RESUMEN
The worldwide obesity epidemic has emerged as a major cause of insulin resistance and Type 2 diabetes. Chronic tissue inflammation is a well-recognized feature of obesity, and the field of immunometabolism has witnessed many advances in recent years. Here, we review the major features of our current understanding with respect to chronic obesity-related inflammation in metabolic tissues and focus on how these inflammatory changes affect insulin sensitivity, insulin secretion, food intake, and glucose homeostasis. There is a growing appreciation of the varied and sometimes integrated crosstalk between cells within a tissue (intraorgan) and tissues within an organism (interorgan) that supports inflammation in the context of metabolic dysregulation. Understanding these pathways and modes of communication has implications for translational studies. We also briefly summarize the state of this field with respect to potential current and developing therapeutics.
Asunto(s)
Trastornos del Metabolismo de la Glucosa/metabolismo , Inmunidad Innata , Integración de Sistemas , Animales , Trastornos del Metabolismo de la Glucosa/etiología , Trastornos del Metabolismo de la Glucosa/inmunología , Humanos , Inflamación/inmunología , Inflamación/metabolismoRESUMEN
MiRNAs are regulatory molecules that can be packaged into exosomes and secreted from cells. Here, we show that adipose tissue macrophages (ATMs) in obese mice secrete miRNA-containing exosomes (Exos), which cause glucose intolerance and insulin resistance when administered to lean mice. Conversely, ATM Exos obtained from lean mice improve glucose tolerance and insulin sensitivity when administered to obese recipients. miR-155 is one of the miRNAs overexpressed in obese ATM Exos, and earlier studies have shown that PPARγ is a miR-155 target. Our results show that miR-155KO animals are insulin sensitive and glucose tolerant compared to controls. Furthermore, transplantation of WT bone marrow into miR-155KO mice mitigated this phenotype. Taken together, these studies show that ATMs secrete exosomes containing miRNA cargo. These miRNAs can be transferred to insulin target cell types through mechanisms of paracrine or endocrine regulation with robust effects on cellular insulin action, in vivo insulin sensitivity, and overall glucose homeostasis.
Asunto(s)
Tejido Adiposo/citología , Resistencia a la Insulina , Macrófagos/metabolismo , MicroARNs/metabolismo , Adipocitos/metabolismo , Animales , Células Cultivadas , Glucosa/metabolismo , Hepatocitos/metabolismo , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Células Musculares/metabolismo , Músculo Esquelético/metabolismo , Transducción de SeñalRESUMEN
Obesity leads to chronic, systemic inflammation and can lead to insulin resistance (IR), ß-cell dysfunction, and ultimately type 2 diabetes (T2D). This chronic inflammatory state contributes to long-term complications of diabetes, including non-alcoholic fatty liver disease (NAFLD), retinopathy, cardiovascular disease, and nephropathy, and may underlie the association of type 2 diabetes with other conditions such as Alzheimer's disease, polycystic ovarian syndrome, gout, and rheumatoid arthritis. Here, we review the current understanding of the mechanisms underlying inflammation in obesity, T2D, and related disorders. We discuss how chronic tissue inflammation results in IR, impaired insulin secretion, glucose intolerance, and T2D and review the effect of inflammation on diabetic complications and on the relationship between T2D and other pathologies. In this context, we discuss current therapeutic options for the treatment of metabolic disease, advances in the clinic and the potential of immune-modulatory approaches.
Asunto(s)
Complicaciones de la Diabetes/inmunología , Diabetes Mellitus Tipo 2/inmunología , Inflamación/inmunología , Obesidad/inmunología , Animales , Humanos , Inmunomodulación , Resistencia a la InsulinaRESUMEN
In obesity, macrophages and other immune cells accumulate in insulin target tissues, promoting a chronic inflammatory state and insulin resistance. Galectin-3 (Gal3), a lectin mainly secreted by macrophages, is elevated in both obese subjects and mice. Administration of Gal3 to mice causes insulin resistance and glucose intolerance, whereas inhibition of Gal3, through either genetic or pharmacologic loss of function, improved insulin sensitivity in obese mice. In vitro treatment with Gal3 directly enhanced macrophage chemotaxis, reduced insulin-stimulated glucose uptake in myocytes and 3T3-L1 adipocytes and impaired insulin-mediated suppression of glucose output in primary mouse hepatocytes. Importantly, we found that Gal3 can bind directly to the insulin receptor (IR) and inhibit downstream IR signaling. These observations elucidate a novel role for Gal3 in hepatocyte, adipocyte, and myocyte insulin resistance, suggesting that Gal3 can link inflammation to decreased insulin sensitivity. Inhibition of Gal3 could be a new approach to treat insulin resistance.
