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

Beneficial effects of simultaneously targeting calorie intake and calorie efficiency in diet-induced obese mice

“…The pseudo-intermittent fasting effect may also have contributed to the decreased fat pad masses that were observed in the group treated with the combination of high-dose semaglutide and BAM15, as intermittent fasting has previously been shown to induce adipose browning in mice [ 67 ]. In the present study, semaglutide treatment did not affect cumulative food intake, which is likely due to the considerably lower doses used when compared with other groups [ 49 , 68 ].…”

“…Therefore, the 0.05% BAM15 dose used in this study is at least 3-fold lower than the maximally effective dose. Similarly, semaglutide studies in diet-induced mice in the literature commonly involve doses of 40–600 µg/kg every 1–3 days [ 49–58 ]. Therefore, we tested semaglutide herein at 5 µg/kg (low dose) and 20 µg/kg (high dose) twice weekly, which are 2- to 8-fold lower than the lowest reported effective dose.…”

Research Progress on the GIP/GLP-1 Receptor Coagonist Tirzepatide, a Rising Star in Type 2 Diabetes

“…On the one hand, the effect of GIP signals on weight loss is transmitted through the central nervous system [47]; on the other hand, GIP may have a neuroprotective effect on animal models of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease by promoting neurogenesis [50]. GLP1 in the brain is involved in various biological reactions such as stress response, aversion, anorexia, hypothalamic pituitary function, neuroinflammation, and neuroprotection [51][52][53]. Extensive preclinical studies have shown that incretinbased drugs can achieve significant cerebral protection and reduce neuronal loss by reducing synaptic loss and amyloid plaque load, decreasing hyperphosphorylation of τ proteins, and anti-inflammatory effects [54].…”

Glycoprotein Non-Metastatic Protein B (GPNMB): The Missing Link Between Lysosomes and Obesity

“…In fact, a weekly dose of the GLP-1R agonist semaglutide was associated with a sustained reduction in body weight [19]. In mice, semaglutide reduced adipocyte hypertrophy and macrophage infiltration and activated adipocyte browning and mitochondrial biogenesis to promote weight loss [20].…”