Abstract
ABSTRACTThe seipin gene (BSCL2) was originally identified in humans as a loss-of-function gene associated with congenital generalized lipodystrophy type 2 (CGL2). Neuronal seipin-knockout (seipin-nKO) mice display a depression-like phenotype with a reduced level of hippocampal peroxisome proliferator-activated receptor gamma (PPARγ). The present study investigated the influence of seipin deficiency on adult neurogenesis in the hippocampal dentate gyrus (DG) and the underlying mechanisms of the effects. We show that the proliferative capability of stem cells in seipin-nKO mice was substantially reduced compared to in wild-type (WT) mice, and that this could be rescued by the PPARγ agonist rosiglitazone (rosi). In seipin-nKO mice, neuronal differentiation of progenitor cells was inhibited, with the enhancement of astrogliogenesis; both of these effects were recovered by rosi treatment during early stages of progenitor cell differentiation. In addition, rosi treatment could correct the decline in hippocampal ERK2 phosphorylation and cyclin A mRNA level in seipin-nKO mice. The MEK inhibitor U0126 abolished the rosi-rescued cell proliferation and cyclin A expression in seipin-nKO mice. In seipin-nKO mice, the hippocampal Wnt3 protein level was less than that in WT mice, and there was a reduction of neurogenin 1 (Neurog1) and neurogenic differentiation 1 (NeuroD1) mRNA, levels of which were corrected by rosi treatment. STAT3 phosphorylation (Tyr705) was enhanced in seipin-nKO mice, and was further elevated by rosi treatment. Finally, rosi treatment for 10 days could alleviate the depression-like phenotype in seipin-nKO mice, and this alleviation was blocked by the MEK inhibitor U0126. The results indicate that, by reducing PPARγ, seipin deficiency impairs proliferation and differentiation of neural stem and progenitor cells, respectively, in the adult DG, which might be responsible for the production of the depression-like phenotype in seipin-nKO mice.
Highlights
Congenital generalized lipodystrophy (CGL) is an autosomal recessive disorder characterized by a near-total loss of adipose tissue, severe insulin resistance, hypertriglyceridemia and fatty liver (Agarwal and Garg, 2003)
They show that the proliferative capability of stem cells and the neuronal differentiation of progenitor cells are significantly reduced in seipin-nKO mice, but that these phenotypes can be rescued by treatment with the PPARγ agonist rosiglitazone
Further work is needed to confirm and extend these findings, the present study raises the possibility that the therapeutic use of PPARγ agonists might help to limit or reverse the intellectual deficiency seen in individuals with congenital generalized lipodystrophy type 2 (CGL2) by reinstating hippocampal neurogenesis
Summary
Congenital generalized lipodystrophy (CGL) is an autosomal recessive disorder characterized by a near-total loss of adipose tissue, severe insulin resistance, hypertriglyceridemia and fatty liver (Agarwal and Garg, 2003). An interesting phenotypic difference between individuals with CGL1 and CGL2 is that those with CGL2 have an increased prevalence of mild mental retardation, which is not usually observed in CGL1 (Agarwal et al, 2003). Clinical studies (Rajab et al, 2003; Van Maldergem et al, 2002) have reported the delayed cognitive development and intellectual impairment in individuals with CGL2. The seipin gene was originally identified as a loss-of-function mutation in individuals with CGL2 (Van Maldergem et al, 2002). It has been speculated that seipin is necessary for developmental processes in the brain
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