Asunto(s)
Galectina 3/sangre , Galectina 3/metabolismo , Adipocitos/metabolismo , Adipocitos/patología , Animales , Quimiotaxis , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patología , Galectina 3/antagonistas & inhibidores , Galectina 3/genética , Hepatocitos/metabolismo , Hepatocitos/patología , Humanos , Insulina/sangre , Resistencia a la Insulina , Macrófagos/inmunología , Macrófagos/patología , Ratones , Ratones Noqueados , Células Musculares/metabolismo , Células Musculares/patología , Obesidad/inmunología , Obesidad/metabolismo , Obesidad/patologíaRESUMEN
Adipose tissue hypoxia and inflammation have been causally implicated in obesity-induced insulin resistance. Here, we report that, early in the course of high-fat diet (HFD) feeding and obesity, adipocyte respiration becomes uncoupled, leading to increased oxygen consumption and a state of relative adipocyte hypoxia. These events are sufficient to trigger HIF-1α induction, setting off the chronic adipose tissue inflammatory response characteristic of obesity. At the molecular level, these events involve saturated fatty acid stimulation of the adenine nucleotide translocase 2 (ANT2), an inner mitochondrial membrane protein, which leads to the uncoupled respiratory state. Genetic or pharmacologic inhibition of either ANT2 or HIF-1α can prevent or reverse these pathophysiologic events, restoring a state of insulin sensitivity and glucose tolerance. These results reveal the sequential series of events in obesity-induced inflammation and insulin resistance.
Asunto(s)
Adipocitos/metabolismo , Dieta Alta en Grasa , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Resistencia a la Insulina , Obesidad/metabolismo , Oxígeno/metabolismo , Translocador 2 del Nucleótido Adenina/metabolismo , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Hipoxia de la Célula , Ácidos Grasos/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Inflamación/metabolismo , Ácido Láctico/metabolismo , Ratones , Ratones Noqueados , Óxido Nítrico/metabolismoRESUMEN
Obesity-induced insulin resistance is the major determinant of metabolic syndrome, which precedes the development of type 2 diabetes mellitus and is thus the driving force behind the emerging diabetes epidemic. The precise causes of insulin resistance are varied, and the relative importance of each is a matter of ongoing research. Here, we offer a Perspective on the heterogeneous etiology of insulin resistance, focusing in particular on the role of inflammation, lipid metabolism, and the gastrointestinal microbiota.
Asunto(s)
Diabetes Mellitus Tipo 2/metabolismo , Resistencia a la Insulina , Diabetes Mellitus Tipo 2/microbiología , Tracto Gastrointestinal/microbiología , Humanos , Inflamación/metabolismo , Metabolismo de los Lípidos , Macrófagos/metabolismo , Obesidad/metabolismoRESUMEN
Macrophage-mediated inflammation is a major contributor to obesity-associated insulin resistance. The corepressor NCoR interacts with inflammatory pathway genes in macrophages, suggesting that its removal would result in increased activity of inflammatory responses. Surprisingly, we find that macrophage-specific deletion of NCoR instead results in an anti-inflammatory phenotype along with robust systemic insulin sensitization in obese mice. We present evidence that derepression of LXRs contributes to this paradoxical anti-inflammatory phenotype by causing increased expression of genes that direct biosynthesis of palmitoleic acid and ω3 fatty acids. Remarkably, the increased ω3 fatty acid levels primarily inhibit NF-κB-dependent inflammatory responses by uncoupling NF-κB binding and enhancer/promoter histone acetylation from subsequent steps required for proinflammatory gene activation. This provides a mechanism for the in vivo anti-inflammatory insulin-sensitive phenotype observed in mice with macrophage-specific deletion of NCoR. Therapeutic methods to harness this mechanism could lead to a new approach to insulin-sensitizing therapies.
