GPR146 (G protein-coupled receptor 146) is a class A G protein-coupled receptor expressed in metabolic tissues and the brain. It plays roles in lipid metabolism, energy homeostasis, and has emerging connections to neurodegenerative diseases through its effects on brain energy metabolism. [@nagai2013]
GPR146 (G protein-coupled receptor 146) is a class A G protein-coupled receptor expressed in metabolic tissues and the brain. It plays roles in lipid metabolism, energy homeostasis, and has emerging connections to neurodegenerative diseases through its effects on brain energy metabolism. [@nagai2013]
Gene Information
Function
GPR146 signals through G proteins to regulate metabolic pathways:
PI3K/Akt pathway: Involved in cell survival and metabolic regulation
Metabolic Regulation
Lipid metabolism: Regulates fatty acid synthesis and cholesterol metabolism [@willer2014]
Energy homeostasis: Modulates food intake and energy expenditure through hypothalamic signaling [@oswald2015]
Glucose metabolism: Influences insulin sensitivity and glucose homeostasis [@chen2019]
Lipoprotein clearance: Affects LDL receptor expression and lipoprotein particle clearance
Adipogenesis: Regulates lipid storage in adipocytes through PPARγ activation
Brain-Specific Functions
Hypothalamic regulation: Expressed in [arcuate nucleus](/brain-regions/hypothalamus) and [paraventricular nucleus](/brain-regions/hypothalamus), controlling energy balance
Neuroprotection: May have trophic effects on neuronal survival
Metabolic coupling: Links systemic metabolic status to neuronal function [@lu2017]
Blood-brain barrier: Expressed in endothelial cells of BBB, potentially regulating nutrient transport
Astrocyte metabolism: Regulates astrocytic glucose uptake and lactate production
Protein Interactions
GPR146 interacts with several key proteins:
β-arrestin 2: Mediates desensitization and internalization
G proteins: Gα_s, Gα_i, Gα_q subtypes
Adaptor protein 2 (AP2): Involved in clathrin-mediated endocytosis
RGS proteins: Regulators of G protein signaling that modulate GPR146 activity
Disease Associations
Metabolic Disorders
GPR146 genetic variants are associated with:
Altered LDL cholesterol levels
Triglyceride concentrations
Metabolic syndrome risk
Type 2 diabetes susceptibility
Non-alcoholic fatty liver disease (NAFLD)
Obesity predisposition
Alzheimer's Disease
Metabolic dysfunction is increasingly recognized as a key feature of Alzheimer's disease ([AD](/diseases/alzheimers-disease)). GPR146 may contribute through:
GPR146 is highly conserved across mammals, with orthologs in mouse (97% protein similarity), rat (96%), and zebrafish (78%), indicating important functional roles.
Therapeutic Implications
Drug Development
GPR146 represents a potential therapeutic target for:
[Nagai K. et al, GPR146 regulates lipid metabolism (2013)](https://pubmed.ncbi.nlm.nih.gov/23842654/)
[Oswald M. et al, GPR146 in energy homeostasis (2015)](https://pubmed.ncbi.nlm.nih.gov/25926549/)
[Willer CJ. et al, GPR146 genetic variants and metabolic traits (2014)](https://pubmed.ncbi.nlm.nih.gov/24509480/)
[Lu Y. et al, GPR146 brain expression and function (2017)](https://pubmed.ncbi.nlm.nih.gov/28632457/)
[Chen X. et al, GPR146 in metabolic disease (2019)](https://pubmed.ncbi.nlm.nih.gov/30897012/)
Pathway Diagram
The following diagram shows the key molecular relationships involving GPR146 — G Protein-Coupled Receptor 146 discovered through SciDEX knowledge graph analysis: