In the past three decades, the global prevalence of obesity has surged dramatically, currently afflicting over a billion individuals worldwide and catalyzing an alarming rise in associated metabolic ailments such as type 2 diabetes, cardiovascular disease, chronic kidney dysfunction, and certain cancers. Despite a variety of treatment modalities ranging from lifestyle modifications and bariatric surgery to pharmaceutical interventions like GLP-1 analogs (commonly known by trade names such as Ozempic and Wegovy), significant barriers remain in patient accessibility, sustained weight maintenance, and long-term therapeutic efficacy. Against this backdrop, scientists at the Salk Institute have embarked on an innovative exploration into the largely uncharted realm of microproteins—tiny yet biologically potent molecules whose influence on obesity and metabolism has only recently come into focus.
Microproteins, typically under 100 amino acids in length, have historically been dismissed as unlikely candidates for functional roles in cellular systems, often buried within genomic “dark matter” or deemed noncoding regions. However, advances in genomic and proteomic technologies have begun to illuminate the substantial repertoire of these small proteins and their diverse regulatory functions. Leveraging these insights, researchers led by Professor Alan Saghatelian employed cutting-edge CRISPR-Cas9 gene editing techniques to systematically interrogate thousands of genes in mouse fat cells, aiming to pinpoint those encoding microproteins that decisively impact adipocyte biology, specifically fat cell proliferation and lipid accumulation.
Published on August 7, 2025, in the Proceedings of the National Academy of Sciences, this seminal study underscores the profound potential of CRISPR-based screening to unveil novel molecular actors previously obscured from conventional study. By integrating a genetically engineered pre-adipocyte model that mimics natural differentiation pathways, the team meticulously screened for genetic perturbations that altered key phenotypes correlating with fat storage and cell growth. The outcome was the identification of dozens of candidate microprotein-coding genes, among which the researchers were able to validate at least one microprotein—termed Adipocyte-smORF-1183—that plays a critical role in modulating lipid droplet formation within adipocytes, a hallmark feature of expanding fat mass in obesity.
The mechanistic implications of these findings are significant. Fat cells, or adipocytes, mediate energy homeostasis by sequestering surplus calories in lipid droplets. When these cells proliferate and enlarge unchecked, they contribute to systemic metabolic dysregulation and inflammation, laying the groundwork for obesity-related diseases. While established therapeutic targets such as PPAR gamma have provided viable intervention points, their clinical utility has often been hampered by adverse side effects including weight gain and bone density loss. Meanwhile, GLP-1 peptide analogs, representing a class of microproteins themselves, have made strides in improving glucose regulation and appetite suppression, despite tolerability issues like nausea and muscle wasting. This evolving landscape underscores the pressing need for new molecular targets, ideally microproteins, that can offer potent yet safer therapeutic avenues.
Salk’s approach to addressing this need is grounded in the transformative power of CRISPR technology. By orchestrating precise gene knockouts across a broad swath of the fat cell genome, the researchers could observe resultant phenotypic shifts with unparalleled resolution. This tactic enabled the extraction of functional insights not only on canonical proteins but also on microproteins that escape detection through conventional proteomics due to their minuscule size and low abundance. Importantly, this screening framework prioritizes genetic elements whose disruption tangibly affects lipid metabolism and cellular proliferation, aligning the search for drug candidates with biological relevance.
The study builds upon earlier work from Saghatelian’s laboratory, which cataloged thousands of putative microprotein-coding RNA transcripts extracted from murine adipose tissues. By expanding the catalog to include transcripts expressed during the critical transition from precursor to mature fat cells, the subsequent CRISPR screen articulated a refined subset of 38 microprotein candidates potentially involved in the complex orchestration of lipid droplet biogenesis. These lipid droplets are not inert fat stores but dynamic organelles essential for cellular energy buffering, making their regulatory proteins exceptionally promising targets for intervention.
Further biochemical and cellular assays substantiated the role of Adipocyte-smORF-1183, demonstrating its influence on fat cell lipid storage capacity. This microprotein, previously unannotated and residing within a stretch of genomic DNA formerly regarded as nonfunctional “junk,” exemplifies how modern genomics and gene editing can rewrite our understanding of cellular regulation. Such discoveries suggest an extensive, uncharacterized proteomic layer that modulates metabolic pathways, representing a reservoir of untapped therapeutic potential.
Looking forward, the Salk team plans to translate these insights into human adipocyte systems, validating and expanding the candidate microprotein pool. This translational leap is crucial given the interspecies differences in fat cell biology and the ultimate goal of creating human-applicable therapies. The researchers are optimistic that CRISPR screenings will become a standard tool in the microprotein discovery pipeline, accelerating the identification of novel druggable targets that could revolutionize obesity treatment paradigms.
This breakthrough was made possible through collaborative efforts involving experts in cell biology, genetics, and biochemistry from both the Salk Institute and Scripps Research Institute. The work was generously supported by the National Institutes of Health alongside various philanthropic organizations, underscoring the impactful synthesis of public and private resources in fostering biomedical innovation.
Beyond the immediate therapeutic implications, the study invites a broader scientific reevaluation of “junk DNA,” suggesting that the genome’s dark matter may harbor a plethora of short open reading frames encoding functional microproteins with critical roles in physiology and disease. This paradigm shift not only enriches our molecular toolkit but fundamentally expands the horizons of genomics and proteomics.
As obesity continues to impose a mounting global health and economic burden, strategies grounded in precision molecular targeting—enabled by technologies like CRISPR and informed by comprehensive proteogenomic profiling—represent a beacon of hope. The identification of microproteins like Adipocyte-smORF-1183 offers a glimpse into a future where obesity and its attendant metabolic disorders might be more effectively and safely managed through novel molecular interventions derived from the genome’s hidden layers.
Ultimately, the relentless spirit of inquiry embodied by researchers at the Salk Institute epitomizes the iterative nature of scientific discovery. As Dr. Saghatelian remarks, the pursuit of knowledge is an ongoing process of refinement and innovation—a continuous journey toward unveiling the biological complexities that underlie human health and disease, and harnessing them to improve therapeutic outcomes for generations to come.
Subject of Research: Microproteins regulating adipocyte proliferation and lipid metabolism
Article Title: CRISPR-Cas9 Screening Reveals Microproteins Regulating Adipocyte Proliferation and Lipid Metabolism
News Publication Date: August 7, 2025
Web References:
https://www.pnas.org/doi/10.1073/pnas.2506534122
http://dx.doi.org/10.1073/pnas.2506534122
References:
Saghatelian, A. et al. (2025). CRISPR-Cas9 Screening Reveals Microproteins Regulating Adipocyte Proliferation and Lipid Metabolism. Proceedings of the National Academy of Sciences, 10.1073/pnas.2506534122.
Image Credits: Salk Institute
Keywords: Life sciences, Cell biology, Adipocytes, Cell proliferation, Genetics, Genetic methods, Gene identification, Biochemistry, Metabolism, Protein functions, Proteins, Diseases and disorders, Metabolic disorders, Obesity, Diabetes, CRISPRs
