From White to Beige: Role of DPP-4 in Adipose Remodeling and Obesity Treatment

Obesity continues to be a significant global health issue associated with type 2 diabetes, cardiovascular disease, and fatty liver disease. Typically, conventional weight management strategies, such as dietary, exercise, and pharmacotherapy, often fail to produce meaningful long-term results due to an adaptive form of resistance to weight loss. The recently identified plasticity of adipose tissue in the treatment of obesity presents an exciting paradigm, including the browning of classic white adipose tissue (WAT) and its energy-dissipating beige adipocytes. Dipeptidyl peptidase-4 (DPP-4) is a type of enzyme primarily known for glucose metabolism due to its degradation of incretins; however, DPP-4 has an unknown role in adipose biology. Beyond enzymatically cleaving peptides like the glucagon-like peptide-1 (GLP-1), neuropeptide Y (NPY), and peptide YY (PYY), DPP-4 acts as a signaling scaffold for pathways associated with thermogenesis, inflammation, and cellular senescence. Numerous preclinical findings demonstrate the ability of DPP-4 inhibition to increase markers of browning, improve insulin sensitivity, and reprogram WAT to an anti-inflammatory and thermogenic phenotype. Clinical evidence is more modest, often focusing on glycemic outcomes instead of examining adipose remodeling resulting from DPP-4 inhibition. The objectives of this review will summarize the existing mechanistic basis linking DPP-4 to adipose browning and will further examine the therapeutic implications of inhibiting DPP-4 in the context of obesity, including translation issues, and optimized pharmacological strategies and rational combination therapies.