IGF2BP2/IMP2-Deficient Mice Resist Obesity through Enhanced Translation of Ucp1 mRNA and Other mRNAs Encoding Mitochondrial Proteins

Abstract

Although variants in the IGF2BP2/IMP2 gene confer risk for Type 2 diabetes, IMP2, an RNA binding protein, is not known to regulate metabolism. Imp2−/− mice gain less lean mass after weaning and have increased lifespan. Imp2−/− mice are highly resistant to diet-induced obesity and fatty liver and display superior glucose tolerance and insulin sensitivity, increased energy expenditure and better defense of core temperature on cold exposure. Imp2−/− brown fat and Imp2−/− brown adipocytes differentiated in vitro contain more UCP1 polypeptide than Imp2+/+ despite similar levels of Ucp1 mRNA; the Imp2−/− adipocytes also exhibit greater uncoupled oxygen consumption. IMP2 binds the mRNAs encoding Ucp1 and other mitochondrial components, and most exhibit increased translational efficiency in the absence of IMP2. In vitro IMP2 inhibits translation of mRNAs bearing the Ucp1 untranslated segments. Thus IMP2 limits longevity and regulates nutrient and energy metabolism in the mouse by controlling the translation of its client mRNAs.

Dwarfism and Altered Craniofacial Development in Rabbits Is Caused by a 12.1 kb Deletion at the HMGA2 Locus

“…The upregulation of mtDNA transcripts did not reflect an increased copy number of mtDNA per cell ( Figure 3C), suggesting that HMGA2 has a direct or indirect role in regulating transcription of these genes. This functional role in mtDNA function is a novel finding not previously reported, but we note that the Igf2bp2-null mice show enhanced translation of Ucp1 mRNA and other mRNAs encoding mitochondrial proteins, which in turn is expected to affect transcription of mtDNA genes (Dai et al 2015).…”

“…These regions varied largely in size (750,000-6,250,000 bp, median 1,500,000 bp), and contained 646 genes in total. Within the most differentiated regions we noticed several genes previously associated with size or skeletal features in other species including LCORL-NCAPG (e.g., Gudbjartsson et al 2008;Rubin et al 2012;Tetens et al 2013;Sahana et al 2015), STC2 (Gagliardi et al 2005;Rimbault et al 2013), HOXD cluster (Zakany and Duboule 2007), COL11A1 (Li et al 1995;Annunen et al 1999), and IGF2BP2 (Dai et al 2015) (Figure 4A). …”

“…IGF2BP2 is an RNA-binding protein and was first described as a protein that binds the IGF2 mRNA, and it enhances IGF2 translation (Dai et al 2011). However, it also binds many other mRNAs and affects their translation (Li et al 2012;Dai et al 2015). Genome-wide association studies in humans have consistently shown that IGF2BP2 is associated with susceptibility to Type 2 Diabetes (e.g., Scott et al 2007;Zeggini et al 2007).…”

“…wild-type litter mates (Dai et al 2015). The fact that Hmga2-null (pygmy) mice show a much more drastic reduction in body size than Igf2bp2-null mice implies that the reduced Igf2bp2 expression in Hmga2-null mice and HMGA2 heterozygous (dwarf) rabbits can only partly be mediated by reduced IGF2BP2 expression.…”

IMP2 axonal localization, RNA interactome, and function in the development of axon trajectories

“…A related member of the IMP family is IMP2 (also known as Igf2bp2), but its function is not well characterized and has only recently begun to emerge. Several studies have now identified roles for IMP2 in adult energy metabolism, obesity and type 2 diabetes (Christiansen et al, 2009;Dai et al, 2015). Additionally, studies have implicated IMP2 in the regulation of myogenesis (Li et al, 2012) and differentiation of neocortical neural precursor cells (Fujii et al, 2013).…”