Asunto(s)
Ácidos Grasos Omega-3/metabolismo , Resistencia a la Insulina , Macrófagos/metabolismo , Co-Represor 1 de Receptor Nuclear/metabolismo , Receptores Nucleares Huérfanos/genética , Animales , Receptores X del Hígado , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Co-Represor 1 de Receptor Nuclear/genéticaRESUMEN
Exosomes are small extracellular vesicles that carry lipids, proteins, and microRNAs (miRNAs). They are released by all cell types and can be found not only in circulation but in many biological fluids. Exosomes are essential for interorgan communication because they can transfer their contents from donor to recipient cells, modulating cellular functions. The miRNA content of exosomes is responsible for most of their biological effects, and changes in exosomal miRNA levels can contribute to the progression or regression of metabolic diseases. As exosomal miRNAs are selectively sorted and packaged into exosomes, they can be useful as biomarkers for diagnosing diseases. The field of exosomes and metabolism is expanding rapidly, and researchers are consistently making new discoveries in this area. As a result, exosomes have great potential for a next-generation drug delivery platform for metabolic diseases.
Asunto(s)
Exosomas , Enfermedades Metabólicas , MicroARNs , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Biomarcadores/metabolismo , Enfermedades Metabólicas/metabolismoRESUMEN
While macrophage heterogeneity during metabolic dysfunction-associated steatohepatitis (MASH) has been described, the fate of these macrophages during MASH regression is poorly understood. Comparing macrophage heterogeneity during MASH progression vs regression, we identified specific macrophage subpopulations that are critical for MASH/fibrosis resolution. We elucidated the restorative pathways and gene signatures that define regression-associated macrophages and establish the importance of TREM2+ macrophages during MASH regression. Liver-resident Kupffer cells are lost during MASH and are replaced by four distinct monocyte-derived macrophage subpopulations. Trem2 is expressed in two macrophage subpopulations: i) monocyte-derived macrophages occupying the Kupffer cell niche (MoKC) and ii) lipid-associated macrophages (LAM). In regression livers, no new transcriptionally distinct macrophage subpopulation emerged. However, the relative macrophage composition changed during regression compared to MASH. While MoKC was the major macrophage subpopulation during MASH, they decreased during regression. LAM was the dominant macrophage subtype during MASH regression and maintained Trem2 expression. Both MoKC and LAM were enriched in disease-resolving pathways. Absence of TREM2 restricted the emergence of LAMs and formation of hepatic crown-like structures. TREM2+ macrophages are functionally important not only for restricting MASH-fibrosis progression but also for effective regression of inflammation and fibrosis. TREM2+ macrophages are superior collagen degraders. Lack of TREM2+ macrophages also prevented elimination of hepatic steatosis and inactivation of HSC during regression, indicating their significance in metabolic coordination with other cell types in the liver. TREM2 imparts this protective effect through multifactorial mechanisms, including improved phagocytosis, lipid handling, and collagen degradation.
