Krüppel-like factor 4 in transcriptional control of the three unique isoforms of Agouti-related peptide in mice.

Agouti-related peptide (AgRP/) within the hypothalamic arcuate nucleus (ARC) contributes to the control of energy balance, and dysregulated may contribute to metabolic adaptation during prolonged obesity. In mice, three isoforms of are encoded via distinct first exons. (ENSMUST00000005849.11) contributed 95% of total in mouse ARC, whereas (ENSMUST00000194654.2) dominated in placenta (73%). Conditional deletion of from -expressing cells ( mice) reduced mRNA and increased energy expenditure but had no effects on food intake or the relative abundance of isoforms in the ARC. Chronic high-fat diet feeding masked these effects of deletion, highlighting the context-dependent contribution of KLF4 to control. In the GT1-7 mouse hypothalamic cell culture model, which expresses all three isoforms of (including , ENSMUST00000194091.6), inhibition of extracellular signal-regulated kinase (ERK) simultaneously increased KLF4 binding to the promoter and stimulated expression. In addition, siRNA-mediated knockdown of reduced expression of . We conclude that the expression of individual isoforms of in the mouse is dependent upon cell type and that KLF4 directly promotes the transcription of via a mechanism that is superseded during obesity. In mice, three distinct isoforms of Agouti-related peptide are encoded via distinct first exons. In the arcuate nucleus of the hypothalamus, Krüppel-like factor 4 stimulates transcription of the dominant isoform in lean mice, but this mechanism is altered during diet-induced obesity.