1. IDOL regulates systemic energy balance through control of neuronal VLDLR expression
- Author
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Lee, Stephen D, Priest, Christina, Bjursell, Mikael, Gao, Jie, Arneson, Douglas V, Ahn, In Sook, Diamante, Graciel, van Veen, J Edward, Massa, Megan G, Calkin, Anna C, Kim, Jason, Andersén, Harriet, Rajbhandari, Prashant, Porritt, Michelle, Carreras, Alba, Ahnmark, Andrea, Seeliger, Frank, Maxvall, Ingela, Eliasson, Pernilla, Althage, Magnus, Åkerblad, Peter, Lindén, Daniel, Cole, Tracy A, Lee, Richard, Boyd, Helen, Bohlooly-Y, Mohammad, Correa, Stephanie M, Yang, Xia, Tontonoz, Peter, and Hong, Cynthia
- Subjects
Medical Biochemistry and Metabolomics ,Medical Physiology ,Biomedical and Clinical Sciences ,Nutrition and Dietetics ,Nutrition ,Genetics ,Digestive Diseases ,Liver Disease ,Obesity ,2.1 Biological and endogenous factors ,1.1 Normal biological development and functioning ,Oral and gastrointestinal ,Stroke ,Metabolic and endocrine ,Animals ,Blood Glucose ,Diet ,Energy Metabolism ,Hypothalamus ,Insulin Resistance ,Mice ,Mice ,Knockout ,Neurons ,Receptors ,LDL ,Ubiquitin-Protein Ligases ,Medical biochemistry and metabolomics ,Medical physiology ,Nutrition and dietetics - Abstract
Liver X receptors limit cellular lipid uptake by stimulating the transcription of Inducible Degrader of the LDL Receptor (IDOL), an E3 ubiquitin ligase that targets lipoprotein receptors for degradation. The function of IDOL in systemic metabolism is incompletely understood. Here we show that loss of IDOL in mice protects against the development of diet-induced obesity and metabolic dysfunction by altering food intake and thermogenesis. Unexpectedly, analysis of tissue-specific knockout mice revealed that IDOL affects energy balance, not through its actions in peripheral metabolic tissues (liver, adipose, endothelium, intestine, skeletal muscle), but by controlling lipoprotein receptor abundance in neurons. Single-cell RNA sequencing of the hypothalamus demonstrated that IDOL deletion altered gene expression linked to control of metabolism. Finally, we identify VLDLR rather than LDLR as the primary mediator of IDOL effects on energy balance. These studies identify a role for the neuronal IDOL-VLDLR pathway in metabolic homeostasis and diet-induced obesity.
- Published
- 2019