Protein Could Be Used To Treat Obesity-Related Diseases

A new research study suggests that a small protein – PEPITEM – could offer a new approach to reducing the risk of obesity-related diseases. The research, conducted in animal models, is led by Dr. Helen MCGettrick and Dr. Asif Iqbal from the University of Birmingham's Institute of Inflammation and Ageing and the Institute of Cardiovascular Sciences.

Preventing obesity-related diseases

Obesity triggers alterations in the metabolism of adipose (fat) tissue and causes damage to the pancreas, resulting in decreased insulin sensitivity and the development of hyperglycemia (high blood sugar levels) – which underpins the development of Type II diabetes. Obesity also causes low-level inflammatory responses in the body, where white blood cells are prompted to infiltrate various tissues , including the visceral adipose tissue and the peritoneal cavity.

PEPITEM was discovered by University of Birmingham researchers in 2015. Its role in the adiponectin–PEPITEM pathway was first outlined by Dr. Ed Ranger, professor at the Institute of Cardiovascular sciences, and colleagues in a paper published in Nature Medicine. Adiponectin is a protein that is secreted mainly by adipose tissue. In response to adiponectin production, B cells inhibit T-cell trafficking through the secretion of PEPITEM.

MCGettrick and Iqbal’s work, published in Clinical and Experimental Immunology, demonstrates that the adiponectin–PEPITEM pathway connects obesity – and the low-level inflammatory response it drives – with changes in the pancreas that occur before the onset of diabetes.

PEPITEM both prevents and reverses the impact that obesity has on metabolism

By dosing mice on a high-fat diet with PEPITEM, the researchers found a significant reduction in the enlargement of insulin-producing beta cells in the pancreas compared to a control group of mice fed a normal diet. They also discovered that there was a reduction in white blood cells infiltrating the visceral adipose tissue and peritoneal cavity.

MCGettrick and colleagues also explored whether PEPITEM dosing could reverse the molecular changes initiated by feeding mice a high-fat diet before treatment with the peptide. “PEPITEM treatment reduced macrophage numbers within the peritoneal cavity of mice on a high-fat diet at both 6 and 12 weeks,” the researchers say in the paper. “Importantly, we reveal for the first time that the actions of PEPITEM uncouple obesity-induced pathogenic lipid storage and metabolism in the adipose tissue (weight gain) from the systemic effects of obesity on pancreas homeostasis.”

The researchers note that little has been understood about how the inflammation that accompanies obesity can drive certain diseases. The results of the current study demonstrate that PEPITEM can both prevent and reverse this impact. 

Next, the team will explore whether their findings can be translated to humans. If so, PEPITEM therapy may offer an alternative strategy for alleviating the risk of developing obesity-related diseases in individuals that find controlling their weight through lifestyle interventions challenging. 

Reference: Pezhman L, Hopkin SJ, Begum J, et al. PEPITEM modulates leukocyte trafficking to reduce obesity-induced inflammation. Clin Exp Immunol. 2023:uxad022. doi: 10.1093/cei/uxad022.

This article is a rework of a press release issued by the University of Birmingham. Material has been edited for length and content.