Abstract

Thermogenic adipose tissue, specialized in dissipating chemical energy as heat, represents a promising therapeutic target for combating obesity and type 2 diabetes. S100A8/S100A9 is an inflammatory alarmin and biomarker implicated in various diseases, including obesity. Here, we investigated the role of S100A8/S100A9 in thermogenesis and whole-body energy homeostasis. Wild-type (WT) and S100A8/S100A9-deficient (S100a9^-/-) mice were subjected to a 14-wk high-fat diet (HFD). Thermogenic responses were assessed through cold exposure and administration of the β3-adrenergic receptor agonist CL-316,423, with additional experiments involving exogenous S100A8/S100A9 administration in WT mice. Under normal chow, S100a9^-/- mice exhibited a leaner phenotype compared with WT controls. Following HFD-induced obesity, S100a9^-/- mice displayed reduced weight gain, improved insulin sensitivity, increased lipid storage in epididymal adipose tissue, and attenuated hepatic steatosis. Physiological studies using metabolic cages revealed higher oxygen consumption and heat production in lean S100a9^-/- mice following chronic CL-316,423 treatment. In line, S100a9^-/- mice exhibited increased beiging in inguinal white adipose tissue (ingWAT), but not in brown adipose tissue (BAT), under cold exposure as well as acute and chronic CL-316,423. Conversely, exogenous S100A8/S100A9 administration under both cold challenge and chronic CL-316,423 suppressed thermogenic gene expression in ingWAT, with no significant effect in BAT. In vitro, stimulation of immortalized beige adipocytes with S100A9 led to downregulation of beige adipocyte marker genes. Collectively, these findings identify S100A8/S100A9 as a negative regulator of ingWAT beiging and energy expenditure, thereby contributing to impaired metabolic homeostasis and exacerbation of diet-induced obesity.NEW & NOTEWORTHY Obesity is a disorder characterized by disrupted energy homeostasis. During obesity, thermogenic pathways decline, making strategies that enhance energy expenditure a promising avenue for intervention. The alarmin complex S100A8/S100A9 is upregulated in both human and experimental models of obesity and type 2 diabetes. In this study, we identify a critical pathogenic role of S100A8/S100A9 in impairing thermogenesis in subcutaneous adipose tissue, reducing energy expenditure, and exacerbating obesity and its related complications.