Finding novel peptides and small proteins that control the formation of fat cells using CRISPR

What is it about?

This study investigates tiny genes called small open reading frames (smORFs), which can make microproteins. Although thousands of smORFs exist, their functions in fat cells have been largely overlooked. To study them, we used CRISPR/Cas9 technology in a rodent fat cell model, which allowed us to systemically “remove” smORFs across the genome and test which ones influence how fat cells grow, divide, and accumulate fat. This unbiased screen uncovered more than a hundred smORFs with functional roles, including 38 that control fat storage. Among these, one microprotein, Adipocyte-smORF-1183, was previously hidden in a gene thought to produce only non-coding RNA. This microprotein turned out to be essential for fat cell development: when it was deleted, fat cells accumulated about 50% fewer lipid droplets. Importantly, Adipocyte-smORF-1183 is rodent-specific, showing that even lineage-restricted smORFs can play critical roles in biology.

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Why is it important?

Obesity and related diseases are major global health problems, but the molecular “switches” that regulate fat cells are still incompletely understood. This work shows that smORFs and microproteins are a hidden layer of biology that can strongly influence fat cell growth and metabolism, even when the smORFs are not conserved between species. If conservation alone had been used as a filter, Adipocyte-smORF-1183 would never have been identified, yet it plays a clear role in fat biology. By establishing an unbiased, CRISPR-based pipeline, this study expands the toolkit for discovering microproteins that shape cell behavior. Beyond fat storage, the same approach could be applied to other cellular features, such as mitochondrial activity, using additional assays. This framework makes it possible to uncover new and unexpected regulators across many biological systems. Extending this work to human fat cells could reveal human-specific microproteins that act as novel regulators of metabolism and potentially provide new therapeutic targets for obesity and metabolic disease.