]
.
David's team guessed that different treatment mechanisms may make PDE9-I have a therapeutic effect on obesity-related cardiovascular diseases in postmenopausal women
.
In order to explore the therapeutic effects of PDE9-I on obesity and cardiometabolic syndrome, Professor David A.
Kass's team first established a diet-induced obesity model (DIO/mTAC) with cardiovascular disease
.
Male, female, and OVX female experimental mice were fed with a high-fat diet (HFD) for 6 consecutive months
.
One group of mice underwent aortic clipping (mTAC) surgery two months after a high-fat diet to cause a mild cardiac pressure load as an obesity model with cardiometabolic syndrome; the other group only Make a high-fat diet treatment to induce obesity model
.
Diet-induced obesity model combined with cardiovascular disease.
Subsequently, the researchers observed the therapeutic effect of oral PDE9-I on the above two model mice
.
They found that PDE9-I can not only significantly reduce the body weight and visceral fat content of obese mice, but also significantly improve the performance of metabolic syndromes such as hyperglycemia, hyperlipidemia, and fatty liver
.
Based on the cardiovascular protective effects of PDE9-I reported in previous studies [5], David's team further explored whether PDF9-I can improve the cardiac structure and function abnormalities of obese mice with cardiometabolic syndrome
.
The results showed that PDE9-I not only significantly improved the left ventricular ejection fraction, isovolumic delay time (IVRT) and other cardiac function indicators in DIO/mTAC mice, but also down-regulated the expression of a series of genes that promote myocardial hypertrophy and fibrosis, effectively controlling Myocardial hypertrophy progresses
.
It is worth noting that the fat reduction and cardioprotection of PDE9-I are more consistent in male and surgically removed ovariectomized (OVX) female mice, but it has no significant effect on obese female mice
.
PDE9-I improves cardiac dysfunction and inhibits myocardial hypertrophy.
So, how does PDE9-I play a therapeutic role in reducing fat and weight and protecting the heart? David's team found through transcriptome sequencing that the PDE9-I treatment group had a higher expression of the transcription factor PPARα than the control group's cardiomyocytes
.
Not only that, the expression levels of multiple downstream fatty acid oxidation (FAO) genes regulated by PPARα were also significantly up-regulated after receiving PDE9-I treatment
.
Considering that fatty acid oxidation is one of the important ways of fat decomposition [1]
.
David's team wanted to know whether PDE9-I up-regulated the expression of genes related to fatty acid oxidation downstream of PPARα, and whether it promoted lipolysis
.
David's team added fatty acids to the cardiomyocytes in vitro culture system to simulate the toxic effect of high-fat diet on cardiomyocytes
.
They found that the deposition of lipid droplets in cardiomyocytes treated with PDE9-I was significantly reduced, accompanied by an increase in the number of mitochondria, and an increase in the level of glycerol, a lipolysis product
.
These experimental results indicate that PDE9-I may reduce the toxic effect of high fat on cardiomyocytes by promoting the oxidation of mitochondrial fatty acids
.
PDE9-I promotes the breakdown of fat by cardiomyocytes.
Subsequently, David's team found that using a small molecule inhibitor of PPARα (GW6471) to inhibit PPARα activity would block the fat-reducing effect of PDE9-I on obese mice
.
This result once again confirmed that activation of PPARα is the core mechanism of PDE9-I to promote lipolysis
.
But there is still an unsolved question: Why does PDE9-I have no obvious fat-reducing effect in high-fat-fed female mice? Previous studies have also found similar findings that endogenous estrogen can inhibit PPARα activity and reduce its downstream fatty acid oxidation-related gene expression levels, but the mechanism is still unclear [8]
.
David's team found that in high-fat-fed female mice, although PDE9-I treatment still up-regulated the expression level of PPARα, there was no significant change in the expression of fatty acid oxidation-related genes regulated downstream
.
They suspected that this may be the estrogen receptor (ER) pathway blocking the binding of the transcription factor PPARα to its downstream regulatory genes
.
In order to confirm this conjecture, David's team used chromatin immunoprecipitation-sequencing (ChIP-seq) experiments and found that when only PPARα agonists were added, about 17,500 DNA binding sites were regulated by the transcription factor PPARα; and When the estrogen receptor ERα is activated at the same time, this number is almost halved; when the estrogen receptor ERβ is co-activated, only about 1/3 of the above-mentioned DNA binding sites are still regulated by PPARα
.
Not only that, KEGG gene enrichment analysis showed that most of the PPARα target genes inhibited by activation of estrogen receptors are related to cell metabolism, especially fatty acid oxidation metabolism
.
This shows that the estrogen receptor pathway does inhibit the regulation of the transcription factor PPARα on fatty acid oxidation-related genes; it also further explains why PDE9-I cannot effectively promote lipolysis and oxidative metabolism in obese female mice
.
In obese female mice, PDE9-I has no obvious regulatory effect on the expression of PPARα fatty acid oxidation genes.
In general, the research of Professor David A.
Kass’s team clarified that PDE9-I, a vasodilator, can activate the transcription factor PPARα Promote fat oxidation metabolism, and then treat obesity-related cardiometabolic syndrome
.
It is worth noting that the fat reduction effect of PDE9-I on premenopausal young and middle-aged women may not be ideal
.
The reason, David's team, pointed out that the estrogen receptor pathway inhibited the regulation of PPARα on fatty acid oxidation-related genes, and even caused the gender difference in the fat-reducing effect of PDE9-I (pig and pig girl cry for a second in the storm.
.
.
)
.
There is a long way to go to reduce fat, and we look forward to scientists developing new weight loss drugs that can also be used by the milk tea fairies! References: [1] Koliaki C, Liatis S, Kokkinos A.
Obesity and cardiovascular disease: revisiting an old relationship.
Metabolism.
2019;92:98-107.
doi:10.
1016/j.
metabol.
2018.
10.
011[2] Mishra S, Sadagopan N, Dunkerly-Eyring B, et al.
Inhibition of phosphodiesterase type 9 reduces obesity and cardiometabolic syndrome in mice [published online ahead of print, 2021 Oct 7].
J Clin Invest.
2021;e148798.
doi:10.
1172/JCI148798 [3] Collins S.
A heart-adipose tissue connection in the regulation of energy metabolism.
Nat Rev Endocrinol.
2014;10(3):157-163.
doi:10.
1038/nrendo.
2013.
234[4] Hoffmann LS, Etzrodt J, Willkomm L, et al.
Stimulation of soluble guanylyl cyclase protects against obesity by recruiting brown adipose tissue.
Nat Commun.
2015;6:7235.
Published 2015 May 26.
doi:10.
1038/ncomms8235[5] Lee DI, Zhu G, Sasaki T , et al.
