In a major leap for obesity and metabolism research, scientists at the Salk Institute have identified dozens of previously overlooked microproteins that help regulate how fat cells grow and store energy.
Published August 7 in Proceedings of the National Academy of Sciences, the study showcases a powerful new approach to uncovering tiny proteins that could become tomorrow’s drug targets for obesity and related metabolic disorders like diabetes and fatty liver disease.
From Junk DNA to Drug Targets
Despite the rising popularity of GLP-1 drugs like Ozempic and Wegovy, long-term weight loss remains elusive for many people. Salk scientists are betting that microproteins—short chains of amino acids encoded by what was once dismissed as “junk DNA”—could hold the key to more effective and durable treatments.
“CRISPR screening is extremely effective at finding important factors in obesity and metabolism that could become therapeutic targets,” said senior author Alan Saghatelian, professor at Salk and holder of the Dr. Frederik Paulsen Chair. “These new screening technologies are allowing us to reveal a whole new level of biological regulation driven by microproteins.”
Unlike conventional proteins, microproteins are too small to be detected easily using traditional biochemical methods. Yet they often act as regulatory agents in complex biological systems. GLP-1 itself is a microprotein, suggesting that others may have similar potential as therapeutics.
Why Fat Storage Is So Hard to Control
Obesity develops when the body stores more energy than it expends, causing fat cells to grow and multiply. But this energy imbalance does more than add weight—it leads to inflammation, insulin resistance, and organ damage.
The challenge lies in identifying the molecular regulators that govern fat cell behavior and lipid metabolism. PPAR gamma, a well-known transcription factor, was once seen as a promising target but led to side effects like bone loss. The search for better alternatives continues.
Enter CRISPR: Lighting Up the Genome’s Dark Matter
Salk researchers turned to CRISPR-Cas9 gene editing to systematically knock out thousands of genes in pre-fat cells. By tracking which deletions affected cell proliferation or lipid droplet formation, the team was able to spotlight candidate microproteins with roles in fat metabolism.
“We wanted to know if there was anything we had been missing in all these years of research into the body’s metabolic processes,” said first author Victor Pai, a postdoctoral researcher in Saghatelian’s lab. “CRISPR allows us to pick out interesting and functional genes that specifically impact lipid accumulation and fat cell development.”
Using a 3T3-L1 preadipocyte model—cells that can differentiate into mature fat cells—the researchers identified 38 potential microproteins involved in lipid droplet formation, a key indicator of fat storage capacity.
Key Discoveries
- Thousands of smORFs (small open reading frames) were screened for roles in fat cell growth
- 38 microproteins were shortlisted for their involvement in lipid storage
- One microprotein, Adipocyte-smORF-1183, was validated as a regulator of fat cell differentiation
- Future work will apply the same method to human fat cells
Proof of Concept: Adipocyte-smORF-1183
To confirm their screening results, the team conducted follow-up experiments on several of the shortlisted smORFs. One of them, Adipocyte-smORF-1183, stood out. This microprotein, encoded by a long noncoding RNA previously dismissed as irrelevant, appears to influence how fat cells form and store lipids.
“We’re not the first to screen for microproteins with CRISPR,” said Pai, “but we’re the first to look for microproteins involved in fat cell proliferation. This is a huge step for metabolism and obesity research.”
What Comes Next
The team now plans to apply their CRISPR-based pipeline to human fat cells. Given the success of their approach in mice, the researchers believe further validation could yield an expanded list of drug candidates tailored to human obesity and metabolic conditions.
“That’s the goal of research, right?” said Saghatelian. “You keep going. It’s a constant process of improvement as we establish better technology and better workflows to enhance discovery and, eventually, therapeutic outcomes down the line.”
Why This Matters
Obesity affects over one billion people globally. Current drugs often have side effects and don’t work for everyone. By tapping into an entirely new category of therapeutic targets—microproteins that were hiding in plain sight—this research opens up exciting new possibilities for treating obesity more precisely and with fewer drawbacks.
It also marks a turning point in how we think about the genome, transforming stretches of so-called “junk DNA” into valuable sources of insight and innovation.
Journal Reference
Proceedings of the National Academy of Sciences
DOI: 10.1073/pnas.2506534122
Published: August 7, 2025
Article Title: CRISPR-Cas9 Screening Reveals Microproteins Regulating Adipocyte Proliferation and Lipid Metabolism
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