Background: Pancreatic β-cells maintain glucose homeostasis by coordinating communication among organs and integrating nutritional and neural cues to regulate insulin secretion. Brown adipose tissue (BAT) is well known for regulating systemic metabolism and protecting against obesity through UCP1-mediated thermogenesis. However, whether BAT influences pancreatic β-cell function and glucose homeostasis has not been fully established.
Methods: Male UCP1KO mice and wild-type littermates were studied under chow diet conditions. Metabolic phenotyping was conducted, including glucose and insulin tolerance tests (GTT/ITT) and fasting insulin levels during GTT. β-cell function was assessed by glucose-stimulated insulin secretion (GSIS) from isolated islets. Immunofluorescence staining was performed on brain and pancreatic sections to assess tyrosine hydroxylase (TH) expression in the brainstem locus coeruleus (LC) and TH-positive sympathetic innervation of pancreatic islets.
Results: UCP1KO mice displayed impaired glucose tolerance but unchanged insulin tolerance. This impaired glucose tolerance was due to insufficient insulin secretion during GTT. Isolated islets from UCP1KO mice showed no change in GSIS. Strikingly, TH-positive neurons were activated in the LC in the brainstem, and TH expression was also found increased in the pancreatic sections of UCP1KO mice, indicating increased SNS activation of β-cells, leading to decreased insulin secretion. However, this SNS induced impaired GTT was diminished under thermoneutral conditions. UCP1KO mice showed no difference in GTT at thermoneutrality, indicating the role of SNS in modulating glucose homeostasis.
Conclusions: Absence of UCP1 mimics dysfunctional BAT, which leads to impaired β-cell insulin secretion and glucose tolerance, at least in part through enhanced sympathetic drive from LC TH neurons to pancreatic islets. These findings provide emerging insights into a BAT–brain–islet axis that integrates neural pathways to regulate glucose homeostasis.