Mice lacking GPR3 receptors display late-onset obese phenotype due to impaired thermogenic function in brown adipose tissue

Godlewski, Grzegorz; Jourdan, Tony; Szanda, Gergö; Tam, Joseph; Çınar, Reşat; Harvey−White, Judith; Liu, Jie; Mukhopadhyay, Bani; Pacher, Pál; Mo, Fong Ming; Osei‐Hyiaman, Douglas; Kunos, George

doi:10.1038/srep14953

Cited by 28 publications

(31 citation statements)

References 56 publications

(65 reference statements)

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“…Glucose tolerance and insulin sensitivity tests were performed as described previously (24). HOMA-IR was calculated as follows: fasting insulin (μU/mL) × fasting glucose (mg/dL)/405 (25).…”

Section: Methodsmentioning

confidence: 99%

Developmental Role of Macrophage Cannabinoid-1 Receptor Signaling in Type 2 Diabetes

et al. 2017

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Islet inflammation promotes β-cell loss and type 2 diabetes (T2D), a process replicated in Zucker Diabetic Fatty (ZDF) rats in which β-cell loss has been linked to cannabinoid-1 receptor (CB1R)–induced proinflammatory signaling in macrophages infiltrating pancreatic islets. Here, we analyzed CB1R signaling in macrophages and its developmental role in T2D. ZDF rats with global deletion of CB1R are protected from β-cell loss, hyperglycemia, and nephropathy that are present in ZDF littermates. Adoptive transfer of CB1R−/− bone marrow to ZDF rats also prevents β-cell loss and hyperglycemia but not nephropathy. ZDF islets contain elevated levels of CB1R, interleukin-1β, tumor necrosis factor-α, the chemokine CCL2, and interferon regulatory factor-5 (IRF5), a marker of inflammatory macrophage polarization. In primary cultured rodent and human macrophages, CB1R activation increased Irf5 expression, whereas knockdown of Irf5 blunted CB1R-induced secretion of inflammatory cytokines without affecting CCL2 expression, which was p38MAPKα dependent. Macrophage-specific in vivo knockdown of Irf5 protected ZDF rats from β-cell loss and hyperglycemia. Thus, IRF5 is a crucial downstream mediator of diabetogenic CB1R signaling in macrophages and a potential therapeutic target.

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Section: Methodsmentioning

confidence: 99%

Developmental Role of Macrophage Cannabinoid-1 Receptor Signaling in Type 2 Diabetes

et al. 2017

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“…The phylogenetic relation of GPR3, GPR6 and GPR12 with the cannabinoids attracted researchers to explore the role of these orphan receptors in metabolic disorders. Thus far, only one study has shown a relation between GPR3 and late-onset obesity, whereas diverse reports have examined how GPR12 interplays in these pathologies (Bjursell et al 2006; Frank et al 2012; Godlewski et al 2015). A patent also claimed the use of GPR6 inverse agonists in the treatment of obesity (Beeley et al 2001).…”

Section: Biological Relevancementioning

confidence: 99%

“…Kunos and coworkers identified a link between GPR3 weight gain and thermogenesis in old mice (Godlewski et al 2015). In these studies, mice lacking GPR3 and maintained on standard chow diet showed an obese phenotype after 5 months of life.…”

Section: Biological Relevancementioning

confidence: 99%

“…In fact, 1-year-old GPR3 −/− subjects displayed higher adiposity indexes and body weight in addition to reduced energy expenditure and lower body temperature. Further evaluation of these metabolic profiles led them to identify a dysfunction in interscapular brown adipose tissue (iBAT) along with lower expression of UCP1 (uncoupling protein 1), tightly involved in BAT heat generation (Godlewski et al 2015). These findings suggest that GPR3 deficiency in mice impaired their ability to generate heat by non-shivering thermogenesis.…”

Section: Biological Relevancementioning

confidence: 99%

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Towards a better understanding of the cannabinoid-related orphan receptors GPR3, GPR6, and GPR12

