Paraventricular NUCB2 is mediating central nervous metformin effects on food intake and energy expenditure in rats

Hypothesis This work aimed to clarify whether nesfatin-1, a peptide of the paraventricular nucleus (PVN) involved in central nervous energy balance regulation, is a mediator for central effects of metformin on energy homeostasis. Focussing in particular on food intake and energy expenditure the central induction of weight loss by metformin was studied.

Methods An adeno-associated virus vector encoding short hairpin RNAs targeting nucleobindin-2 (NUCB2) as precursor of nesfatin-1 was used to knockdown NUCB2 in the PVN of rats. After a successful knockdown, 30 µg of metformin or vehicle were intracerebroventricularly injected. Animals were subjected to direct calorimetry measuring dry heat loss and infrared thermography accounting for thermoregulation. Food intake and body weight were monitored. The underlying molecular mechanisms were studied by gene expression analysis in the brain and adipose tissues.

Results Metformin injection led to a decrease in food intake in control but not in NUCB2 knockdown animals. Additionally, an increase in dry heat loss could only be observed in control animals. Furthermore, phenotypical characterization of the knockdown highlights the importance of paraventricular nesfatin-1 in energy homeostatic processes in general: a decreased energy expenditure together with a decreased brown adipose tissue temperature was observed, while body core temperature and heat dissipation remained unchanged. An additional peripheral effect of the paraventricular NUCB2 knockdown on adipose tissue was revealed.

Conclusion Overall, this work demonstrates a central role of NUCB2 / nesfatin-1 in regulating energy expenditure and food intake and reveal the paraventricular nesfatinergic system as possible mediator for metformin’s actions on energy balance.

Publication History

Article published online:
06 May 2021