Discrepancies in β-adrenergic receptor signaling and cAMP pathway in high-fat simple carbohydrate diet-fed C57BL/6J mice: implications for metabolic syndrome pathophysiology

The regulation of beta-adrenergic receptors (β-ARs) is crucial for maintaining pancreatic function and metabolic balance. However, the rising incidence of metabolic syndrome (MetS) highlights the need to understand how a high-fat simple carbohydrate (HFSC) diet affects β-AR signaling in the pancreas. Despite its potential significance, this aspect remains underexplored. We hypothesized that MetS-induced alterations in β-AR subtypes may disrupt regulatory mechanisms, potentially affecting adenylate cyclase coupling. This study investigated the impact of an HFSC diet on β-AR subtype expression and downstream signaling in pancreatic islets. MetS was induced in C57BL/6J mice through a 150-day HFSC diet. Metabolic changes were assessed through anthropometric parameters, blood glucose levels, lipid profiles, and pancreatic islet morphology. β-AR subtype expression (Adrb1/ADRB1, Adrb2/ADRB2, Adrb3/ADRB3), cAMP levels, and receptor localization were evaluated using quantitative real-time PCR (qRT-PCR), Western blotting, and immunofluorescence. The HFSC diet led to metabolic disturbances and pancreatic inflammation. Adrb1 mRNA expression was elevated (p < 0.001), but β1-AR localization did not show a corresponding increase. Both β2-AR transcription and translation were downregulated (p < 0.001). Although β3-AR protein levels were markedly increased (p < 0.001), cAMP levels were significantly reduced (p < 0.01). These findings indicate significant β-AR dysregulation under metabolic stress. Altered β1-AR and β2-AR expression, along with increased but functionally insufficient β3-AR signaling, suggest impaired adrenergic regulation in pancreatic islets during MetS. This study contributes to understanding MetS pathophysiology and highlights the relevance of β-AR signaling as a potential therapeutic target. Graphical abstract illustrating the metabolic alterations and beta-adrenergic receptor (β-AR) dysregulation induced by high-fat simple carbohydrate (HFSC) diet in C57BL/6J mice. HFSC feeding leads to increased adiposity, hyperglycemia, and dyslipidemia, accompanied by disrupted β-AR expression and signaling in pancreatic islets. These combined effects may contribute to impaired cAMP regulation and early pancreatic dysfunction associated with metabolic syndrome progression.