The Genetics of Brown Adipocyte Induction in White Fat Depots

Evidence that adult humans have functional brown adipose tissue has stirred interest in the possibility that the impressive effectiveness of induction of brown adipocytes to reduce obesity in mice may be translated to the human condition. A major focus recently on the identification of signaling and transcription factor that stimulate the induction of brown adipocytes has come from transgenic and gene KO models. However, these models have created a very complex picture of the regulatory mechanisms for brown fat induction. In this review insights into the critical regulatory pathways involved in brown adipocyte induction in the retroperitoneal fat depot of mice are described from quantitative trait locus (QTL) analysis of allelic variability determining Ucp1 levels and brown adipocyte induction in A/J vs. B6 mice. The key observation is that recombinant genotypes, found in recombinant inbred stains and backcross and intercross progeny, show transgressive variation for Ucp1 mRNA levels. These genetic crosses also show that the levels of Ucp1 mRNA are determined by interactions that control the levels of PPARα, PGC-1α, and type 2 deiodinase (DIO2) and that each factor is controlled by a subset of QTLs that also control Ucp1 expression. These results indicate that induction of Ucp1 in the retroperitoneal fat depot involves synergy between signaling and transcription factors that vary depending upon the environmental conditions. Inherent in this model is the idea that there is a high level of redundancy that can involve any factor with the potential to influence expression of the core factors, PPARα, PGC-1a, and DIO2.