A macrophage-expressed micro-peptide, Smim30, maintains adipose tissue insulin sensitivity and safeguards systemic metabolic homeostasis

A growing number of micro-peptides (miPs) have been identified in recent years, but their biological roles remain largely unexplored. We identified a conserved 6 kDa miP, named 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 drives systemic insulin resistance, though intriguingly, adipocyte-expressed Smim30 is dispensable to this effect. Instead, Smim30 is mainly expressed in adipose tissue-residential macrophages, and loss of Smim30 led to increased macrophage infiltration and production of pro-inflammatory cytokines and chemokines. Smim30 also modulated inflammatory responses in ex vivo/in vitro macrophage systems, which is conserved in both human and mouse. Collectively, 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.