Kallistatin contributes to the beneficial metabolic effects of weight loss

After weight loss, people with overweight and obesity express more of the protein Kallistatin* in subcutaneous white adipose tissue. This was demonstrated by researchers from the DZD in a recent study. In addition, Kallistatin improves metabolism and could open up new therapeutic options for people with obesity and type 2 diabetes in future. The results have now been published in Molecular Metabolism.

An increasing number of people are developing type 2 diabetes and obesity.

These are highly complex and multifaceted diseases. In order to treat them sustainably, new approaches to therapy are needed.

Clinical studies on humans have shown that heavily overweight individuals produce less Kallistatin.

Kallistatin is a protein that has various effects in the body.

Among other things, it is involved in counteracting inflammation and healing wounds.

The role that Kallistatin plays in glucose metabolism and its potential suitability as a therapeutic target are currently being investigated by researchers from the German Center for Diabetes Research (DZD), the Institute for Diabetes Research and Metabolic Diseases (IDM) of Helmholtz Munich at the Eberhard-Karls-University of Tübingen, and the Department of Diabetology, Endocrinology and Nephrology at the University Hospital Tübingen.

Kallistatin Expression Increases After Weight Loss

To this end, they measured Kallistatin expression in subcutaneous white adipose tissue in 47 individuals with overweight to obesity before and after weight loss.

The result: Kallistatin expression increases after weight loss.

Kallistatin Improves Hepatic Insulin Sensitivity

Additionally, the researchers examined the effect of the protein in an animal model.

In the process, they observed that human Kallistatin improves hepatic insulin sensitivity in diet-induced obese mice.

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Obesity treatment could offer dramatic weight loss without surgery or nausea

Imagine getting the benefits of gastric bypass surgery without going under the knife -- a new class of compounds could do just that. In lab animals, these potential treatments reduce weight dramatically and lower blood glucose. The injectable compounds also avoid the side effects of nausea and vomiting that are common with current weight-loss and diabetes drugs. Now, scientists report that the new treatment not only reduces eating but also boosts calorie burn.

The researchers will present their results today at the spring meeting of the American Chemical Society (ACS).

"Obesity and diabetes were the pandemic before the COVID-19 pandemic," says Robert Doyle, Ph.D., one of the two principal investigators on the project, along with Christian Roth, M.D. "They are a massive problem, and they are projected to only get worse."

Gastric bypass and related procedures, known collectively as bariatric surgery, offer one solution, often resulting in lasting weight loss and even remission of diabetes. But these operations carry risk, aren't suitable for everyone and aren't accessible for many of the hundreds of millions of people worldwide who are obese or diabetic. As an alternative, Doyle says, they could tackle their metabolic problems with a drug that replicates the long-term benefits of surgery.

Those benefits are linked to a post-bypass-surgery change in the gut's secretion levels of certain hormones -- including glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) -- that signal fullness, curb appetite and normalize blood sugar. Current drugs that aim to replicate this effect primarily activate cellular receptors for GLP-1 in the pancreas and brain. That approach has shown great success in reducing weight and treating type 2 diabetes, drawing a lot of social media postings from celebrities in recent months. But many people can't tolerate the drugs' side effects, says Doyle. "Within a year, 80 to 90% of people who start on these drugs are no longer taking them." Doyle is at Syracuse University and SUNY Upstate Medical University, and Roth is at Seattle Children's Research Institute.

To address that drawback, various researchers have designed other treatments that interact with more than one type of gut hormone receptor. For example, Doyle's group created a peptide that activates two receptors for PYY, as well as the receptor for GLP-1. Dubbed GEP44, this compound caused obese rats to eat up to 80% less than they would typically eat. By the end of one 16-day study, they lost an average of 12% of their weight. That was more than three times the amount lost by rats treated with liraglutide, an injected drug that activates only the GLP-1 receptor and that is approved by the U.S. Food and Drug Administration for treating obesity. In contrast to liraglutide, tests with GEP44 in rats and shrews (a mammal that, unlike rats, is capable of vomiting) revealed no sign of nausea or vomiting, possibly because activating multiple receptors may cancel out the intracellular signaling pathway that drives those symptoms, Doyle says.

In its latest results, his team is now reporting that the weight loss caused by GEP44 can be traced not only to decreased eating, but also to higher energy expenditure, which can take the form of increased movement, heart rate or body temperature.

GEP44 has a half-life in the body of only about an hour, but Doyle's group has just designed a peptide with a much longer half-life. That means it could be injected only once or twice a week instead of multiple times a day. The researchers are now reporting that rats treated with this next-generation compound keep their new, slimmer physique even after treatment ends, which often isn't the case with currently approved drugs, Doyle says.

But weight loss isn't the only benefit of the peptide treatments. They also reduce blood sugar by pulling glucose into muscle tissue, where it can be used as fuel, and by converting certain cells in the pancreas into insulin-producing cells, helping replace those that are damaged by diabetes. And there's yet another benefit: Doyle and Heath Schmidt, Ph.D., of the University of Pennsylvania, recently reported that GEP44 reduces the craving for opioids such as fentanyl in rats. If that also works in humans, Doyle says, it could help addicts quit the illicit drugs or fend off a relapse.

The researchers have filed for patents on their compounds, and they plan to test their peptides in primates. They will also study how the treatments change gene expression and rewire the brain, and what that could mean for these compounds, as well as other types of medication.

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Giant stars undergo dramatic weight loss program

Astronomers at the University of Sydney have found a slimmer type of red giant star for the first time. These stars have undergone dramatic weight loss, possibly due to the presence a greedy neighbour. Published in Nature Astronomy, the discovery is an important step forward to understanding the life of stars in the Milky Way -- our closest stellar neighbours.

