Abstract
The neuropeptide kisspeptin, encoded by the Kiss1 gene, binds the G- protein-coupled receptor Kiss1r (also known as GPR54) and is a novel player in the delicate balance of energy intake and expenditure. Mice that have a dysfunctional gene for Kiss1r develop an obese and diabetic phenotype. To further study how kisspeptin signalling impacts on energy balance, we investigated the relationship between absent kisspeptin signalling and locomotor behaviour in Kiss1rKO and wild type mice. Mice had free access to running wheels, and we examined the characteristics of wheel running over three weeks, and its flow-on effects on body mass. We subsequently examined dopaminergic neurons (via tyrosine hydroxylase (TH) staining) and hypothalamic inflammation (via Iba1 stained microglia). These studies also were performed following gonadectomy (GDX), to control for gonadal steroids. In intact males, the knockout (KO) mice covered only 10% of the distance travelled by wild-type (WT) per 24h (WT, 6363±643m; KO, 652±219m; P<0.0001). Moreover, in the WT there was a clear circadian pattern to the wheel-running activity, with most activity during lights off, while in the KO the running appeared randomly distributed across the 24h. After GDX, KO males continued to run significantly less than their WT counterparts (WT, 1652±474m; KO, 998±219m). In intact females, the KO mice covered only 23% of the distance travelled by WT per 24h (WT, 6030±747m; KO, 1379±364m; P<0.004). In OVX females, there was no difference between WT and KO mice (WT, 4150±1367m; KO, 3117±830m). Bodyweight analysis showed that access to running wheels prevented obesity usually seen in the Kiss1rKO mouse. In fact, in GDX males and females (at days 21 and 22 of wheel running) the KO mice were significantly lighter than WTs (at day 22: males, WT 28.67g; KO, 23.70g; P<0.05; females, WT, 27.38g; KO, 23.30g; P<0.05). Examination of TH revealed no significant difference in expression in the different genotypes in both sexes, in all areas examined. Investigation of Iba1 revealed significant higher counts in the male KO compared to the WT in the arcuate nucleus, but no difference in any other regions. We show that the locomotor activity in male and female Kiss1r KO mice is heavily dependent on the status of gonadal sex steroids. However, the lower running activity in male KO compared to WT remained after GDX, and this was paired with an elevated inflammation marker in the arcuate nucleus. Whether absent kisspeptin signalling acts as a significant regulator of voluntary activity is debatable, but patterns of locomotion behaviour could be disrupted, potentially involving circadian rhythm, this is under further investigation.
Strain screen and haplotype association mapping of wheel running in inbred mouse strains
