Krüppel-like factor 4 in transcriptional control of the three unique isoforms of Agouti-related peptide in mice. Physiol Genomics 2024 Mar 01;56(3):265-275
Date
12/25/2023Pubmed ID
38145289Pubmed Central ID
PMC10866620DOI
10.1152/physiolgenomics.00042.2023Scopus ID
2-s2.0-85185200180 (requires institutional sign-in at Scopus site)Abstract
Agouti-related peptide (AgRP/Agrp) within the hypothalamic arcuate nucleus (ARC) contributes to the control of energy balance, and dysregulated Agrp may contribute to metabolic adaptation during prolonged obesity. In mice, three isoforms of Agrp are encoded via distinct first exons. Agrp-A (ENSMUST00000005849.11) contributed 95% of total Agrp in mouse ARC, whereas Agrp-B (ENSMUST00000194654.2) dominated in placenta (73%). Conditional deletion of Klf4 from Agrp-expressing cells (Klf4Agrp-KO mice) reduced Agrp mRNA and increased energy expenditure but had no effects on food intake or the relative abundance of Agrp isoforms in the ARC. Chronic high-fat diet feeding masked these effects of Klf4 deletion, highlighting the context-dependent contribution of KLF4 to Agrp control. In the GT1-7 mouse hypothalamic cell culture model, which expresses all three isoforms of Agrp (including Agrp-C, ENSMUST00000194091.6), inhibition of extracellular signal-regulated kinase (ERK) simultaneously increased KLF4 binding to the Agrp promoter and stimulated Agrp expression. In addition, siRNA-mediated knockdown of Klf4 reduced expression of Agrp. We conclude that the expression of individual isoforms of Agrp in the mouse is dependent upon cell type and that KLF4 directly promotes the transcription of Agrp via a mechanism that is superseded during obesity.NEW & NOTEWORTHY In mice, three distinct isoforms of Agouti-related peptide are encoded via distinct first exons.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.
Author List
Ritter ML, Wagner VA, Balapattabi K, Opichka MA, Lu KT, Wackman KK, Reho JJ, Keen HL, Kwitek AE, Morselli LL, Geurts AM, Sigmund CD, Grobe JLAuthors
Aron Geurts PhD Professor in the Physiology department at Medical College of WisconsinJustin L. Grobe PhD Professor in the Physiology department at Medical College of Wisconsin
Anne E. Kwitek PhD Professor in the Physiology department at Medical College of Wisconsin
Lisa Morselli MD, PhD Assistant Professor in the Medicine department at Medical College of Wisconsin
John J. Reho Research Scientist II in the Physiology department at Medical College of Wisconsin
Curt Sigmund PhD Chair, Professor in the Physiology department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
Agouti-Related ProteinAnimals
Hypothalamus
Mice
Neurons
Obesity
Protein Isoforms
