The link between a hunger hormone, immune response and COVID-19

During the worst of the pandemic, a few things became clear: certain segments of the population were getting hit harder than others, and it wasn’t just the elderly. It’s typically the oldest and the youngest among us that fall victim to viral infections, like influenza.

But during COVID, children seemed less affected. But younger adults (under 50), that was another story. Of course, certain pre-existing conditions like heart problems or diabetes could set up anyone up for a harsher bout of COVID that could even require hospitalization, but that wasn’t always the case.

But as the pandemic went on, a clear connection between obesity came to the forefront. Adults, young and old alike, who were overweight were experiencing the worst that COVID-19 had to offer.

And while the statistics clearly showed a link between obesity and COVID-19 severity, researchers have been working to get to the bottom of the connection. Up until now, some investigators thought it may be due to excessive inflammation in obese patients.

Cytokines, molecules that set off an inflammatory response that combats infection, were firing… and kept firing. This phenomenon has come to be known as a “cytokine storm.” And it was believed to have caused the death of seemingly healthy, younger people during the pandemic.

However, a new study indicates the opposite may have been true….

Underactive, not overactive, immune response

“During the pandemic, the majority of younger patients I saw on the COVID wards were obese,” says Professor Menna Clatworthy, a clinician scientist at the University of Cambridge. “Given what we know about obesity, if you’d asked me why this was the case, I would have said that it was most likely due to excessive inflammation. What we found was the absolute opposite.”

Clatworthy and her team analyzed blood and lung tissue samples taken from obese patients with severe COVID-19 requiring mechanical ventilation and intensive care treatment, as well as a group of control patients who did not have severe COVID-19 and had not been ventilated.

Contrary to their expectations, the team found that obese patients had underactive immune and inflammatory responses in their lungs.

Specifically, when compared to the control patients, cells in the lining of the obese patients’ lungs and some immune cells had lower levels of activity among genes responsible for producing interferon-alpha and interferon-gamma as well as those responsible for producing tumor necrosis factor. Interferon-alpha and interferon-gamma are two molecules that help control the immune system, while tumor necrosis factor causes inflammation.

The researchers then looked at immune cells in the blood of adults from an independent cohort. Results showed a similar, but less pronounced, reduction in the activity of interferon-producing genes as well as lower levels of interferon-alpha in the blood.

“This was really surprising and unexpected,” Clatworthy says. “Across every cell type we looked at, we found that that the genes responsible for the classical antiviral response were less active. They were completely muted.”

The researchers were able to replicate these findings in nasal immune cells taken from obese children with COVID-19. Because the nose is one of the entry points for the SARS-CoV-2 virus, a robust immune response there could keep the infection from spreading further, while a weaker immune response would be less effective against the virus.

“Hunger hormone” could be the link

A surprising explanation for the finding involves the hunger hormone, leptin. Leptin is produced by fat cells and controls appetite. But it turns out leptin also plays a role in the body’s immune response. In individuals of “normal weight,” leptin levels increase in response to infection, and the hormone directly stimulates immune cells.

However, obese people have chronically elevated levels of leptin. And, because of this, Clatworthy says, it’s possible that those with obesity no longer produce sufficient additional leptin in response to infection. It’s also possible those who are obese may have lost their sensitivity to the hormone. Both these possibilities could lead to inadequate stimulation of their immune cells.

These findings could have implications both for the treatment of COVID-19 and the design of clinical trials to test new COVID-19 treatments.

For instance, doctors have been using anti-inflammatory drugs to quell the overactive immune and inflammatory response associated with severe COVID-19 in some patients. However, these drugs may not be appropriate for obese patients.

“What we’ve shown is that not all patients are the same, so we might need to tailor treatments,” says study co-author Dr. Andrew Conway Morris from the University of Cambridge. “Obese subjects might need fewer anti-inflammatory treatments and potentially more help for their immune system.”

Fighting leptin resistance: for healthy weight and healthy immune response

Clearly, one way of addressing this issue is to treat obesity. But it can be difficult for people who are obese to lose the weight they need to get into a healthier weight range. One reason for this could be the lack of leptin sensitivity the Cambridge researchers cited in their study.

If you’re obese and you find yourself struggling to lose weight, it could very well be leptin resistance that’s blocking your efforts.

Research into leptin resensitization in mice found that dietary interventions, including fasting, energy (caloric) restriction and switching from a high-fat diet to a low-fat diet can help. Phenolic compounds, like resveratrol, can also modulate leptin sensitivity.

Additional tips for resetting your leptin sensitivity include:

• Avoiding certain foods. In addition to avoiding high-fat, high-sugar foods, also, try to lower your intake of refined carbohydrates, which can reduce your level of leptin resistance-causing triglycerides.
• Moving your body. It doesn’t matter what type of exercise you do, it’s just important to do it consistently. Regular exercise will help decrease your leptin resistance and your weight.
• Getting good sleep. Lack of sleep, or a shortage of good quality sleep, can both contribute to leptin resistance.
• Managing stress levels. Too much day-to-day stress can increase your body’s resistance to leptin.
• Giving yourself a cheat day. Once a week, let yourself have that piece of pizza or scoop of ice cream. This can help your brain become more responsive to the leptin your body produces.

One last thing: it’s always a good idea to discuss any major lifestyle changes with your doctor first. They can help you narrow down which areas are most important for you to focus on in your effort to combat obesity.

Sources:

Underactive immune response may explain obesity link to COVID-19 severity — University of Cambridge

Obesity Is Associated with Attenuated Tissue Immunity in COVID-19 — American Journal of Respiratory and Critical Care Medicine

Leptin resensitisation: a reversion of leptin-resistant states — Journal of Endocrinoloyg

Obesity Statistics — Forbes Health