Single-nucleus RNA sequencing elucidates DHM's therapeutic mechanisms against HFD-induced BAT dysfunction
Obesity is associated with chronic diseases such as atherosclerosis and type 2 diabetes. In obesity, brown adipose tissue (BAT) activity declines, and lipid accumulation impairs its function. Dihydromyricetin (DHM) exhibits multiple biological functions, including inhibiting adipogenesis, promoting lipolysis, suppressing mitochondrial autophagy, and exerting anti-inflammatory and antioxidant effects, collectively demonstrating significant potential in obesity prevention and treatment. However, research on DHM's mechanisms in the BAT of obese mice remains limited.  In this study, we performed single-nucleus RNA sequencing (snRNA-seq) to systematically characterize obesity-induced BAT dysfunction and DHM's effects at single-cell resolution in high-fat diet (HFD)-fed C57BL/6J mice. The results demonstrated that DHM ameliorated HFD-induced brown adipocyte dysfunction by modulating energy balance in Ad3 and Ad5 adipocyte subpopulations, promoting lipolysis, suppressing pro-inflammatory factor expression, inhibiting extracellular matrix remodeling, and regulating adipocyte-perivascular cell interactions. These findings provide insights into DHM's role in preventing BAT dysfunction and support its clinical application for obesity. Overall design: snRNA-seq was conducted on three groups: normal diet (ND), high-fat diet (HFD), and HFD with DHM treatment (DHM_HFD). Bioinformatics analyses included multi-sample integration, cell annotation, pathway enrichment, transcription factor networks, and cell-cell communication prediction. These analyses identified dysfunctional adipocyte subpopulations and elucidated DHM's regulatory mechanisms.