Circadian, Sleep and Caloric Intake Phenotyping in Type 2 Diabetes Patients With Rare Melatonin Receptor 2 Mutations and Controls: A Pilot Study.

Background: Melatonin modulates circadian rhythms in physiology and sleep initiation. Genetic variants of the locus, encoding the melatonin MT receptor, have been associated with increased type 2 diabetes (T2D) risk. Carriers of the common intronic rs10830963 T2D risk variant have modified sleep and circadian traits such as changes of the melatonin profile.

Melatonin MT and MT receptor ERK signaling is differentially dependent on G and G proteins.

G protein-coupled receptors (GPCRs) transmit extracellular signals into cells by activating G protein- and β-arrestin-dependent pathways. Extracellular signal-regulated kinases (ERKs) play a central role in integrating these different linear inputs coming from a variety of GPCRs to regulate cellular functions. Here, we investigated human melatonin MT and MT receptors signaling through the ERK1/2 cascade by employing different biochemical techniques together with pharmacological inhibitors and siRNA molecules.

O-linked melatonin dimers as bivalent ligands targeting dimeric melatonin receptors.

A series of dimeric melatonin analogues 3a-e obtained by connecting two melatonin molecules through the methoxy oxygen atoms with spacers spanning 16-24 atoms and the agomelatine dimer 7 were synthesized and characterized in 2-[-I]-iodomelatonin binding assays, bioluminescence resonance energy transfer (BRET) experiments, and in functional cAMP and β-arrestin recruitment assays at MT and MT receptors. The binding affinity of 3a-e generally increased with increasing linker length. Bivalent ligands 3a-e increased BRET signals of MT dimers up to 3-fold compared to the monomeric control ligand indicating the simultaneous binding of the two pharmacophores to dimeric receptors.

Melatonin in type 2 diabetes mellitus and obesity.

Despite considerable advances in the past few years, obesity and type 2 diabetes mellitus (T2DM) remain two major challenges for public health systems globally. In the past 9 years, genome-wide association studies (GWAS) have established a major role for genetic variation within the MTNR1B locus in regulating fasting plasma levels of glucose and in affecting the risk of T2DM. This discovery generated a major interest in the melatonergic system, in particular the melatonin MT receptor (which is encoded by MTNR1B).

Type 2 diabetes-associated variants of the MT melatonin receptor affect distinct modes of signaling.

Melatonin is produced during the night and regulates sleep and circadian rhythms. Loss-of-function variants in , which encodes the melatonin receptor MT, a G protein-coupled receptor (GPCR), are associated with an increased risk of type 2 diabetes (T2D). To identify specific T2D-associated signaling pathway(s), we profiled the signaling output of 40 MT variants by monitoring spontaneous (ligand-independent) and melatonin-induced activation of multiple signaling effectors.

Melatonin receptors limit dopamine reuptake by regulating dopamine transporter cell-surface exposure.

Melatonin, a neuro-hormone released by the pineal gland, has multiple effects in the central nervous system including the regulation of dopamine (DA) levels, but how melatonin accomplishes this task is not clear. Here, we show that melatonin MT and MT receptors co-immunoprecipitate with the DA transporter (DAT) in mouse striatal synaptosomes. Increased DA re-uptake and decreased amphetamine-induced locomotor activity were observed in the striatum of mice with targeted deletion of MT or MT receptors.

The orphan GPR50 receptor promotes constitutive TGFβ receptor signaling and protects against cancer development.

Transforming growth factor-β (TGFβ) signaling is initiated by the type I, II TGFβ receptor (TβRI/TβRII) complex. Here we report the formation of an alternative complex between TβRI and the orphan GPR50, belonging to the G protein-coupled receptor super-family. The interaction of GPR50 with TβRI induces spontaneous TβRI-dependent Smad and non-Smad signaling by stabilizing the active TβRI conformation and competing for the binding of the negative regulator FKBP12 to TβRI.

Nocturnal activation of melatonin receptor type 1 signaling modulates diurnal insulin sensitivity via regulation of PI3K activity.

Recent genetic studies have highlighted the potential involvement of melatonin receptor 1 (MT ) and melatonin receptor 2 (MT ) in the pathogenesis of type 2 diabetes. Here, we report that mice lacking MT (MT KO) tend to accumulate more fat mass than WT mice and exhibit marked systemic insulin resistance. Additional experiments revealed that the main insulin signaling pathway affected by the loss of MT was the activation of phosphatidylinositol-3-kinase (PI3K).

Orphan GPR61, GPR62 and GPR135 receptors and the melatonin MT receptor reciprocally modulate their signaling functions.

Understanding the function of orphan G protein-coupled receptors (GPCRs), whose cognate ligand is unknown, is of major importance as GPCRs are privileged drug targets for many diseases. Recent phylogenetic studies classified three orphan receptors, GPR61, GPR62 and GPR135 among the melatonin receptor subfamily, but their capacity to bind melatonin and their biochemical functions are not well characterized yet. We show here that GPR61, GPR62 and GPR135 do not bind [H]-melatonin nor 2-[I]iodomelatonin and do not respond to melatonin in several signaling assays.

