Supporting Data for “Gut dysbiosis-induced suppression of pulmonary SCGB3A2 promotes adipogenesis in obesity: a potential target for Chinese Medicine Panax Notoginseng.”

Microbiota from obese donors increased circulating ceramides, reduced SCGB3A2, and worsened adiposity, adipose inflammation, insulin resistance, and glucose intolerance in recipient mice. Human metagenomic analysis further identified microbial taxa associated with circulating ceramides and SCGB3A2, although these associations did not establish species-level causality.</p><p dir="ltr">Recombinant SCGB3A2 administration attenuated HFD-induced weight gain, adiposity, adipocyte hypertrophy, adipose inflammation, insulin resistance, and glucose intolerance, whereas AAV9-mediated <i>Scgb3a2</i> knockdown aggravated these abnormalities.

Neither intervention materially affected food intake. SCGB3A2 did not directly alter lipid accumulation or major lipid-metabolism genes in differentiated adipocytes. Instead, single-cell RNA sequencing identified adipose tissue macrophages as an important responsive population.

SCGB3A2 reduced proinflammatory and lipid-associated macrophage populations and, in lipid-loaded bone marrow-derived macrophages, enhanced fatty acid oxidation and reduced intracellular free fatty acids. Polyguanylic acid diminished these macrophage and whole-body effects, supporting the involvement of MARCO-associated scavenger receptor activity without establishing direct SCGB3A2–MARCO binding.</p><p dir="ltr">Circulating ceramides were elevated in human and murine obesity and inversely associated with SCGB3A2.

In pulmonary epithelial cells, ceramide reduced SCGB3A2 expression and promoter activity and impaired the binding of the transcription factor NKX2.1 to the SCGB3A2 promoter. In mice, inhibition of de novo ceramide synthesis with FTY720 reduced circulating ceramides, restored SCGB3A2 expression, and improved metabolic dysfunction. These benefits were attenuated by <i>Scgb3a2</i> knockdown, supporting a functional role for SCGB3A2 downstream of ceramide inhibition.</p><p dir="ltr">Finally, an exploratory open-label intervention in 20 individuals with obesity showed that three months of <i>Panax notoginseng</i> saponin (PNS) administration was associated with reductions in body weight, adiposity, and circulating ceramides, and an increase in SCGB3A2.

Post-intervention microbiota conferred metabolic protection to HFD-fed recipient mice, whereas heat inactivation or Scgb3a2 knockdown diminished these effects, suggesting that viable components of the PNS-modified microbiota acted in part through SCGB3A2.</p><p dir="ltr">Collectively, these findings define a gut–lung–adipose axis in which obesity-associated microbial dysbiosis contributes to ceramide accumulation, suppression of pulmonary SCGB3A2, and impaired macrophage lipid handling.

SCGB3A2 therefore represents a candidate endocrine regulator and potential therapeutic target in obesity.</p><p><br></p>