There is no shortage of people who carry excess weight but have impeccable blood pressure and cholesterol levels and no known health problems. Consider the example of professional athletes whose livelihoods are dependent on being heavy, such as football linemen or sumo wrestlers.

At first glance, it is easy to notice their rotund shape, but they also possess greater physical endurance and strength than the average person. On the other hand, some maintain a thin figure but eat poorly, seldom exercise, and have a host of health issues.  Granted, most of us don’t train like professional athletes but it gets to the heart of the question: What matters more when it comes to health– weight or fitness?

Some studies do suggest that regular physical activity can mitigate some of the negative effects of being overweight, which does lend credibility to the idea of being both. Regardless of your weight, exercising regularly is sure to be a good thing. However, even when controlling for physical activity level, those who are overweight tend to be at higher risk of disease than their normal-weight peers.

Here are three reasons why being overweight does not always harmonize with being fit:

1. Fat is a hormonally and metabolically active tissue – Fat cells do more than just add inches. They can influence the balance of hormones and energy systems in our bodies. For example, fat cells can increase cortisol levels, which can further contribute to weight gain, and can promote insulin resistance, which can lead to diabetes.   It can also release substances that contribute to a steady level of chronic inflammation in the body – which increases risk of some cancers.
2. Excess weight, irrespective of fitness level, can be a risk factor for development of disease. While some people may be overweight but still maintain healthy blood pressure, cholesterol, and glucose levels, it is important to recognize that they are a snapshot of their present health status. The reality is that being chronically overweight carries the risk of developing other health problems in the future, although there is no way to predict exactly when that might occur.  Health is about the long-term strategy. Some of these health problems include diabetes, high blood pressure, heart disease, and stroke. Certainly, maintaining a regular physical activity regimen to keep fit may delay the development of these conditions, but losing body fat is another important way to reduce the risk of developing them.
3. Carrying extra fat can put undue stress on various body structures. Many discussions about fitness focus on cardiovascular health and reducing the risk of some cancers, but being overweight can also worsen back and joint pain. Chronic back and joint pains are significant causes of disability as we get older.  Extra fat around the neck can also contribute to the development of obstructive sleep apnea by causing the airway to collapse while sleeping.

The COVID pandemic has taught us important lessons about the importance of self-care. It’s not just about our lifespan, but also our health span.  That requires each of us to do our part in striving for a healthier lifestyle, whether that means eating more healthfully, exercising more consistently, or implementing better stress reduction techniques. While it’s possible to achieve good health despite being overweight, reducing excess body fat is yet another way to further optimize health and fitness and reduce the development of chronic disease.

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Immunologists have determined the process driving life-threatening inflammation, lung damage and organ failure in patients with COVID-19, sepsis and other inflammatory disorders suggesting possible treatment using existing drugs.

Date of Release: Nov. 18, 2020

MEMPHIS, Tenn /PRNewswire/ — The COVID-19 pandemic continues to cause significant illness and death while treatment options remain limited. St. Jude Children’s Research Hospital scientists have discovered a potential strategy to prevent life-threatening inflammation, lung damage, and organ failure in patients with COVID-19. The research appeared online in the journal Cell.

The scientists identified the drugs after discovering that the hyperinflammatory immune response associated with COVID-19 leads to tissue damage and multi-organ failure in mice by triggering inflammatory cell death pathways. The researchers detailed how the inflammatory cell death signaling pathway worked, which led to potential therapies to disrupt the process.

“Understanding the pathways and mechanism driving this inflammation is critical to develop effective treatment strategies,” said corresponding author Thirumala-Devi Kanneganti, Ph.D., vice chair of the St. Jude Department of Immunology. “This research provides that understanding. We also identified the specific cytokines that activate inflammatory cell death pathways and have considerable potential for treatment of COVID-19 and other highly fatal diseases, including sepsis.”

COVID-19, cytokines, and inflammatory cell death

COVID-19 is caused by the SARS-CoV-2 virus. The infection has killed more than 1.2 million people in less than one year and sickened millions more.

The infection is marked by increased blood levels of multiple cytokines. These small proteins are secreted primarily by immune cells to ensure a rapid response to restrict the virus. Some cytokines also trigger inflammation.

