NFIL3-mediated non-shivering thermogenesis via calcium cycling

Abstract

Non-shivering thermogenesis (NST) plays a crucial role in maintaining body temperature in mammals, particularly in response to cold exposure. The primary tissue responsible for NST is brown adipose tissue (BAT), which is derived from the same developmental precursor as skeletal muscle myocytes. Interestingly, brown adipocytes and skeletal myocytes share many molecular features, but the underlying biological significance is poorly understood. This project focusses on elucidating the role of the transcription factor E4bp4 (Also, known as nuclear factor interleukin 3, Nfil3) in thermogenic function. Our preliminary data show that Nfil3 expression was induced in response to cold exposure in BAT and skeletal muscle of mice. We found that NFIL3 overexpression (Nfil3-OE) using adeno-associated virus in BAT, led to a higher BAT temperature, independent of adrenergic stimuli. RNA-seq analysis of BAT revealed upregulation of genes related to calcium cycling. Notably, Serca1 and Myoregulin were the most upregulated genes, suggesting the involvement of calcium cycling in enhancing BAT temperature in the Nfil3-OE. Intriguingly, we also found that Nfil3-OE led to higher mRNA expression of myogenic genes in BAT compared to controls. These findings led us to propose the following model: 1) cold exposure enhances the expression of Nfil3 in BAT and skeletal muscle as an adaptive mechanism of NST; 2) Nfil3 integrates distinct transcriptional complexes in BAT and skeletal muscle. Our propose is to understand the molecular mechanisms related to Nfil3-mediated thermogenesis.