There are millions of 'red giant' stars found in our galaxy. These cool and luminous objects are what our Sun will become in four billion years. For some time, astronomers have predicted the existence of slimmer red giants. After finding a smattering of them, the University of Sydney team can finally confirm their existence.

"It's like finding Waldo," said lead author, PhD candidate Mr Yaguang Li from the University of Sydney. "We were extremely lucky to find about 40 slimmer red giants, hidden in a sea of normal ones. The slimmer red giants are either smaller in size or less massive than normal red giants."

How and why did they slim down? Most stars in the sky are in binary systems -- two stars that are gravitationally bound to each other. When the stars in close binaries expand, as stars do as they age, some material can reach the gravitational sphere of their companion and be sucked away. "In the case of relatively tiny red giants, we think a companion could possibly be present," Mr Li said.

An intragalactic treasure hunt

The team analysed archival data from NASA's Kepler space telescope. From 2009 to 2013, the telescope continuously recorded brightness variations on tens of thousands of red giants. Using this incredibly accurate and large dataset, the team conducted a thorough census of this stellar population, providing the groundwork for spotting any outliers.

Two types of unusual stars were revealed: very low-mass red giants, and underluminous (dimmer) red giants.

The very low-mass stars weigh only 0.5 to 0.7 solar mass -- around half the weight of our Sun. If the very low-mass stars had not suddenly lost weight, their masses would indicate they were older than the age of the Universe -- an impossibility.

"So, when we first obtained the masses of these stars, we thought there was something wrong with the measurement," Mr Li said. "But it turns out there wasn't."

The underluminous stars, on the other hand, have normal masses, ranging from 0.8 to 2.0 solar mass. "However, they are much less 'giant' than we expect," said study co-author, Dr Simon Murphy from the University of Southern Queensland. "They've slimmed down somewhat and because they're smaller, they're also fainter, hence 'underluminous' compared to normal red giants."

Only seven such underluminous stars were found, and the authors suspect many more are hiding in the sample. "The problem is that most of them are very good at blending in. It was a real treasure hunt to find them," Dr Murphy said.

These unusual data points could not be explained by simple expectations from stellar evolution. This led the researchers to conclude that another mechanism must be at work, forcing these stars to undergo dramatic weight loss: theft of mass by nearby stars.

Stellar population census

The researchers relied on asteroseismology -- the study of stellar vibrations -- to determine the properties of the red giants.

Traditional methods to study a star are limited to their surface properties, for example, surface temperature and luminosity. By contrast, asteroseismology, which uses sound waves, probes beneath this. "The waves penetrate the stellar interior, giving us rich information on another dimension," Mr Li said.

The researchers could precisely determine stars' evolutionary stages, masses, and sizes with this method. And when they looked at the distributions of these properties, something unusual was immediately noticed: some stars have tiny masses or sizes.

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Researchers call for a focus on fitness over weight loss for obesity-related health conditions

The prevalence of obesity around the world has tripled over the past 40 years, and, along with that rise, dieting and attempts to lose weight also have soared. But according to a review article publishing September 20 in the journal iScience, when it comes to getting healthy and reducing mortality risk, increasing physical activity and improving fitness appear to be superior to weight loss. The authors say that employing a weight-neutral approach to the treatment of obesity-related health conditions also reduces the health risks associated with yo-yo dieting.

"We would like people to know that fat can be fit, and that fit and healthy bodies come in all shapes and sizes," says co-author Glenn Gaesser of the College of Health Solutions at Arizona State University. "We realize that in a weight-obsessed culture, it may be challenging for programs that are not focused on weight loss to gain traction. We're not necessarily against weight loss; we just think that it shouldn't be the primary criterion for judging the success of a lifestyle intervention program."

"This is especially important when you consider the physiological realities of obesity," says co-author Siddhartha Angadi of the School of Education and Human Development at the University of Virginia. "Body weight is a highly heritable trait, and weight loss is associated with substantial metabolic alterations that ultimately thwart weight loss maintenance."

Obesity is associated with a number of health conditions, including cardiovascular disease, diabetes, cancer, and problems with the bones and joints. But weight cycling, commonly called yo-yo dieting, is also associated with health problems, including muscle loss, fatty liver disease, and diabetes. The authors say that by focusing on fitness rather than weight loss, people can gain the benefits of exercise while avoiding the risks associated with weight cycling.

Current public health guidelines recommend that adults accumulate 150-300 minutes per week of moderate-intensity physical activity (the intensity equivalent to walking at casual-to-brisk pace) or 75-150 minutes per week of vigorous-intensity physical activity (the intensity equivalent to jogging or running). "But it's important to note that the benefits of exercise are dose dependent, with the biggest benefits coming from just moving out of the couch-potato zone to doing at least some moderate-intensity activity," Gaesser says. "It's also important to emphasize that physical activity can be accumulated throughout the day. For example, multiple short walks during the day (even as short as two to ten minutes each) are just as beneficial as one long walk for health benefits."

In the review, the authors cite recent research focused on the magnitude of mortality risk reduction associated with weight loss compared to that associated with an increase in physical activity or cardiorespiratory fitness. The risk reduction associated with increasing fitness and physical activity was consistently greater than that associated with intentional weight loss. They also looked at the magnitude of reduction in the risk markers of cardiovascular disease that are associated with either weight loss or increased physical activity. They used meta-analyses from several studies done over a range of time periods and across a broad geographical area. "Science has generally supported the main points proposed in Big Fat Lies, a book on this topic that I first published in 1996," Gaesser notes.

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