Macrophage-Expressed Micropeptide Smim30 Maintains Adipose Tissue Insulin Sensitivity and Safeguards Systemic Metabolic Homeostasis

A growing number of micropeptides (miPs) have been identified in recent years, but their biological roles remain largely unexplored. We identified a conserved 6-kDa miP, named small integral membrane protein 30 (SMIM30), as a potential metabolic regulator. To study the physiological function of Smim30, we generated a loss-of-function mouse strain using the CRISPR/Cas9-mediated knock-in strategy. When fed both normal chow and high-fat diets, these mice exhibited elevated blood glucose and insulin levels, with reduced insulin sensitivity. We further showed that Smim30 loss in adipose tissue drove systemic insulin resistance, although intriguingly, adipocyte-expressed Smim30 was dispensable in this effect. Instead, Smim30 was mainly expressed in adipose tissue–residential macrophages, and loss of Smim30 led to increased macrophage infiltration and production of proinflammatory cytokines and chemokines. Smim30 also modulated inflammatory responses in ex vivo/in vitro macrophage systems, which are conserved in both humans and mice. The results indicate that Smim30 plays a key role in maintaining adipose tissue insulin sensitivity and safeguarding systemic metabolic homeostasis, offering potential as both a diagnostic biomarker and therapeutic target for metabolic disorders. Article Highlights Understanding the role of micropeptides (miPs) in metabolic regulation could enhance insights into metabolic diseases and open new pathways for treatment. Small integral membrane protein 30 (Smim30), an adipose tissue macrophage–expressed miP, maintains insulin sensitivity and safeguards systemic metabolic homeostasis. Smim30 modulates inflammatory responses and macrophage–adipocyte communication in adipose tissue. Smim30 could serve as a potential diagnostic biomarker and therapeutic target for metabolic disorders.