RESUMO
Genome-wide association studies (GWAS) have demonstrated the ability to identify the strongest causal common variants in complex human diseases. However, to date, the massive data generated from GWAS have not been maximally explored to identify true associations that fail to meet the stringent level of association required to achieve genome-wide significance. Genetics of gene expression (GGE) studies have shown promise towards identifying DNA variations associated with disease and providing a path to functionally characterize findings from GWAS. Here, we present the first empiric study to systematically characterize the set of single nucleotide polymorphisms associated with expression (eSNPs) in liver, subcutaneous fat, and omental fat tissues, demonstrating these eSNPs are significantly more enriched for SNPs that associate with type 2 diabetes (T2D) in three large-scale GWAS than a matched set of randomly selected SNPs. This enrichment for T2D association increases as we restrict to eSNPs that correspond to genes comprising gene networks constructed from adipose gene expression data isolated from a mouse population segregating a T2D phenotype. Finally, by restricting to eSNPs corresponding to genes comprising an adipose subnetwork strongly predicted as causal for T2D, we dramatically increased the enrichment for SNPs associated with T2D and were able to identify a functionally related set of diabetes susceptibility genes. We identified and validated malic enzyme 1 (Me1) as a key regulator of this T2D subnetwork in mouse and provided support for the association of this gene to T2D in humans. This integration of eSNPs and networks provides a novel approach to identify disease susceptibility networks rather than the single SNPs or genes traditionally identified through GWAS, thereby extracting additional value from the wealth of data currently being generated by GWAS.
Assuntos
Tecido Adiposo/metabolismo , Diabetes Mellitus Tipo 2/genética , Expressão Gênica , Estudo de Associação Genômica Ampla , Fígado/metabolismo , Polimorfismo de Nucleotídeo Único , Animais , Estudos de Coortes , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Obesos , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
A series of six-membered heterocycle carboxamides were synthesized and evaluated as cholecystokinin 1 receptor (CCK1R) agonists. A pyrimidine core proved to be the best heterocycle, and SAR studies resulted in the discovery of analog 5, a potent and structurally diverse CCK1R agonist.
Assuntos
Amidas/síntese química , Amidas/farmacologia , Receptor de Colecistocinina A/agonistas , Amidas/química , Animais , Células Cultivadas , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Humanos , Concentração Inibidora 50 , Camundongos , Estrutura Molecular , Ligação Proteica/efeitos dos fármacos , Pirimidinas/química , Relação Estrutura-AtividadeRESUMO
The discovery and structure-activity relationship of 1,2-diarylimidazole piperazine carboxamides bearing polar side chains as potent and selective cholecystokinin 1 receptor (CCK1R) agonists are described. Optimization of this series resulted in the discovery of isopropyl carboxamide 40, a CCK1R agonist with sub-nanomolar functional and binding activity as well as excellent potency in a mouse overnight food intake reduction assay.
Assuntos
Fármacos Antiobesidade/farmacologia , Benzodiazepinas/farmacologia , Indóis/farmacologia , Obesidade/tratamento farmacológico , Receptor de Colecistocinina A/agonistas , Tiazóis/farmacologia , Animais , Fármacos Antiobesidade/síntese química , Fármacos Antiobesidade/química , Benzodiazepinas/síntese química , Benzodiazepinas/química , Quimiocinas CC , Humanos , Indóis/síntese química , Indóis/química , Metilaminas/síntese química , Metilaminas/química , Metilaminas/farmacologia , Camundongos , Piperazina , Piperazinas/química , Receptores da Colecistocinina/agonistas , Receptores da Colecistocinina/química , Tiazóis/síntese química , Tiazóis/químicaRESUMO
High-throughput screening revealed diaryl pyrazole 3 as a selective albeit modest cholecystokinin 1 receptor (CCK1R) agonist. SAR studies led to the discovery and optimization of a novel class of 1,2-diaryl imidazole carboxamides. Compound 44, which was profiled extensively, showed good in vivo mouse gallbladder emptying (mGBE) and lean mouse overnight food intake (ONFI) reduction activities.
Assuntos
Amidas/síntese química , Amidas/farmacologia , Fármacos Antiobesidade/síntese química , Fármacos Antiobesidade/farmacologia , Imidazóis/síntese química , Imidazóis/farmacologia , Receptores da Colecistocinina/agonistas , Amidas/química , Animais , Fármacos Antiobesidade/química , Quimiocinas CC , Técnicas de Química Combinatória , Ingestão de Alimentos/efeitos dos fármacos , Esvaziamento da Vesícula Biliar/efeitos dos fármacos , Humanos , Imidazóis/química , Camundongos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Melanin-concentrating hormone (MCH) is a cyclic 19-aa hypothalamic neuropeptide derived from a larger prohormone precursor of MCH (Pmch), which also encodes neuropeptide EI (NEI) and neuropeptide GE (NGE). Pmch-deficient (Pmch-/-) mice are lean, hypophagic, and have an increased metabolic rate. Transgenic mice overexpressing Pmch are hyperphagic and develop mild obesity. Consequently, MCH has been implicated in the regulation of energy homeostasis. The MCH 1 receptor (MCH1R) is one of two recently identified G protein-coupled receptors believed to be responsible for the actions of MCH. We evaluated the physiological role of MCH1R by generating MCH1R-deficient (Mch1r-/-) mice. Mch1r-/- mice have normal body weights, yet are lean and have reduced fat mass. Surprisingly, Mch1r-/- mice are hyperphagic when maintained on regular chow, and their leanness is a consequence of hyperactivity and altered metabolism. Consistent with the hyperactivity, Mch1r-/- mice are less susceptible to diet-induced obesity. Importantly, chronic central infusions of MCH induce hyperphagia and mild obesity in wild-type mice, but not in Mch1r-/- mice. We conclude that MCH1R is a physiologically relevant MCH receptor in mice that plays a role in energy homeostasis through multiple actions on locomotor activity, metabolism, appetite, and neuroendocrine function.