Glibenclamide restores dopaminergic reward circuitry in obese mice through interscauplar brown adipose tissue.

BACKGROUND

Obesity, a critical feature in metabolic disorders, is associated with medical depression. Recent evidence reveals that brown adipose tissue (BAT) activity may contribute to mood disorders, Adenosine triphosphate (ATP)-sensitive K (K) channels regulate BAT sympathetic nerve activity. However, the mechanism through which BAT activity affects mood control remains unknown. We hypothesized the BAT is involved in depressive-like symptoms regulation by trafficking K channels.

METHODS

Eight-week-old male B6 mice fed with a high-fat diet (HFD) for 12 weeks exhibited characteristics of metabolic disorders, including hyperglycemia, hyperinsulinemia, and hyperlipidemia, as well as depressive symptoms. In this study, we surgically removed interscapular BAT in mice, and these mice exhibited immobility in the forced swim test and less preference for sugar water compared with other mice. To delineate the role of K channels in BAT activity regulation, we implanted a miniosmotic pump containing glibenclamide (GB), a K channel blocker, into the interscapular BAT of HFD-fed mice.

RESULTS

GB infusion improved glucose homeostasis, insulin sensitivity, and depressive-like symptoms. K channel expression was lower in HFD-fed mice than in chow-fed mice. Notably, GB infusion in HFD-fed mice restored K channel expression.

CONCLUSION

K channels are functionally expressed in BAT, and inhibiting BAT-K channels improves metabolic syndromes and reduces depressive symptoms through beta-3-adrenergic receptor-mediated protein kinase A signaling.