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A cousin of Viagra reduces obesity by stimulating cells to burn fat, study shows

FOR IMMEDIATE RELEASE Credit: Images courtesy of David Kass FOR IMMEDIATE RELEASE Researchers at Johns Hopkins Medicine have found that a drug first developed to treat Alzheimer’s disease, schizophrenia and sickle cell disease reduces obesity and fatty…

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FOR IMMEDIATE RELEASE

Credit: Images courtesy of David Kass

FOR IMMEDIATE RELEASE

Researchers at Johns Hopkins Medicine have found that a drug first developed to treat Alzheimer’s disease, schizophrenia and sickle cell disease reduces obesity and fatty liver in mice and improves their heart function — without changes in food intake or daily activity.

These findings, published online Oct. 7 in the Journal of Clinical Investigation, reveal that a chemical inhibitor of the enzyme PDE9 stimulates cells to burn more fat. This occurred in male mice and in female mice whose sex hormones were reduced by removing their ovaries, thus mimicking menopause. Postmenopausal women are well known to be at increased risk for obesity around their waist as well as at risk for cardiovascular and metabolic disease.

Inhibiting PDE9 did not cause these changes in female mice that had their ovaries, so female sex hormone status was important in the study.

 “Currently, there isn’t a pill that has been proven effective for treating severe obesity, yet such obesity is a global health problem that increases the risk of many other diseases,” says senior investigator David Kass, M.D., Abraham and Virginia Weiss Professor of Cardiology at the Johns Hopkins University School of Medicine. “What makes our findings exciting is that we found an oral medication that activates fat-burning in mice to reduce obesity and fat buildup in organs like the liver and heart that contribute to disease; this is new.”

This study follows work reported by the same laboratory in 2015 that first showed the PDE9 enzyme is present in the heart and contributes to heart disease triggered by high blood pressure. Blocking PDE9 increases the amount of a small molecule known as cyclic GMP, which in turn controls many aspects of cell function throughout the body. PDE9 is the enzyme cousin of another protein called PDE5, which also controls cyclic GMP and is blocked by drugs such as Viagra. Inhibitors of PDE9 are experimental, so there is no drug name yet. 

Based on these results, the investigators suspected PDE9 inhibition might improve cardiometabolic syndrome (CMS), a constellation of common conditions including high blood pressure; high blood sugar, cholesterol and triglycerides; and excess body fat, particularly around the waist. CMS is considered a pandemic by medical experts and a major risk factor for heart disease, stroke, type 2 diabetes, cancers and COVID-19.  

While PDE9 inhibitors remain experimental, they have been developed by several pharmaceutical companies and tested in humans for diseases such as Alzheimer’s and sickle cell. The current mouse study used a PDE9 inhibitor made by Pfizer Inc. (PF-04447943) that was first tested for Alzheimer’s disease, though eventually abandoned for this use. Between the two reported clinical trials, over 100 subjects received this drug, and it was found to be well tolerated with no serious adverse side effects. A different PDE9 inhibitor is now being tested for human heart failure.

To test the effects of a PDE9 inhibitor on obesity and cardiometabolic syndrome, the researchers put mice on a high-fat diet that led to doubling their body weight, high blood lipids and diabetes after four months. A group of female mice had their ovaries surgically removed, and most of the mice also had a pressure stress applied to the heart to better mimic cardiometabolic syndrome. The mice were then assigned to receive either the PDE9 inhibitor or a placebo by mouth over the next six to eight weeks.

In female mice without their ovaries (a model of postmenopause), the difference in median percent weight change between the drug and placebo groups was -27.5%, and in males it was -19.5%. Lean body mass was not altered in either group, nor was daily food consumption or physical activity. The PDE9 inhibitor lowered blood cholesterol and triglycerides, and reduced fat in the liver to levels found in mice fed a normal diet. The heart also improved with PDE9 inhibition, with ejection fraction (which measures the percentage of blood leaving the heart each time it contracts) relatively higher by 7%–15% and heart mass (hypertrophy) rising 70% less compared with the placebo. An increase in heart mass is evidence of abnormal heart stress. However, having this lowered by the inhibitor indicates stress on the heart was reduced.

The investigators found PDE9 inhibition produces these effects by activating a master regulator of fat metabolism known as PPARa. By stimulating PPARa, levels of genes for proteins that control fat uptake into cells and their use as fuel are broadly increased. When PPARa was blocked in cells or the whole animal, the effects from PDE9 inhibition on obesity and fat-burning were also lost. They found estrogen normally plays this role of PPARa on fat regulation in females, but when its levels fall like they do after menopause, PPARa becomes more important to regulate fat and so PDE9 inhibition has a greater effect.

