By Nick Lavars March 14, 2022
A three-dimensional image of the interior of a diseased mouse liver cell shows alterations brought on by obesityHarvard University
Improving our understanding of the impact obesity has on individual cells could go a long way to preventing some of its deleterious downstream effects, such as diabetes and cardiovascular disease. Harvard scientists studying the molecular structure of cells under obesity-related stress have spotted alterations in their architecture that can be patched up, with “striking” results that restore them to healthy metabolic function.
Learning more about the mechanisms that drive adverse health effects resulting from obesity can offer new ways to manage the condition and prevent its impacts. We’ve seen some interesting advances in this area that show how next-generation drugs could be used to prevent the development of high cholesterol, insulin resistance and diabetes. The Harvard team behind this latest breakthrough began by exploring fatty liver disease, another common condition driven by obesity.
The team took liver samples from healthy lean mice and from obese mice with fatty liver disease, and turned to a variety of cutting-edge technologies to examine them in fine detail. This included a mix of artificial intelligence, deep learning and high-resolution imaging through ion-beam scanning electron microscopy.
This led to three-dimensional reconstructions of multipurpose structures in the liver cells called organelles, enabling them to compare the diseased specimens from the healthy ones on a molecular level. The images used by the scientists are actually the most detailed visualizations ever produced of these subcellular structures intact in their regular tissue environment.
“I was first mesmerized with the complexity, beauty, and harmony of the constructions in the extremely crowded internal space of a cell,” said study author Gökhan Hotamışlıgil. “This is like watching an artistic masterpiece while traveling into the center of a cell.”
The images showed that the organelles in the obese mice with fatty liver disease featured dramatic alterations to the molecular architecture compared to the healthy samples. The team was then actually able to partially patch up these alterations with technology used to repair molecules and proteins. This resulted in the repaired cells looking normal, featuring much improved metabolism and remaining stress free.
“The outcome was really striking – when structure is repaired, so is the cell’s metabolism,” said Arruda. “What we are describing here is a whole new way of controlling metabolism by regulating molecular architecture, which is critical for health and disease.”
The scientist see this discovery as a basis for therapeutics that target the mechanism as a way of treating metabolic conditions like fatty liver disease, but also could be used to gauge an overweight person’s vulnerability or resistance to them.
“Chronic metabolic disease, which includes obesity, diabetes, and cardiovascular and liver diseases, is the biggest global public health problem,” said Hotamışlıgil. “The fundamental regulatory mechanism that we discovered can be used to evaluate the susceptibility – or resistance – of individuals to a disease state like obesity, and determine what steps, such as diet, nutrients, or fasting, will reduce, eliminate, or exacerbate these states. We can imagine a whole new array of therapeutic strategies targeting molecular architecture, similar to the restoration of an ailing building or preventing its deterioration.”
The research was published in the journal Nature.
Source: Harvard University
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