Morales

Isawi

Reggio

2018

Drug Metabolism Reviews

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GPR3, GPR6 and GPR12 are three orphan receptors that belong to the Class A family of G protein-coupled receptors (GPCRs). These GPCRs share over 60% of sequence similarity among them. Because of their close phylogenetic relationship GPR3, GPR6 and GPR12 share a high percentage of homology with other lipid receptors such as the lysophospholipid and the cannabinoid receptors. On the basis of sequence similarities at key structural motifs, these orphan receptors have been related to the cannabinoid family. However, further experimental data is required to confirm this association. GPR3, GPR6 and GPR12 are predominantly expressed in mammalian brain. Their high constitutive activation of adenylyl cyclase triggers increases in cAMP levels similar in amplitude to fully activated GPCRs. This feature defines their physiological role under certain pathological conditions. In this review, we aim to summarize the knowledge attained so far on the understanding of these receptors. Expression patterns, pharmacology, physiopathological relevance, and molecules targeting GPR3, GPR6 and GPR12 will be analyzed herein. Interestingly, certain cannabinoid ligands have been reported to modulate these orphan receptors. The current debate about sphingolipids as putative endogenous ligands will also be addressed. A special focus will be on their potential role in the brain, particularly under neurological conditions such as Parkinson or Alzheimer’s disease. Reported physiological roles outside the central nervous system will also be covered. This critical overview may contribute to a further comprehension of the physiopathological role of these orphan GPCRs, hopefully attracting more research towards a future therapeutic exploitation of these promising targets.

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“…Interestingly, different researchers have demonstrated its ability to modulate amyloid-beta production suggesting that it may play a critical role in Alzheimer’s disease (Huang et al, 2015; Nelson & Sheng, 2013; Thathiah et al, 2009, 2013). In addition, GPR3 has been reported to promote neurite outgrowth (Tanaka et al, 2014; Tanaka, Ishii, Kasai, Sung, & Saeki, 2007; Tanaka, Shaikh, Chiocca, & Saeki, 2009), to regulate meiotic prophase arrest in oocyte maturation (Mehlmann et al, 2004), alter emotional behaviors (Valverde et al, 2009), to modulate early phases of cocaine reinforcement (Tourino et al, 2012), to control neuropathic pain after peripheral nerve injury (Ruiz-Medina, Ledent, & Valverde, 2011) and to be involved in age-related obesity (Godlewski et al, 2015). All these data indicate that GPR3 represents a potential therapeutic target for the treatment of a variety of physiopathological conditions.…”

Section: Introductionmentioning

confidence: 99%

Methods for the Development of In Silico GPCR Models

Morales

Hurst

Reggio

2017

Methods in Enzymology

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The Reggio group has constructed computer models of the inactive and G-protein activated states of the cannabinoid CB1 and CB2 receptors, as well, several orphan receptors that recognize a sub-set of cannabinoid compounds, including GPR55 and GPR18. These models have been used to design ligands, mutations and covalent labeling studies. The resultant second generation models have been used to design ligands with improved affinity, efficacy and sub-type selectivity. Herein, we provide a guide for the development of GPCR models using the most recent orphan receptor studied in our lab, GPR3. GPR3 is an orphan receptor that belongs to the Class A family of G-Protein Coupled Receptors. It shares high sequence similarity with GPR6, GPR12, the lysophospholipid receptors, and the cannabinoid receptors. GPR3 is predominantly expressed in mammalian brain and oocytes and it is known as a Gαs-coupled receptor activated constitutively in cells. GPR3 represents a possible target for the treatment of different pathological conditions such as Alzheimer’s disease, oocyte maturation or neuropathic pain. However, the lack of potent and selective GPR3 ligands is delaying the exploitation of this promising therapeutic target. In this context, we aim to develop a homology model that helps us to elucidate the structural determinants governing ligand-receptor interactions at GPR3. In this chapter, we detail the methods and rationale behind the construction of the GPR3 active and inactive state models. These homology models will enable the rational design of novel ligands, which may serve as research tools for further understanding of the biological role of GPR3.

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Mice lacking GPR3 receptors display late-onset obese phenotype due to impaired thermogenic function in brown adipose tissue

Cited by 28 publications

References 56 publications

Developmental Role of Macrophage Cannabinoid-1 Receptor Signaling in Type 2 Diabetes

Developmental Role of Macrophage Cannabinoid-1 Receptor Signaling in Type 2 Diabetes

Towards a better understanding of the cannabinoid-related orphan receptors GPR3, GPR6, and GPR12

Methods for the Development of In Silico GPCR Models

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