“The finding that the experimental drug did not benefit female mice that had their ovaries shows that these sex hormones, particularly estrogen, had already achieved what inhibiting PDE9 does to stimulate fat-burning,” notes Sumita Mishra, the research associate who performed much of the work. “Menopause reduces sex hormone levels, and their control over fat metabolism then shifts to the protein regulated by PDE9, so the drug treatment is now effective.”

According to the U.S. Centers for Disease Control and Prevention, more than 40% of people living in the U.S. are obese; and 43% of American women over the age of 60 — long past menopause — are considered obese.

Kass notes that if his lab’s findings in mice apply to people, someone weighing 250 pounds could lose about 50 pounds with an oral PDE9 inhibitor without changing eating or exercise habits.

“I’m not suggesting to be a couch potato and take a pill, but I suspect that combined with diet and exercise, the effects from PDE9 inhibition may be even greater,” says Kass. The next step would be testing in humans to see if PDE9 inhibitors produce similar effects in men and postmenopausal women.

“PDE9 inhibitors are already being studied in humans, so a clinical obesity study should not be that far away,” Kass says.

###

 The other researchers involved in the study include Nandhini Sadagopan, Brittany Dunkerly-Ering, Susana Rodriguez, Dylan Sarver, Sean Murphy, Hildur Knutsdottir, Vivek Jani, Deepthi Ashok, Christian Oeing, Brian O’Rourke and G. William Wong from Johns Hopkins Medicine; Ryan Ceddia and Sheila Collins from Vanderbilt University; and John Gangoiti and Dorothy Sears from the University of California San Diego.

The Johns Hopkins University has filed a patent on behalf of investigators Kass, Mishra and a prior member of the Kass laboratory, D.I. Lee, for the use of PDE9 inhibitors to treat cardiometabolic syndrome.

Funding for this study was supported by NIH R35-HL135827, RO1-HL-119012, P01HL10715, and AHA 16SFRN28620000 (DAK), NIH DK084171 (GWW), NIH-RO1-HL134821 (BOR), NIH T32-HL007227 (VSH), 16SFRN27870000 (KS), DK116625, AHA 16SFRN28620000 (SC), 16SFRN28420002 (DDS), F32 DK-116520 (RPC), and OE 688/1-1 (CUO). PF-04447943 was provided by Pfizer Inc. under a material transfer agreement.


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Survey Shows Declining Concerns Among Americans About COVID-19

Survey Shows Declining Concerns Among Americans About COVID-19

A new survey reveals that only 20% of Americans view covid-19 as "a major threat"…

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Survey Shows Declining Concerns Among Americans About COVID-19

A new survey reveals that only 20% of Americans view covid-19 as "a major threat" to the health of the US population - a sharp decline from a high of 67% in July 2020.

(SARMDY/Shutterstock)

What's more, the Pew Research Center survey conducted from Feb. 7 to Feb. 11 showed that just 10% of Americans are concerned that they will  catch the disease and require hospitalization.

"This data represents a low ebb of public concern about the virus that reached its height in the summer and fall of 2020, when as many as two-thirds of Americans viewed COVID-19 as a major threat to public health," reads the report, which was published March 7.

According to the survey, half of the participants understand the significance of researchers and healthcare providers in understanding and treating long COVID - however 27% of participants consider this issue less important, while 22% of Americans are unaware of long COVID.

What's more, while Democrats were far more worried than Republicans in the past, that gap has narrowed significantly.

"In the pandemic’s first year, Democrats were routinely about 40 points more likely than Republicans to view the coronavirus as a major threat to the health of the U.S. population. This gap has waned as overall levels of concern have fallen," reads the report.

More via the Epoch Times;

The survey found that three in ten Democrats under 50 have received an updated COVID-19 vaccine, compared with 66 percent of Democrats ages 65 and older.

Moreover, 66 percent of Democrats ages 65 and older have received the updated COVID-19 vaccine, while only 24 percent of Republicans ages 65 and older have done so.

“This 42-point partisan gap is much wider now than at other points since the start of the outbreak. For instance, in August 2021, 93 percent of older Democrats and 78 percent of older Republicans said they had received all the shots needed to be fully vaccinated (a 15-point gap),” it noted.

COVID-19 No Longer an Emergency

The U.S. Centers for Disease Control and Prevention (CDC) recently issued its updated recommendations for the virus, which no longer require people to stay home for five days after testing positive for COVID-19.

The updated guidance recommends that people who contracted a respiratory virus stay home, and they can resume normal activities when their symptoms improve overall and their fever subsides for 24 hours without medication.

