Obesity (Silver Spring, Md.)

Acute oral metformin enhances satiation and activates brainstem nesfatinergic neurons.

PMID 25236366


The study was designed to determine metformin effects on meal pattern, gastric emptying, energy expenditure, and to identify metformin-sensitive neurons and their phenotype. This study was performed on C57BL/6J and obese/diabetic (db/db) mice. Metformin (300 mg/kg) was administered by oral gavage. Food intake, meal pattern, oxygen consumption (VO2 ), and carbon dioxide production (VCO2 ) were obtained using an Oxylet Physiocage System. Gastric emptying assay and real-time RT-PCR from dorsal vagal complex extracts were also performed. C-Fos expression was used as a marker of neuronal activation. Phenotypic characterization of activated neurons was performed using either proopiomelanocortin (POMC)-Tau-Topaz GFP transgenic mice or NUCB2/nesfatin-1 and tyrosine hydroxylase (TH) labeling. Acute per os metformin treatment slowed down gastric emptying, reduced meal size, but not meal number in a leptin-independent manner, and transiently decreased energy expenditure in a leptin-dependent manner. Metformin specifically activated central circuitry within the brainstem, independently of vagal afferents. Finally, while POMC neurons seemed sparsely activated, we report that a high proportion of the c-Fos positive cells were nesfatinergic neurons, some of which coexpressing TH. Altogether, these results show that metformin modifies satiation by activating brainstem circuitry and suggest that NUCB2/nesfatin-1 could be involved in this metformin effect.