Targeted Inactivation of GPR26 Leads to Hyperphagia and Adiposity by Activating AMPK in the Hypothalamus

Abstract

G-protein coupled receptor 26 (GPR26) is a brain-specific orphan GPCR with high expression in the brain region that controls satiety. Depletion of GPR26 has been shown to increase fat storage in C. elegans, whereas GPR26 deficiency in the hypothalamus is associated with high genetic susceptibility to the onset of obesity in mice. However, the metabolic function of GPR26 in mammals remains elusive. Herein, we investigated a role of GPR26 in regulating energy homeostasis by generating mice with targeted deletion of the GPR26 gene. We show that GPR26 deficiency causes hyperphagia and hypometabolism, leading to early onset of diet-induced obesity. Accordingly, GPR26 deficiency also caused metabolic complications commonly associated with obesity, including glucose intolerance, hyperinsulinemia, and dyslipidemia. Moreover, consistent with hyperphagia in GPR26 null mice, GPR26 deficiency significantly increased hypothalamic activity of AMPK, a key signaling event that stimulates appetite. In further support of a regulatory role of GPR26 in satiety, GPR26 knockout mice also demonstrate hypersensitivity to treatment of rimonabant, an endocannabinoid receptor-1 antagonist commonly used to treat obesity by suppressing appetite in humans. Together, these findings identified a key role of GPR26 as a central regulator of energy homeostasis though modulation of hypothalamic AMPK activation.

Genetic variants associated with motion sickness point to roles for inner ear development, neurological processes and glucose homeostasis

“…In addition, rs705145 ( P = 1.4 × 10 −21 ) is located just upstream of GPR26, encoding a G protein-coupled receptor. Mice with a deletion of the GPR26 gene develop hyperphagia and diet-induced obesity, which leads to metabolic complications linked to obesity including glucose intolerance, hyperinsulemia and dyslipidemia ( 27 ). The SNP rs4076764 ( P = 2.9 × 10 −9 ) is located upstream of RGS5, a regulator of G protein signaling.…”

G-protein coupled receptor 64 (GPR64) acts as a tumor suppressor in endometrial cancer

“…Several adhesion GPCRs have been shown to be involved in cell adhesion and migration, hereby influencing tumor progression [46]. GPR26 is a potent regulator of energy homeostasis through controlling hypothalamic AMP-activated protein kinase (AMPK) activation [48]. AMPK inhibits Cx43 expression in bladder smooth muscle cells [36].…”

Hunting for the function of orphan GPCRs – beyond the search for the endogenous ligand

“…GPR83 modulates ghrelin action and regulates systemic metabolism through other ghrelin‐independent pathways. Several other orphan 7TM proteins have also been linked to lipid metabolism and type 2 diabetes (Bhattacharyya et al ., ; Engel et al ., ; Chen et al ., ).…”

“…(), GPR82 ‐/‐ mice show reduced body weight, food intake and triglyceride levels, and increased insulin sensitivity and glucose tolerance. Similarly, GPR26 was a potent regulator of energy homeostasis through controlling hypothalamic AMP‐activated protein kinase (AMPK) activation and its targeted deletion caused hyperphagia and hypometabolism, which leads to early onset of diet‐induced obesity (Chen et al ., ). Similarly, GPR21 ‐/‐ animals are protected from high‐fat diet‐induced inflammation and reduced insulin sensitivity.…”

“…A constitutive coupling to Gα i proteins has been demonstrated for GPR20 (Hase et al ., ). The constant G‐protein coupling results in different downstream signalling activities as shown for the Gα s coupled GPR26 (Jones et al ., ), which inhibits AMPK activity at the hypothalamic level in order to prevent adiposity (Chen et al ., ) and increases CREB phosphorylation in the amygdala, revealing its possible regulatory role in anxiety (Zhang et al ., ). GPR12 promotes ERK1/2 phosphorylation and the expression of the anti‐apoptotic protein Bcl2, which is important for its role in supporting proliferation, cell survival (Lu et al ., ) and neurite outgrowth (Lu et al ., ).…”