“We still must use the commonsense solutions we know work to protect ourselves and others from serious illness from respiratory viruses, this includes vaccination, treatment, and staying home when we get sick,” CDC director Dr. Mandy Cohen said in a statement.

The CDC said that while the virus remains a threat, it is now less likely to cause severe illness because of widespread immunity and improved tools to prevent and treat the disease.

Importantly, states and countries that have already adjusted recommended isolation times have not seen increased hospitalizations or deaths related to COVID-19,” it stated.

The federal government suspended its free at-home COVID-19 test program on March 8, according to a website set up by the government, following a decrease in COVID-19-related hospitalizations.

According to the CDC, hospitalization rates for COVID-19 and influenza diseases remain “elevated” but are decreasing in some parts of the United States.

Tyler Durden Sun, 03/10/2024 - 22:45

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International

Rand Paul Teases Senate GOP Leader Run – Musk Says “I Would Support”

Rand Paul Teases Senate GOP Leader Run – Musk Says "I Would Support"

Republican Kentucky Senator Rand Paul on Friday hinted that he may jump…

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Rand Paul Teases Senate GOP Leader Run - Musk Says "I Would Support"

Republican Kentucky Senator Rand Paul on Friday hinted that he may jump into the race to become the next Senate GOP leader, and Elon Musk was quick to support the idea. Republicans must find a successor for periodically malfunctioning Mitch McConnell, who recently announced he'll step down in November, though intending to keep his Senate seat until his term ends in January 2027, when he'd be within weeks of turning 86. 

So far, the announced field consists of two quintessential establishment types: John Cornyn of Texas and John Thune of South Dakota. While John Barrasso's name had been thrown around as one of "The Three Johns" considered top contenders, the Wyoming senator on Tuesday said he'll instead seek the number two slot as party whip. 

Paul used X to tease his potential bid for the position which -- if the GOP takes back the upper chamber in November -- could graduate from Minority Leader to Majority Leader. He started by telling his 5.1 million followers he'd had lots of people asking him about his interest in running...

...then followed up with a poll in which he predictably annihilated Cornyn and Thune, taking a 96% share as of Friday night, with the other two below 2% each. 

Elon Musk was quick to back the idea of Paul as GOP leader, while daring Cornyn and Thune to follow Paul's lead by throwing their names out for consideration by the Twitter-verse X-verse. 

Paul has been a stalwart opponent of security-state mass surveillance, foreign interventionism -- to include shoveling billions of dollars into the proxy war in Ukraine -- and out-of-control spending in general. He demonstrated the latter passion on the Senate floor this week as he ridiculed the latest kick-the-can spending package:   

In February, Paul used Senate rules to force his colleagues into a grueling Super Bowl weekend of votes, as he worked to derail a $95 billion foreign aid bill. "I think we should stay here as long as it takes,” said Paul. “If it takes a week or a month, I’ll force them to stay here to discuss why they think the border of Ukraine is more important than the US border.”

Don't expect a Majority Leader Paul to ditch the filibuster -- he's been a hardy user of the legislative delay tactic. In 2013, he spoke for 13 hours to fight the nomination of John Brennan as CIA director. In 2015, he orated for 10-and-a-half-hours to oppose extension of the Patriot Act

Rand Paul amid his 10 1/2 hour filibuster in 2015

Among the general public, Paul is probably best known as Capitol Hill's chief tormentor of Dr. Anthony Fauci, who was director of the National Institute of Allergy and Infectious Disease during the Covid-19 pandemic. Paul says the evidence indicates the virus emerged from China's Wuhan Institute of Virology. He's accused Fauci and other members of the US government public health apparatus of evading questions about their funding of the Chinese lab's "gain of function" research, which takes natural viruses and morphs them into something more dangerous. Paul has pointedly said that Fauci committed perjury in congressional hearings and that he belongs in jail "without question."   

Musk is neither the only nor the first noteworthy figure to back Paul for party leader. Just hours after McConnell announced his upcoming step-down from leadership, independent 2024 presidential candidate Robert F. Kennedy, Jr voiced his support: 

In a testament to the extent to which the establishment recoils at the libertarian-minded Paul, mainstream media outlets -- which have been quick to report on other developments in the majority leader race -- pretended not to notice that Paul had signaled his interest in the job. More than 24 hours after Paul's test-the-waters tweet-fest began, not a single major outlet had brought it to the attention of their audience. 

That may be his strongest endorsement yet. 