Asunto(s)
Macrófagos del Hígado , Cirrosis Hepática , Macrófagos , Glicoproteínas de Membrana , Receptores Inmunológicos , Receptores Inmunológicos/metabolismo , Receptores Inmunológicos/genética , Glicoproteínas de Membrana/metabolismo , Glicoproteínas de Membrana/genética , Animales , Ratones , Macrófagos/metabolismo , Cirrosis Hepática/metabolismo , Cirrosis Hepática/patología , Cirrosis Hepática/genética , Macrófagos del Hígado/metabolismo , Hígado/metabolismo , Hígado/patología , Metabolismo de los Lípidos , Ratones Endogámicos C57BL , Masculino , Lípidos , Hígado Graso/metabolismo , Hígado Graso/patología , Hígado Graso/genética , Ratones NoqueadosRESUMEN
Insulin resistance, tissue inflammation, and adipose tissue dysfunction are features of obesity and Type 2 diabetes. We generated adipocyte-specific Nuclear Receptor Corepressor (NCoR) knockout (AKO) mice to investigate the function of NCoR in adipocyte biology, glucose and insulin homeostasis. Despite increased obesity, glucose tolerance was improved in AKO mice, and clamp studies demonstrated enhanced insulin sensitivity in liver, muscle, and fat. Adipose tissue macrophage infiltration and inflammation were also decreased. PPARγ response genes were upregulated in adipose tissue from AKO mice and CDK5-mediated PPARγ ser-273 phosphorylation was reduced, creating a constitutively active PPARγ state. This identifies NCoR as an adaptor protein that enhances the ability of CDK5 to associate with and phosphorylate PPARγ. The dominant function of adipocyte NCoR is to transrepress PPARγ and promote PPARγ ser-273 phosphorylation, such that NCoR deletion leads to adipogenesis, reduced inflammation, and enhanced systemic insulin sensitivity, phenocopying the TZD-treated state.
Asunto(s)
Adipocitos/metabolismo , Proteínas Co-Represoras/genética , Diabetes Mellitus Tipo 2/metabolismo , Resistencia a la Insulina , Co-Represor 1 de Receptor Nuclear/metabolismo , PPAR gamma/metabolismo , Animales , Diabetes Mellitus Tipo 2/patología , Dieta Alta en Grasa , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , PPAR gamma/antagonistas & inhibidores , Fosforilación , TiazolidinedionasRESUMEN
Omega-3 fatty acids (omega-3 FAs), DHA and EPA, exert anti-inflammatory effects, but the mechanisms are poorly understood. Here, we show that the G protein-coupled receptor 120 (GPR120) functions as an omega-3 FA receptor/sensor. Stimulation of GPR120 with omega-3 FAs or a chemical agonist causes broad anti-inflammatory effects in monocytic RAW 264.7 cells and in primary intraperitoneal macrophages. All of these effects are abrogated by GPR120 knockdown. Since chronic macrophage-mediated tissue inflammation is a key mechanism for insulin resistance in obesity, we fed obese WT and GPR120 knockout mice a high-fat diet with or without omega-3 FA supplementation. The omega-3 FA treatment inhibited inflammation and enhanced systemic insulin sensitivity in WT mice, but was without effect in GPR120 knockout mice. In conclusion, GPR120 is a functional omega-3 FA receptor/sensor and mediates potent insulin sensitizing and antidiabetic effects in vivo by repressing macrophage-induced tissue inflammation.
Asunto(s)
Ácidos Grasos Omega-3/administración & dosificación , Ácidos Grasos Omega-3/metabolismo , Resistencia a la Insulina , Receptores Acoplados a Proteínas G/metabolismo , Células 3T3-L1 , Animales , Antiinflamatorios/administración & dosificación , Antiinflamatorios/metabolismo , Línea Celular , Grasas de la Dieta/metabolismo , Suplementos Dietéticos , Humanos , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/metabolismo , Macrófagos/inmunología , Ratones , Ratones Noqueados , Obesidad/complicaciones , Receptores Acoplados a Proteínas G/genéticaRESUMEN
Obesity leads to tissue inflammation and insulin resistance, which are features of metabolic diseases such as type 2 diabetes. Chiang et al. (2009) now show that the IkappaB kinase IKKepsilon is an important link between obesity and inflammation and may be a new therapeutic target for treating obesity-related metabolic diseases.
Asunto(s)
Quinasa I-kappa B/metabolismo , Inflamación/metabolismo , Obesidad/metabolismo , Animales , Humanos , Ratones , Obesidad/inmunologíaRESUMEN
Chronic, low-grade adipose tissue inflammation is a key etiological mechanism linking the increasing incidence of type 2 diabetes (T2D) and obesity. It is well recognized that the immune system and metabolism are highly integrated, and macrophages, in particular, have been identified as critical effector cells in the initiation of inflammation and insulin resistance. Recent advances have been made in the understanding of macrophage recruitment and retention to adipose tissue and the participation of other immune cell populations in the regulation of this inflammatory process. Here we discuss the pathophysiological link between macrophages, obesity, and insulin resistance, highlighting the dynamic immune cell regulation of adipose tissue inflammation. We also describe the mechanisms by which inflammation causes insulin resistance and the new therapeutic targets that have emerged.
