Abstract Individual variation in sexually differentiated brain structures may contribute to variation in sex-related behavior, but the developmental origins of such individual differences remain unclear. We first examined several sexually dimorphic nuclei in the preoptic area and bed nucleus of the stria terminalis to identify brain structures associated with individual variation in partner preference in adult mice. In males, female-directed partner preference was consistently associated with the characteristics of the sexually dimorphic nucleus of the preoptic area (SDN-POA), including its volume, number of calbindin-D28K (Calb)-positive neurons, and neuronal activity. Therefore, we examined whether natural variation in fetal testosterone was associated with development of this nucleus. At embryonic day 18.5, higher fetal testosterone was associated with increased expression of genes related to GABAergic neuronal differentiation and phenotype in hypothalamic tissue and with altered spatial organization of developing GABAergic neurons around the presumptive SDN-POA. A longitudinal follow-up showed that males exposed to higher fetal testosterone concentrations during the late fetal period subsequently developed a larger SDN-POA and stronger female-directed partner preference. They also showed more frequent tail rattling toward unfamiliar males and initiated sexual behavior more readily toward receptive females. The difference in partner preference disappeared after orchiectomy and re-emerged following testosterone replacement despite comparable circulating testosterone concentrations between the fetal testosterone groups. These findings suggest that natural variation in fetal testosterone during brain sexual differentiation contributes to individual differences in SDN-POA development and the expression of adult male social behaviors.
Abstract Imeglimin is a novel antidiabetic agent that improves glycemic control by enhancing glucose-stimulated insulin secretion (GSIS). Although previous studies have suggested that imeglimin acts through increased NAD+ production and CD38-dependent calcium signaling, the mechanism responsible for its insulinotropic effect at clinically relevant concentrations remains incompletely understood. In particular, how clinically relevant concentrations of imeglimin affect mitochondrial bioenergetics in pancreatic beta cells remains unclear. To address this question, we examined the effects of imeglimin in normal glucose-tolerant C57BL/6 mice and isolated mouse islets using concentrations corresponding to clinically achieved plasma levels. Chronic administration of imeglimin at a pharmacological dose corresponding to clinically relevant exposure enhanced GSIS without affecting insulin sensitivity in vivo. In isolated islets, continuous exposure to imeglimin at a clinically relevant concentration (10 μmol/L) significantly enhanced GSIS, whereas supraphysiological imeglimin (1000 μmol/L) reduced GSIS. Mechanistically, 10 μmol/L imeglimin increased mitochondrial respiration, mitochondrial membrane potential, and ATP production while suppressing glucose-induced reactive oxygen species generation. Notably, blue native polyacrylamide gel electrophoresis revealed that clinically relevant concentrations of imeglimin promoted mitochondrial respiratory supercomplex formation, whereas supraphysiological concentrations did not. These findings suggest that mitochondrial respiratory supercomplex formation may contribute to the insulinotropic action of imeglimin. Our results provide new insight into mitochondrial regulation of pancreatic beta cell function and suggest that enhancement of mitochondrial supercomplex assembly represents a potential mechanism by which clinically relevant imeglimin improves beta cell function, in addition to previously proposed NAD+-dependent pathways.
