Semaglutide (GLP‐1 receptor agonist) stimulates browning on subcutaneous fat adipocytes and mitigates inflammation and endoplasmic reticulum stress in visceral fat adipocytes of obese mice

Abstract Semaglutide (GLP‐1 agonist) was approved for treating obesity. Although the effects on weight loss and metabolism are known, the responses of adipocytes to semaglutide are yet limited. C57BL/6 male mice ( n = 20/group) were fed a control diet (C) or a high‐fat (HF) diet for 16 weeks and then separated into four groups ( n = 10/group) for an additional four weeks: C, C diet and semaglutide, HF, and HF diet and semaglutide. Epididymal white adipose tissue (eWAT) and subcutaneous white adipose tissue (sWAT) fat pads were studied with biochemistry, immunohistochemistry/fluorescence, stereology, and reverse transcription‐quantitative polymerase chain reaction. In obese mice, semaglutide reduced the fat pad masses (eWAT, −55%; sWAT, −40%), plasmatic cytokines, and proinflammatory gene expressions: tumor necrosis factor‐alpha (−60%); interleukin (IL)‐6 (−55%); IL‐1 beta (−40%); monocyte chemoattractant protein‐1 (−90%); and leptin (−80%). Semaglutide also lessened endoplasmic reticulum (ER) stress genes of activating transcription factor‐4 (−85%), CCAAT enhancer‐binding protein homologous protein (−55%), and growth arrest and DNA damage‐inducible gene 45 (−45%). The obese mice's adipocyte hypertrophy and macrophage infiltration were equally reduced by semaglutide. Semaglutide enhanced multiloculation and uncoupled protein 1 (UCP1) labeling in obese mice: peroxisome proliferator‐activated receptor‐alpha (+560%) and gamma (+150%), fibronectin type III domain‐containing protein 5 (+215%), peroxisome proliferator‐activated receptor‐alpha coactivator (+110%), nuclear respiratory factor 1 (+260%), and mitochondrial transcription factor A (+120%). Semaglutide also increased thermogenetic gene expressions for the browning phenotype maintenance: beta‐3 adrenergic receptor (+520%), PR domain containing 16 (+90%), and Ucp1 (+110%). In conclusion, semaglutide showed significant beneficial effects beyond weight loss, directly on fat pads and adipocytes of obese mice, remarkably anti‐inflammatory, and reduced adipocyte size and ER stress. Besides, semaglutide activated adipocyte browning, improving UCP1, mitochondrial biogenesis, and thermogenic marker expressions help weight loss.