Neuroendocrine Crosstalk of Berberine: Targeting NPY, 5-HT, and Leptin Signaling Axes via Optimized Nanoemulsion for Appetite Control and Energy Balance
Egyptian Journal of Chemistry, vol.69, no.11, pp.583-602, 2026 (ESCI, Scopus)
- Publication Type: Article / Article
- Volume: 69 Issue: 11
- Publication Date: 2026
- Doi Number: 10.21608/ejchem.2026.440012.12587
- Journal Name: Egyptian Journal of Chemistry
- Journal Indexes: Emerging Sources Citation Index (ESCI), Scopus
- Page Numbers: pp.583-602
- Keywords: Appetite regulation, Berberine, Nanoemulsion, NPY-5-HT-Leptin signaling, QbD optimization
- Ataturk University Affiliated: No
Abstract
Berberine, a natural isoquinoline alkaloid, modulates hypothalamic appetite circuitry by suppressing neuropeptide Y (NPY), enhancing serotonin (5-HT), and restoring leptin sensitivity; however, poor solubility, low oral exposure, and limited brain penetration constrain its efficacy. We engineered a berberine nanoemulsion to enhance solubilization, gastrointestinal uptake, and brain delivery. A Central Composite Design (CCD) with MCT, Tween-80, Transcutol P, and oleic acid optimized critical quality attributes particle size (PS), zeta potential (ZP), and entrapment efficiency (EE%). Ten prototypes were prepared and characterized. While the statistical model predicted F6 as the nominal optimum within the design space, checkpoint verification identified F8 as the superior experimental performer. F8 (MCT 5 g, Tween-80 15 g, Transcutol P 5 g, oleic acid 1 g per batch) achieved a mean diameter of 77.6 nm, ZP of-30 mV, and EE of 91%, indicating efficient loading and interfacial stabilization; FTIR confirmed excipient-drug compatibility, and TEM showed spherical, narrowly dispersed nanodroplets. An in-vivo study was then conducted based on the best response formulation (F8) and the best statistically predicted formulation (F6), evaluating neuroendocrine markers (NPY, 5-HT, and leptin), bodyweight trajectory and food intake (FER), supported by histopathological and metabolic biochemical analyses. In a high-fat/high-fructose rat model, oral F8 reduced bodyweight gain, improved indices of leptin responsiveness, elevated central 5-HT, and downregulated hypothalamic NPY, alongside favorable metabolic readouts. Collectively, these findings show that rationally engineered NEs can overcome practical biopharmaceutical barriers that have historically limited berberine, translating physicochemical optimization (small size, negative surface charge, high loading) into neuroendocrine efficacy. F8 emerges as a practical, scalable platform for brain-engaging delivery targeting the NPY-5-HT-leptin axes in obesity management.