Transcriptional analysis of brown adipose tissue in leptin-deficient mice lacking inducible nitric oxide synthase: evidence of the role of Med1 in energy balance.

Leptin and nitric oxide (NO) are implicated in the control of energy homeostasis. The aim of the present study was to examine the impact of the absence of the inducible NO synthase (iNOS) gene on the regulation of energy balance in ob/ob mice analyzing the changes in gene expression levels in brown adipose tissue (BAT). Double knockout (DBKO) mice simultaneously lacking the ob and iNOS genes were generated and the expression of genes involved in energy balance including fatty acid and glucose metabolism as well as mitochondrial genes were analyzed by microarrays. DBKO mice exhibited an improvement in energy balance with a decrease in body weight (P < 0.001), total fat pads (P < 0.05), and food intake (P < 0.05), as well as an enhancement in BAT function compared with ob/ob mice. To better understand the molecular events associated with this improvement, BAT gene expression was analyzed. Of particular interest, gene expression levels of the key subunit of the Mediator complex Med1 was upregulated (P < 0.05) in DBKO mice. Real-time PCR and immunohistochemistry further confirmed this data. Med1 is implicated in adipogenesis, lipid metabolic and biosynthetic processes, glucose metabolism, and mitochondrial metabolic pathways. Med1 plays an important role in the transcriptional control of genes implicated in energy homeostasis, suggesting that the improvement in energy balance and BAT function of the DBKO mice is mediated, at least in part, through the transcription coactivator Med1.