The phrase cytokine storm has been used to describe the dramatically elevated cytokine levels in the blood and other immune changes that have also been observed in COVID-19, sepsis and inflammatory disorders such as hemophagocytic lymphohistiocytosis (HLH). But the specific pathways that initiate the cytokine storm and the subsequent inflammation, lung damage and organ failure in COVID-19 and the other disorders was unclear. The cellular and molecular mechanisms that comprehensively define cytokine storm was also lacking.

Kanneganti’s team focused on a select set of the most elevated cytokines in COVID-19 patients. The scientists showed that no single cytokine induced cell death in innate immune cells.

The St. Jude investigators then tried 28 cytokine combinations and found just one duo that, working together, induced a form of inflammatory cell death previously described by Kanneganti as PANoptosis. The cytokines are tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma. PANoptosis is a unique type of cell death that features coordination of three different cell death pathways—pyroptosis, apoptosis and necroptosis. PANoptosis fuels inflammation through cell death, resulting in the release of more cytokines and inflammatory molecules.

The investigators showed that blocking individual cell death pathways was ineffective in stopping cell death caused by TNF-alpha and IFN-gamma. A closer look at proteins that make up the pathways identified several, including caspase-8 and STAT1, that were essential for PANoptosis in response to these cytokines. Deleting those proteins blocked PANoptosis in innate immune cells called macrophages.

Potential for repurposing TNF-alpha and IFN-gamma blockers to treat COVID-19

Because TNF-alpha and IFN-gamma are produced during COVID-19 and cause inflammatory cell death, the investigators questioned whether these cytokines were responsible for the clinical manifestations and deadly effects of the disease. They found that the TNF-alpha and IFN-gamma combination triggered tissue damage and inflammation that mirror the symptoms of COVID-19 along with rapid death.

Neutralizing antibodies against TNF-alpha and IFN-gamma are currently used to treat inflammatory diseases in the clinic. The investigators found that treatment with these antibodies protected mice from death associated with SARS-CoV-2 infection, sepsis, HLH and cytokine shock.

“The findings link inflammatory cell death induced by TNF-alpha and IFN-gamma to COVID-19,” Kanneganti said. “The results also suggest that therapies that target this cytokine combination are candidates for rapid clinical trials for treatment of not only COVID-19, but several other often fatal disorders associated with cytokine storm.”

Added co-first author Rajendra Karki, Ph.D., a scientist in the Kanneganti laboratory: “We were excited to connect these dots to understand how TNF-alpha and IFN-gamma trigger PANoptosis.” Co-first author Bhesh Raj Sharma, Ph.D., a scientist in the Kanneganti laboratory, added: “Indeed, understanding how PANoptosis contributes to disease and mortality is critical for identifying therapies.”

Redefining cytokine storm

Based on this fundamental research, Kanneganti and her colleagues have proposed a definition of cytokine storm that puts the cytokine-mediated inflammatory cell death via PANoptosis at the center of the process. The researchers noted that PANoptosis results in the release of more cytokines and inflammatory molecules, which intensifies systemic inflammation.

“We have solved a major piece of the cytokine storm mystery by characterizing critical factors responsible for initiating this process, and thereby identifying a unique combination therapy using existing drugs that can be applied in the clinic to save lives,” Kanneganti said.

The other authors are Shraddha Tuladhar, Parimal Samir, Min Zheng, Balamurugan Sundaram, Balaji Banoth, R. K. Subbarao Malireddi, Patrick Schreiner, Geoffrey Neale, Peter Vogel and Richard Webby, of St. Jude; and Evan Peter Williams, Lillian Zalduondo and Colleen Beth Jonsson, of the University of Tennessee Health Science Center.

The research was supported in part by grants (AI101935, AI124346, AR056296, CA253095) from the National Institutes of Health; and ALSAC, the awareness and fundraising organization of St. Jude.

St. Jude Children’s Research Hospital

St. Jude Children’s Research Hospital is leading the way the world understands, treats and cures childhood cancer and other life-threatening diseases. It is the only National Cancer Institute-designated Comprehensive Cancer Center devoted solely to children. Treatments developed at St. Jude have helped push the overall childhood cancer survival rate from 20% to 80% since the hospital opened more than 50 years ago. St. Jude freely shares the breakthroughs it makes, and every child saved at St. Jude means doctors and scientists worldwide can use that knowledge to save thousands more children. Families never receive a bill from St. Jude for treatment, travel, housing and food — because all a family should worry about is helping their child live. To learn more, visit stjude.org or follow St. Jude on social media at @stjuderesearch.

SOURCE St. Jude Children’s Research Hospital

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