miR 12137 3p as a Novel Regulator of Adipogenesis and Lipid Accumulation.

Abstract

While modern antiretroviral (ARV) therapies have transformed HIV from a fatal diagnosis into a manageable chronic condition, they have introduced a new pervasive health challenge: metabolic dysregulation and obesity. Antiretroviral treatment regimens containing Integrase Strand Transfer Inhibitors (ISTIs such as Biktarvy) and Protease Inhibitors (PIs such as Symtuza) are highly effective at suppressing viral loads and boosting immune function. However, clinical observations reveal a concerning trend where patients on the above ARV drugs experience significant weight gain. This weight gain may not simply be a matter of caloric intake but suggests a deeper, molecular disruption within the body’s genetic network. To identify target specific markers or trends that help pinpoint the root cause of this phenomenon, we conducted a longitudinal clinical study following HIV-positive patients over 48 weeks of treatment with either Biktarvy or Symtuza. By using Next Generation Sequencing (NGS) to analyze patient blood samples, we identified a specific "genetic switch"—a novel microRNA, miR-12137-3p, that was significantly elevated in patients on ARVs and experiencing weight gain. This molecule appears to act as a pro-adipogenic regulator, meaning it instructs cells to accumulate fat. Further analysis revealed that miR-12137-3p works by directly suppressing key genes (specifically PPAR-gamma-2 and WNT3A) that are normally responsible for regulating fat metabolism and energy expenditure. Essentially, ARVs flip the miR-12137-3p switch, causing the body to store fat rather than burn it. Initial laboratory tests using standard oligo-based inhibitors to block miR-12137-3p were promising, resulting in reduced fat storage in human cells. However, these inhibitors acted like a "blunt instrument," creating "transcriptional noise" by accidentally activating unrelated genes (such as BMP7) and stressing the cells, which obscured the true biological mechanism. To achieve definitive proof, we employed advanced CRISPR-Cas9 gene-editing technology. Unlike temporary inhibitors, CRISPR allowed us to precisely and permanently disable the production of miR-12137-3p without harming the surrounding DNA. The CRISPR-based approach provided a "clean" genetic background that confirmed ARV-driven miR-12137-3p expression is indeed the driver of lipid accumulation. This high-fidelity editing revealed that the mechanism by which miR-12137-3p induced adipogenesis. By establishing miR-12137-3p as a confirmed biomarker for ARV-associated obesity, this research offers a dual breakthrough: (i) Circulatory miR-12137-3p may serve as biomarker of obesity. It provides a potential early warning sign of obesity for clinicians monitoring patients on HIV medication; and (ii) Mir-12137-3p may serve as a target for future RNAi-based therapies that could prevent weight gain without compromising viral suppression.