Background: Maintaining glucose homeostasis involves pancreatic beta cells receiving nutritional signals from various organs and tissues to regulate insulin production and secretion. Disruption of this coordination is linked to diabetes development. Brown fat (BAT) significantly benefits glucose regulation through their thermogenic properties, particularly via uncoupling protein 1 (UCP1). However, it is unclear whether it can influence beta cell function to improve glucose homeostasis and what the underlying mechanisms are.
Methods: Male 8-week-old UCP1KO mice and littermate WT controls were fed a chow diet. Metabolic profiling included measurements of body weight, glucose levels, GTT, and ITT. Islets were isolated for glucose-stimulated insulin secretion (GSIS) to assess beta cell function. A separate batch of chow-fed WT mice underwent a BAT removal regimen, and GTT was performed and compared with sham-treated and UCP1KO mice. Islet qPCR analysis and immunofluorescence staining on brain and pancreas was performed to investigate molecular mechanisms.
Results: UCP1KO mice exhibited decreased basal insulin levels and impaired glucose tolerance. Similarly, the BAT removal WT mice showed a strong trend towards impaired glucose tolerance. Mechanistically, GSIS showed significantly impaired insulin secretion after three bouts of high glucose challenge in UCP1KO islets, associated with significantly downregulated beta cell-specific transcription factors, membrane receptors and genes important in glucose metabolism. Notably, tyrosine hydroxylase (TH) expression in the hypothalamic paraventricular nucleus (PVN) of UCP1KO mice was significantly elevated, leading to an increase in TH expression in pancreatic islets.
Conclusions: Ablation of UCP1 leads to impaired glucose tolerance and insulin secretion in mice, partly due to increased sympathetic innervation in the pancreas and increased sympathetic activity from the brain PVN, inhibiting insulin release. This study demonstrates, for the first time, that thermogenic adipose tissue affects pancreatic islet function via the modulation of the PVN TH pathway.