Asunto(s)
Tejido Adiposo/inmunología , Diabetes Mellitus Tipo 2/inmunología , Resistencia a la Insulina/inmunología , Macrófagos/inmunología , Obesidad/inmunología , Tejido Adiposo/citología , Animales , Citocinas/inmunología , Citocinas/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/fisiopatología , Humanos , Inflamación/tratamiento farmacológico , Inflamación/inmunología , Hígado/citología , Hígado/inmunología , Activación de Macrófagos/inmunología , Ratones , Músculo Esquelético/citología , Músculo Esquelético/inmunología , Obesidad/tratamiento farmacológico , Obesidad/fisiopatología , Transducción de Señal/inmunologíaRESUMEN
Fat metabolism and glucose homeostasis are processes that are highly interconnected. Cao et al. (2008) now take this concept a step further by identifying a fatty acid metabolite generated in adipose tissue that regulates insulin sensitivity in liver and muscle.
Asunto(s)
Tejido Adiposo/metabolismo , Metabolismo de los Lípidos , Hígado/metabolismo , Músculos/metabolismo , Animales , Proteínas de Unión a Ácidos Grasos/metabolismo , Glucosa/metabolismo , Humanos , Insulina/metabolismoRESUMEN
Obesity impacts over 30% of the United States population, resulting in a wide array of complications. Included among these is the deterioration of the intestinal barrier, which has been implicated in type 2 diabetes and susceptibility to bacterial transepithelial migration. The intestinal epithelium is maintained by αß and γδ intraepithelial T lymphocytes, which migrate along the epithelia, support epithelial homeostasis, and protect from infection. In this study, we investigate how obesity impacts intraepithelial lymphocyte (IEL) persistence and function in intestinal homeostasis and repair. Mice were fed a high-fat diet to induce obesity and to study immunomodulation in the intestine. There is a striking reduction in αß and γδ IEL persistence as obesity progresses with a different mechanism in αß versus γδ IEL populations. CD4+ and CD4+CD8+ αß intraepithelial T lymphocytes exhibit reduced homeostatic proliferation in obesity, whereas both αß and γδ IELs downregulate CD103 and CCR9. The reduction in intraepithelial T lymphocytes occurs within 7 wk of high-fat diet administration and is not dependent on chronic inflammation via TNF-α. Young mice administered a high-fat diet upon weaning exhibit the most dramatic phenotype, showing that childhood obesity has consequences on intestinal IEL seeding. Together, this dysfunction in the intestinal epithelium renders obese mice more susceptible to dextran sulfate sodium-induced colitis. Diet-induced weight loss restores IEL number and CD103/CCR9 expression and improves outcome in colitis. Together, these data confirm that obesity has immunomodulatory consequences in intestinal tissues that can be improved with weight loss.
Asunto(s)
Colitis/etiología , Colitis/metabolismo , Inmunomodulación , Linfocitos Intraepiteliales/inmunología , Linfocitos Intraepiteliales/metabolismo , Obesidad/inmunología , Obesidad/metabolismo , Factores de Edad , Animales , Antígenos CD/genética , Antígenos CD/metabolismo , Biomarcadores , Colitis/patología , Sulfato de Dextran/efectos adversos , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Técnica del Anticuerpo Fluorescente , Regulación de la Expresión Génica , Inmunohistoquímica , Cadenas alfa de Integrinas/genética , Cadenas alfa de Integrinas/metabolismo , Masculino , Ratones , Obesidad/complicaciones , Receptores CCR/genética , Receptores CCR/metabolismo , Receptores del Factor de Necrosis Tumoral/metabolismo , Índice de Severidad de la Enfermedad , Transducción de Señal , Bazo/inmunología , Bazo/metabolismo , Timo/inmunología , Timo/metabolismoRESUMEN
Insulin increases glucose uptake into adipose tissue and muscle by increasing trafficking of the glucose transporter Glut4. In cultured adipocytes, the exocytosis of Glut4 relies on activation of the small G protein RalA by insulin, via inhibition of its GTPase activating complex RalGAP. Here, we evaluate the role of RalA in glucose uptake in vivo with specific chemical inhibitors and by generation of mice with adipocyte-specific knockout of RalGAPB. RalA was profoundly activated in brown adipose tissue after feeding, and its inhibition prevented Glut4 exocytosis. RalGAPB knockout mice with diet-induced obesity were protected from the development of metabolic disease due to increased glucose uptake into brown fat. Thus, RalA plays a crucial role in glucose transport in adipose tissue in vivo.
