The Effet Of BDNF And TrkB On Mouse Body Weight Control And Energy Expenditure

Brain-derived neurotrophic factor（BDNF） is a member of neurotrophic family, which binds with its receptor tropomyosin-related kinase receptor B（TrkB） to promote cell signal transmission between each other by activating phospholipase C-gamma（PLC-γ）,mitogen-activated protein kinase（MAPK） and phosphatidylinositol-3 kinase（PI3K）, and then regulates neuron differentiation and dendrite plasticity. So it is involved in many diseases such as Parkinson disease, Alzheimer’s disease and Huntington’s disease et al. Hypothalamus is a critical area, which controls animal food intake and energy homeostasis. Bdnf and TrkB gene are widely expressed in ventromedial hypothalamus（VMH）, dorsomedial hypothalamus（DMH）, lateral hypothalamus（LH） and paraventricular hypothalamus（PVH）. However, only TrkB is expressed in arcuate nucleus（ARC）, not Bdnf, and they have different role in different hypothalamic area. So far, the effect and mechanism of Bdnf/TrkB on obesity procession is still needed further study. In this study, we used Cre-loxp system to delete Bdnf or TrkB in specific area or time to find out the reason that Bdnf or TrkB controls body weight, food intake or energy expenditure. Theses finding may be the base of obesity and relative disease.We got following results:1. The effect of Bdnf in the VMH on mouse body weight control.Firstly, Bdnf was deleted in VMH during embryo-genesis by using Sf1-Cre transgenic mouse crossing with Bdnf^lox/loxmouse. In contrast, the Bdnf gene was deleted in adult VMH by using Cre-expressing virus, which excluded developmental problem. Results showed:（1） the deletion efficiency was more than 90% in the Sf1-Cre; Bdnf^lox/lox mouse with immunohistochemistry and in situ hybridization test,（2） deletion of Bdnf gene in the VMH during embryo-genesis had no effect on mouse body weight. It may be due to developmental compensation from other relative area that controls appetite or energy expenditure,（3） deleted Bdnf in VMH of adult mouse by injection with AAV-Cre-GFP virus,（4） tt showed that deleting adult VMH Bdnf significantly increased mouse body weight and daily food intake.2. The effect of Bdnf in VMH on mouse energy expenditure and loco-motor activity.Bdnf in VMH regulated mouse body weight and food intake from last chapter. However,whether it regulates mouse energy expenditure is still not clear and needs more studies. In thissection, we used CLMAS system to determine energy expenditure of adult VMH Bdnf deletion mouse in order to find out the role of Bdnf in energy expenditure. Results showed that:（1） the lean mass energy expenditure of Bdnf deletion mice was significant lower than its control group. However, individual mouse energy expenditure was higher,（2） their loco-motor activity was decreased in Bdnf deletion mouse,（3） Bdnf in VMH participated in controlling mouse body weight by regulating its daily food intake. However, developmental problem will be a negative factor,（4） there was no correlation between Bdnf in DMH and mouse body weight.3. The effect of Bdnf on body weight control and energy expenditure out of PVH and VMH area.We deleted Bdnf gene out of PVH by using Nkx2.1-Cre mouse, which Bdnf gene was also deleted during embryogenesis. Results showed that:（1） We obtained Nkx2.1-Cre;Bdnf^lox/loxmice by crossing, their body weight were increased comparing with their control group,（2） They had normal daily food intake and fasting glucose,（3） Compared with their control group, the energy expenditure of Nkx2.1-Cre; Bdnf^lox/lox mice were decreased,（4） The basic metabolic rate and heat production of brawn fat in Nkx2.1-Cre; Bdnf^lox/loxmice were not changed, but the activity of sympathetic nervous system in Nkx2.1-Cre; Bdnf^lox/lox mice were decreased.4. The role of TrkB on mouse body weight control.We deleted TrkB gene by using LepR-Cre mouse to learn the effect of TrkB on monitoring mouse body weight and energy balance. Results showed that:（1） Mice body weight were significant increased in TrkB deleted mouse, and there was no difference in daily food intake and fasting glucose,（2） Their energy expenditure were decreased in TrkB deleted mice, not loco-motor activities,（3） The p-STST3 expression was lower in ARC, DMH and PMV, but higher in VMH when TrkB was deleted in leptin receptor neurons.All in all, hypothalamus different Bndf has different role in regulating body weight, food intake and energy expenditure. We found that PVH and VMH Bdnf gene had key role in controlling mouse food intake. Out of PVH and VMH area, other hypothalamic Bdnf played an important role in regulating energy expenditure. As a receptor of Bdnf, TrkB was also involved in body weight control by itself. Leptin signal pathway would be damaged in LepR-Cre; fB/fB mouse, causing TrkB was deleted in leptin receptor expression neurons, and the mutant mouse would be obesity.