Design and validation of the first cell-impermeant melatonin receptor agonist.

Background And Purpose: The paradigm that GPCRs are able to prolong or initiate cellular signalling through intracellular receptors recently emerged. Melatonin binds to G protein-coupled MT and MT receptors. In contrast to most other hormones targeting GPCRs, melatonin and its synthetic analogues are amphiphilic molecules easily penetrating into cells, but the existence of intracellular receptors is still unclear mainly due to a lack of appropriate tools.

Extracellular acidification stimulates GPR68 mediated IL-8 production in human pancreatic β cells.

Acute or chronic metabolic complications such as diabetic ketoacidosis are often associated with extracellular acidification and pancreatic β-cell dysfunction. However, the mechanisms by which human β-cells sense and respond to acidic pH remain elusive. In this study, using the recently developed human β-cell line EndoC-βH2, we demonstrate that β-cells respond to extracellular acidification through GPR68, which is the predominant proton sensing receptor of human β-cells.

[Involvement of melatonin MT2 receptor mutants in type 2 diabetes development].

Genetic and environmental factors participate in the development of type 2 diabetes (T2D). Genome-wide association studies have revealed new genetic variants associated with T2D, including the rs10830963 variant located in the intron of the MTNR1B gene. This gene encodes the melatonin MT2 receptor, a member of the family of G protein-coupled receptors involved in the regulation of circadian and seasonal rhythms.

Cold-induced changes in gene expression in brown adipose tissue, white adipose tissue and liver.

Cold exposure imposes a metabolic challenge to mammals that is met by a coordinated response in different tissues to prevent hypothermia. This study reports a transcriptomic analysis in brown adipose tissue (BAT), white adipose (WAT) and liver of mice in response to 24 h cold exposure at 8°C. Expression of 1895 genes were significantly (P<0.

Minireview: Toward the establishment of a link between melatonin and glucose homeostasis: association of melatonin MT2 receptor variants with type 2 diabetes.

The existence of interindividual variations in G protein-coupled receptor sequences has been recognized early on. Recent advances in large-scale exon sequencing techniques are expected to dramatically increase the number of variants identified in G protein-coupled receptors, giving rise to new challenges regarding their functional characterization. The current minireview will illustrate these challenges based on the MTNR1B gene, which encodes the melatonin MT2 receptor, for which exon sequencing revealed 40 rare nonsynonymous variants in the general population and in type 2 diabetes (T2D) cohorts.

Ascertainment and critical assessment of the views of the general public and healthcare professionals on nutrigenomics in Greece.

Aim: The aim of this study was to understand the general public's and healthcare professionals' views on nutrigenomics.

Patients & Methods: We designed a cross-sectional survey of healthcare professionals (n = 87) and the general public (n = 1504) in the three largest cities in Greece (Athens, Thessaloniki and Patras).

Results: Our data revealed that only 11.

Combinatorial transcription factor regulation of the cyclic AMP-response element on the Pgc-1alpha promoter in white 3T3-L1 and brown HIB-1B preadipocytes.

Cold stress in rodents increases the expression of UCP1 and PGC-1alpha in brown and white adipose tissue. We have previously reported that C/EBPbeta specifically binds to the CRE on the proximal Pgc-1alpha promoter and increases forskolin-sensitive Pgc-1alpha and Ucp1 expression in white 3T3-L1 preadipocytes. Here we show that in mice exposed to a cold environment for 24 h, Pgc-1alpha, Ucp1, and C/ebpbeta but not C/ebpalpha or C/ebpdelta expression were increased in BAT.

C/EBPbeta reprograms white 3T3-L1 preadipocytes to a Brown adipocyte pattern of gene expression.

cAMP-dependent protein kinase induction of PPARgamma coactivator-1alpha (PGC-1alpha) and uncoupling protein 1 (UCP1) expression is an essential step in the commitment of preadipocytes to the brown adipose tissue (BAT) lineage. We studied the molecular mechanisms responsible for differential expression of PGC-1alpha in HIB1B (BAT) and 3T3-L1 white adipose tissue (WAT) precursor cell lines. In HIB1B cells PGC-1alpha and UCP1 expression is cAMP-inducible, but in 3T3-L1 cells, expression is reduced and is cAMP-insensitive.

Ontogenic loss of brown adipose tissue sensitivity to beta-adrenergic stimulation in the ovine.

In ruminants and other large animals, expression of uncoupling protein-1 (UCP1) in brown adipose tissue (BAT) is confined to the perinatal period when it plays a key role in nonshivering thermogenesis. This study determined whether loss of expression of the BAT phenotype was due to reduced response to a beta-agonist, isoprenaline, and expression of the peroxisome proliferator-activated receptor (PPAR) family [PPARalpha, PPARgamma, PPAR coactivator 1alpha (PGC-1alpha)], which regulates UCP1 gene expression. Perirenal adipose tissue (PAT) was sampled from ovine fetuses, newborn lambs, and lambs on d 1, 5, 7, and 21 of life.