Tyler Durden Sun, 03/10/2024 - 20:25

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Government

The Great Replacement Loophole: Illegal Immigrants Score 5-Year Work Benefit While “Waiting” For Deporation, Asylum

The Great Replacement Loophole: Illegal Immigrants Score 5-Year Work Benefit While "Waiting" For Deporation, Asylum

Over the past several…

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The Great Replacement Loophole: Illegal Immigrants Score 5-Year Work Benefit While "Waiting" For Deporation, Asylum

Over the past several months we've pointed out that there has  been zero job creation for native-born workers since the summer of 2018...

... and that since Joe Biden was sworn into office, most of the post-pandemic job gains the administration continuously brags about have gone foreign-born (read immigrants, mostly illegal ones) workers.

And while the left might find this data almost as verboten as FBI crime statistics - as it directly supports the so-called "great replacement theory" we're not supposed to discuss - it also coincides with record numbers of illegal crossings into the United States under Biden.

In short, the Biden administration opened the floodgates, 10 million illegal immigrants poured into the country, and most of the post-pandemic "jobs recovery" went to foreign-born workers, of which illegal immigrants represent the largest chunk.

Asylum seekers from Venezuela await work permits on June 28, 2023 (via the Chicago Tribune)

'But Tyler, illegal immigrants can't possibly work in the United States whilst awaiting their asylum hearings,' one might hear from the peanut gallery. On the contrary: ever since Biden reversed a key aspect of Trump's labor policies, all illegal immigrants - even those awaiting deportation proceedings - have been given carte blanche to work while awaiting said proceedings for up to five years...

... something which even Elon Musk was shocked to learn.

Which leads us to another question: recall that the primary concern for the Biden admin for much of 2022 and 2023 was soaring prices, i.e., relentless inflation in general, and rising wages in particular, which in turn prompted even Goldman to admit two years ago that the diabolical wage-price spiral had been unleashed in the US (diabolical, because nothing absent a major economic shock, read recession or depression, can short-circuit it once it is in place).

Well, there is one other thing that can break the wage-price spiral loop: a flood of ultra-cheap illegal immigrant workers. But don't take our word for it: here is Fed Chair Jerome Powell himself during his February 60 Minutes interview:

PELLEY: Why was immigration important?

POWELL: Because, you know, immigrants come in, and they tend to work at a rate that is at or above that for non-immigrants. Immigrants who come to the country tend to be in the workforce at a slightly higher level than native Americans do. But that's largely because of the age difference. They tend to skew younger.

PELLEY: Why is immigration so important to the economy?

POWELL: Well, first of all, immigration policy is not the Fed's job. The immigration policy of the United States is really important and really much under discussion right now, and that's none of our business. We don't set immigration policy. We don't comment on it.

I will say, over time, though, the U.S. economy has benefited from immigration. And, frankly, just in the last, year a big part of the story of the labor market coming back into better balance is immigration returning to levels that were more typical of the pre-pandemic era.

PELLEY: The country needed the workers.

POWELL: It did. And so, that's what's been happening.

Translation: Immigrants work hard, and Americans are lazy. But much more importantly, since illegal immigrants will work for any pay, and since Biden's Department of Homeland Security, via its Citizenship and Immigration Services Agency, has made it so illegal immigrants can work in the US perfectly legally for up to 5 years (if not more), one can argue that the flood of illegals through the southern border has been the primary reason why inflation - or rather mostly wage inflation, that all too critical component of the wage-price spiral  - has moderated in in the past year, when the US labor market suddenly found itself flooded with millions of perfectly eligible workers, who just also happen to be illegal immigrants and thus have zero wage bargaining options.

None of this is to suggest that the relentless flood of immigrants into the US is not also driven by voting and census concerns - something Elon Musk has been pounding the table on in recent weeks, and has gone so far to call it "the biggest corruption of American democracy in the 21st century", but in retrospect, one can also argue that the only modest success the Biden admin has had in the past year - namely bringing inflation down from a torrid 9% annual rate to "only" 3% - has also been due to the millions of illegals he's imported into the country.

We would be remiss if we didn't also note that this so often carries catastrophic short-term consequences for the social fabric of the country (the Laken Riley fiasco being only the latest example), not to mention the far more dire long-term consequences for the future of the US - chief among them the trillions of dollars in debt the US will need to incur to pay for all those new illegal immigrants Democrat voters and low-paid workers. This is on top of the labor revolution that will kick in once AI leads to mass layoffs among high-paying, white-collar jobs, after which all those newly laid off native-born workers hoping to trade down to lower paying (if available) jobs will discover that hardened criminals from Honduras or Guatemala have already taken them, all thanks to Joe Biden.

Tyler Durden Sun, 03/10/2024 - 19:15

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