Emerging Microproteins as Promising Targets for Obesity and Metabolic Disorders

The global obesity epidemic has seen its prevalence more than double over the past three decades, now affecting over one billion individuals worldwide. This condition not only impacts weight but is also closely associated with a range of metabolic issues such as type 2 diabetes, cardiovascular diseases, chronic kidney disease, and certain cancers.

Current treatment options include lifestyle modifications, surgical interventions like bariatric surgery, and pharmacological agents such as GLP-1 receptor agonists like Ozempic and Wegovy. However, many patients face difficulties in accessing these treatments, and sustaining long-term weight loss remains a challenge.

In pursuit of new therapeutic avenues, scientists at the Salk Institute have turned their attention to microproteins—a class of small, often overlooked molecules that play vital roles in health and disease. Through extensive CRISPR gene editing screens, researchers identified dozens of these microproteins in fat cells that influence either cell proliferation or lipid accumulation. Among these, one microprotein has been confirmed to affect fat cell biology, opening promising pathways for drug development.

The study, published in Proceedings of the National Academy of Sciences, highlights the potential of these microproteins as novel drug targets for obesity and metabolic disorders. The research demonstrates that CRISPR screening effectively uncovers critical regulators within the body’s complex metabolic framework, offering insights into previously unrecognized mechanisms. Senior author Alan Saghatelian emphasizes that understanding and harnessing these microproteins could lead to innovative treatments in the future.

Obesity results from an imbalance where energy intake exceeds expenditure, promoting fat cell growth and lipid storage. Fat cells typically store excess energy as lipids, but an overload can lead to harmful deposits, inflammation, and organ dysfunction. The regulation of these processes involves numerous factors, many of which remain unidentified.

While drugs targeting PPAR gamma—a key regulator of fat cell development—have been developed, they often pose side effects like weight gain and bone loss. Similarly, GLP-1-based therapies, which regulate blood sugar and appetite, show promise but also have limitations. The discovery of microproteins offers an exciting new frontier, potentially allowing for more precise and effective interventions.

The Salk team utilizes innovative CRISPR screening techniques to explore the genome’s less-understood regions, often deemed "junk DNA," which harbor numerous microproteins. This approach has expanded the known protein library significantly, revealing new candidates involved in fat cell regulation. The focus now shifts to validating these potential microproteins and understanding their specific roles.

In their recent experiments, the researchers identified a microprotein named Adipocyte-smORF-1183 that appears to influence lipid droplet formation in fat cells, a critical step in fat storage. Confirming its function provides a vital proof-of-concept that CRISPR screening can uncover microproteins relevant to obesity. The research team plans to extend these studies to human fat cells, with hopes of translating findings into new therapeutic options.

By advancing the understanding of microproteins and their functions in fat cell biology, scientists aim to develop more targeted, effective treatments for obesity and associated metabolic conditions. This research emphasizes the importance of exploring the genome’s "dark matter," which could hold the key to combating some of the most pressing health issues of our time.