Blocking PTP1B protects the heart from obesity-induced damage

A groundbreaking new study led by researchers at the Masonic Medical Research Institute (MMRI) has identified a promising molecular target to protect the heart against damage caused by high-fat diet and obesity. The study, published this week in the leading journal Science Signaling, highlights the protein tyrosine phosphatase PTP1B, a nodal enzyme involved in insulin signaling, as a key driver in maladaptive cardiac metabolism and dysfunction under dietary stress.

In obesity and high-fat diet conditions, the heart undergoes a metabolic switch, moving from its healthy preference for fatty acid oxidation to an overreliance on glucose. This shift contributes to cardiac steatosis, mitochondrial dysfunction, and ultimately a cardiac disease condition called cardiomyopathy, a thickening and stiffening of the heart. The research team discovered that mice lacking PTP1B specifically in cardiomyocytes (heart muscle cells) were resistant to these harmful changes.

These findings reveal a novel major mechanism by which high-fat diet compromises cardiac function and show how targeting PTP1B in the heart can help prevent those effects. By preserving fatty acid oxidation and preventing excessive lipid accumulation, we can protect against heart disease progression in at-risk populations."

Dr. Maria I. Kontaridis, executive director, Gordon K. Moe professor and chair of biomedical research and translational medicine at MMRI and senior author of the study

The study utilized a mouse model with cardiomyocyte-specific deletion of PTP1B. When subjected to a high-fat diet, these mice maintained healthy heart structure and function, showed reduced lipid buildup, and preserved mitochondrial integrity. Advanced metabolic and phosphoproteomic analyses revealed that PTP1B deletion sustained fatty acid metabolism while suppressing lipogenesis and pathological glucose utilization, via signaling pathways involving AMPK and PKM2.

"PTP1B acts like a metabolic switch that pushes the heart toward glucose dependence during stress, which may worsen cardiac outcomes," added Dr. Yan Sun, postdoctoral fellow in the Kontaridis lab and leading author of the manuscript. "Disabling this switch allows the heart to remain metabolically flexible and resilient."

With an alarming 50 percent of Americans on track to be classified as obese by the year 2030 (World Health Organization), including a disproportionate number of children, the urgency of this epidemic cannot be overstated. These findings have the potential to impact society significantly. These results position PTP1B as a potential therapeutic target for preventing heart disease in obese patients and those with diet-induced metabolic disorders. The team hopes this foundational research will pave the way for future clinical studies.