Mitigating Metabolic Disorders of Obesity by Reducing Carbonyl Stress

November 2019

We have known for a very long time that obesity is associated with many cardiovascular and metabolic diseases. Type 2 diabetes, fatty liver disease (where liver stores fat in large lipid droplets), coronary artery disease, heart failure, and many more chronic diseases are all linked to obesity. Although there are many factors at play in an obese human that contribute to these diseases, one common theme that all have in common is something called ‘carbonyl stress.’ Carbonyl stress is a particular form of oxidative stress (i.e., ‘free radicals, hydrogen peroxide, etc). Although carbonyl stress can be a good thing in small quantities, such as with exercise, we know that with obesity, carbonyl stress coming from highly reactive lipids and sugars can cause lasting damage to proteins, DNA, and other necessary ‘building blocks’ in the cell. Fortunately, cells have many natural defense systems that work to counteract this stress, and one of these is the amino L-carnosine.

L-carnosine is a naturally occurring dipeptide that humans have in high quantities in muscle, heart and brain, and it is beneficial because it neutralizes carbonyls, thus rendering them harmless. Humans actually consume carnosine with the meat that we eat- white meat such as chicken has particularly very high levels of carnosine. Unfortunately, immediately after getting absorbed into our bloodstream, our bodies have an enzyme called ‘carnosinase’ that breaks down the carnosine, making it no longer effective as a carbonyl scavenger.

The work by Ethan Anderson, PhD, Associate Professor of Pharmacology and member of the FOEDRC, and collaborators which was recently published in the Journal of Clinical Investigation is the result of a collaboration between his laboratory and other labs across the United States and Italy. It is important for two main reasons. First, Anderson’s group and another group of medicinal chemists in Italy had the clever idea to create a slightly modified version of l-carnosine that is resistant to carnosinase, yet still retains the ability to scavenge the reactive lipids and sugars. Since it is essentially the same structure as the natural carnosine, this new molecule, ‘Carnosinol,’ displays almost no toxicity at all, and can be administered in drinking water because it is tasteless. Most importantly, Anderson’s group used multiple rodent models of obesity caused by high fat, high sugar diet, to show that Carnosinol substantially reversed metabolic syndrome and fatty liver disease in the obese animals. Of particular importance is that Carnosinol restored insulin sensitivity in the treated mice, meaning that it may be effective as a drug for ‘pre-diabetes’ in obese patients. Unpublished findings from this study also demonstrated that Carnosinol greatly improved the structure and metabolic capacity of the heart.

Collectively, what is most exciting is that this work may represent a ‘first-in-class’ new drug therapy that could help reverse the metabolic and cardiovascular disorders known to be associated with obesity. As a recent recruit to the University of Iowa and the FOEDRC, Anderson and his group in the College of Pharmacy will continue to find new and better ways to exploit the beneficial effects of l-carnosine through medicinal chemistry, and work to bring these therapies to the clinic.