Potential of Microproteins in Addressing Obesity and Metabolic Conditions

The rising rate of obesity, which has more than doubled over the past three decades, now affects over one billion individuals globally. This condition is often linked to various metabolic disorders, including type 2 diabetes, cardiovascular diseases, chronic kidney issues, and certain cancers.

Current treatment methods for obesity include lifestyle changes, bariatric surgery, and medications like GLP-1 drugs (e.g., Ozempic and Wegovy). However, many patients face challenges in accessing these therapies or maintaining weight loss post-treatment. Researchers at the Salk Institute are investigating microproteins, a lesser-known class of molecules, as a novel treatment strategy for obesity and related metabolic disorders.

In a recent study, scientists utilized CRISPR gene editing to screen thousands of genes in fat cells, identifying numerous genes that likely code for microproteins. Among these, the researchers confirmed the existence of one microprotein that influences either the proliferation of fat cells or the accumulation of lipids.

Published in the Proceedings of the National Academy of Sciences, this research highlights new microproteins that could serve as potential drug targets for treating obesity and metabolic disorders, emphasizing the effectiveness of CRISPR technology in discovering these molecules.

Senior researchers indicate that CRISPR screening is proving to be a powerful tool in uncovering crucial factors in obesity and metabolism that could lead to new therapeutic targets. As more screenings are conducted, researchers anticipate identifying additional disease-associated microproteins that could be pivotal in drug development.

When energy intake surpasses energy expenditure, fat cells increase in both number and size as they store excess energy in the form of lipids. While some degree of fat storage is manageable, excessive accumulation can trigger inflammation and dysfunction across various organs.

Numerous factors influence this intricate energy storage mechanism, raising questions about how to identify and selectively target those that may offer therapeutic benefits. This challenge has captivated Salk scientists for many years, particularly Professor Ronald Evans, who has studied PPAR gamma, a significant regulator of fat cell development and a target for diabetes treatment.

While several drugs have aimed to target PPAR gamma, they have been associated with side effects such as weight gain and bone loss, indicating that an ideal PPAR gamma-based therapeutic remains elusive. The emergence of GLP-1 drugs, which function as appetite and blood sugar regulators, has also presented challenges, including muscle loss and nausea. Nevertheless, the success of GLP-1 medications suggests a promising future for microprotein-based treatments in obesity management.

The Salk team is actively searching for new microprotein therapeutics, leveraging advanced genetic tools to uncover previously overlooked regions of the genome that were once deemed non-essential. Recent technological advancements have enabled scientists to explore these so-called 'dark' sections of the genome, revealing a hidden repository of microproteins, thereby expanding the known protein library by 10% to 30%.

The innovative CRISPR screening approach allows researchers to simultaneously identify thousands of potential microproteins implicated in lipid storage and fat cell biology, accelerating the quest for new therapeutic candidates.

CRISPR screens function by removing specific genes from cells and observing the resultant effects on cell viability. This method enables scientists to discern the role and importance of particular genes, particularly those hypothesized to code for microproteins that play a role in fat cell differentiation or proliferation.

The recent study built upon a prior investigation that identified thousands of potential microproteins from RNA strands associated with mouse fat tissues. This study expanded the search to include additional microproteins from a pre-fat cell model, which captures the transformation from pre-fat cells to fully mature fat cells.

Following the CRISPR screening, the researchers compiled a shortlist of 38 potential microproteins linked to lipid droplet formation, a marker of increased fat storage during fat cell maturation.

While these microproteins were identified as potential candidates, further validation is necessary to confirm their functionality. The Salk team successfully verified one microprotein, designated as Adipocyte-smORF-1183, which appears to influence lipid droplet formation in adipocytes.

This verification marks a significant advancement in the ongoing exploration of microproteins associated with lipid accumulation and fat cell regulation in obesity. It also underscores the utility of CRISPR screening in identifying microproteins relevant to metabolism and obesity.

Moving forward, researchers plan to replicate their findings using human fat cells and hope their success will inspire further investigations into microproteins, including those previously dismissed as 'junk' DNA. Continued validation and screening of new cell libraries aim to broaden the list of potential drug candidates, paving the way for innovative obesity and metabolic disorder treatments in the future.