Research Reveals Potential Drug Target for Treating Obesity and Other Metabolic Conditions

Dr. Wu and his team show that targeting the protein hepsin may be a viable option for treating diabetes and other diseases, finding that inhibiting its expression prevented or reduced obesity and diabetes severity in preclinical models.

07/23/2020

Researchers from the Department of Cardiovascular & Metabolic Sciences have identified a new drug target that may help to treat or prevent diabetes, dyslipidemia (abnormal amounts of lipids, including cholesterol, in the blood) and obesity.

Findings from the study—led by Qingyu Wu, MD, PhD, and published in Proceedings of the National Academy of Sciences—show that the protein hepsin is an important regulator of metabolism and energy homeostasis and that inhibiting its expression may reduce the risk and severity of these metabolic disorders.

It’s long been recognized that hepsin is a transmembrane protein expressed primarily in liver tissue (also in adipose, or fat, tissue). As a transmembrane protein, it spans the entirety of the cell membrane and functions like a gatekeeper to control what goes in and out of cells. To date, its physiological function and role in disease had not been well defined.

Preventing hepsin expression has positive effect on several indicators of disease

To understand hepsin’s potential role in disease, Dr. Wu and his team studied preclinical models engineered to not express hepsin (termed hepsin-deficient). Compared to hepsin-expressing models, hepsin deficiency resulted in lower glycogen and lipid levels and increased metabolic rates and adipose tissue browning.

“Fat tissue can either be white or brown,” explained Dr. Wu. “Too much white adipose tissue can have negative effects on a patient’s metabolism and risk for related disorders. Research suggests, though, that adipose tissue browning can reverse the negative effects of white adipose tissue and actually confer metabolic benefits.”

Importantly, the researchers also saw that healthy weight hepsin-deficient models were resistant to developing obesity, hyperglycemia and hyperlipidemia when fed a high-fat diet. Additionally, preventing hepsin expression in models that were already obese and diabetic actually reduced the severity of those conditions over time.

Potential benefits of a drug for obesity

“Given that the prevalence of metabolic disorders, including obesity and diabetes, is higher than ever before, identifying a drug target to not only treat, but also prevent, these conditions would have profound patient and economic benefit,” said Dr. Wu. “We believe our study offers pretty compelling evidence that hepsin may be a viable option.”

The researchers also conduct protein expression analyses to understand the downstream effects of hepsin deficiency. On a mechanistic level, hepsin deficiency caused reduced expression of hepatocyte growth factor (HGF) and impaired signaling between HGF and its receptor, Met.

Although more research will be important, taken together, these results suggest that hepsin (through the hepsin/HGF-Met signaling cascade) increases glycogen and lipid production in the liver and lowers metabolic rates and adipose tissue browning, and that targeting and inhibiting its activity may help treat a host of metabolic disorders.

For years, Dr. Wu’s laboratory has been focused on uncovering the role cell membrane proteases play in cardiovascular biology and disease. While this, his most recent work, identified the role of hepsin in metabolic disorders, he previously discovered a transmembrane protein named corin in the heart, and defined its role in several cardiac-related conditions. His corin work was named a top research finding of 2012 by the National Heart, Lung and Blood Institute, which also provided support for this study.

Shou Li, PhD, a postdoctoral researcher in the Wu laboratory, is first author on the study, which was also supported in part by the American Heart Association.

Image: Brown adipose tissue



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