This narrative review examined obesity-induced pathological remodeling of subcutaneous (scWAT) and visceral (vWAT) white adipose tissue, and synthesized evidence from animal models and human studies on how incretin-based therapies (GLP-1R agonists, dual GLP-1/GIP agonists, triple GLP-1/GIP/glucagon agonists) and bariatric surgery (RYGB, sleeve gastrectomy) influence WAT beyond weight loss across inflammatory, mitochondrial/thermogenic, and endocrine pathways.
Both incretin-based therapies and bariatric surgery are associated with changes in WAT inflammatory markers, mitochondrial pathways, and adipokine signaling; however, human tissue-level evidence is heterogeneous and most changes occur alongside weight loss. One key divergence: RYGB upregulated OXPHOS-related transcripts in scWAT at 12 months, while diet-induced weight loss of equivalent magnitude downregulated them—suggesting surgery-specific mitochondrial remodeling. Tirzepatide preclinical data indicate ~30% of insulin sensitization occurs independently of weight loss. Retatrutide achieved >24% body weight reduction at 48 weeks (phase 2), with vWAT transcriptomic evidence of reduced inflammation and restored fatty acid oxidation pathways in mice.
- Narrative (non-systematic) design introduces selection bias; most human tissue-level data come from scWAT with sparse paired-depot analyses. - Nearly all mechanistic evidence for weight-independent WAT remodeling comes from animal models or in vitro systems; human studies lack weight-matched comparators. - Sex-stratified adipose outcomes are rarely reported, limiting generalizability across sexes.
Clinicians should recognize that bariatric surgery and incretin-based therapies likely differ in their adipose tissue effects beyond weight reduction—RYGB shows stronger evidence for mitochondrial remodeling and microbiota-mediated gut–adipose signaling. For patients with post-bariatric weight regain, adjunctive tirzepatide or semaglutide can provide additional metabolic benefit, with tirzepatide showing greater weight reduction than semaglutide in that setting.
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