Asunto(s)
Tejido Adiposo Pardo/metabolismo , Glucosa/metabolismo , Homeostasis , Proteínas de Unión al GTP ral/metabolismo , Células 3T3-L1 , Tejido Adiposo Pardo/patología , Animales , Proteínas Activadoras de GTPasa/genética , Proteínas Activadoras de GTPasa/metabolismo , Eliminación de Gen , Glucosa/genética , Transportador de Glucosa de Tipo 4/genética , Transportador de Glucosa de Tipo 4/metabolismo , Ratones , Ratones Noqueados , Proteínas de Unión al GTP ral/genéticaRESUMEN
Fibroblast growth factor 1 (FGF1) is an autocrine/paracrine regulator whose binding to heparan sulphate proteoglycans effectively precludes its circulation. Although FGF1 is known as a mitogenic factor, FGF1 knockout mice develop insulin resistance when stressed by a high-fat diet, suggesting a potential role in nutrient homeostasis. Here we show that parenteral delivery of a single dose of recombinant FGF1 (rFGF1) results in potent, insulin-dependent lowering of glucose levels in diabetic mice that is dose-dependent but does not lead to hypoglycaemia. Chronic pharmacological treatment with rFGF1 increases insulin-dependent glucose uptake in skeletal muscle and suppresses the hepatic production of glucose to achieve whole-body insulin sensitization. The sustained glucose lowering and insulin sensitization attributed to rFGF1 are not accompanied by the side effects of weight gain, liver steatosis and bone loss associated with current insulin-sensitizing therapies. We also show that the glucose-lowering activity of FGF1 can be dissociated from its mitogenic activity and is mediated predominantly via FGF receptor 1 signalling. Thus we have uncovered an unexpected, neomorphic insulin-sensitizing action for exogenous non-mitogenic human FGF1 with therapeutic potential for the treatment of insulin resistance and type 2 diabetes.
Asunto(s)
Factor 1 de Crecimiento de Fibroblastos/farmacología , Glucosa/metabolismo , Insulina/metabolismo , Animales , Glucemia/metabolismo , Peso Corporal/efectos de los fármacos , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Dieta Alta en Grasa , Relación Dosis-Respuesta a Droga , Factor 1 de Crecimiento de Fibroblastos/administración & dosificación , Factor 1 de Crecimiento de Fibroblastos/efectos adversos , Prueba de Tolerancia a la Glucosa , Humanos , Resistencia a la Insulina , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , Mitógenos/farmacología , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/metabolismoRESUMEN
Free fatty acid-2 (FFA2) receptor is a G-protein coupled receptor of interest in the development of therapeutics in metabolic and inflammatory disease areas. The discovery and optimization of an N-thiazolylamide carboxylic acid FFA2 agonist scaffold is described. Dual key objectives were to i) evaluate the potential of this scaffold for lead optimization in particular with respect to safety de-risking physicochemical properties, i.e. lipophilicity and aromatic content, and ii) to demonstrate the utility of selected lead analogues from this scaffold in a pertinent in vivo model such as oral glucose tolerance test (OGTT). As such, a concomitant improvement in bioactivity together with lipophilic ligand efficiency (LLE) and fraction sp3 content (Fsp3) parameters guided these efforts. Compound 10 was advanced into studies in mice on the basis of its optimized profile vs initial lead 1 (ΔLLEâ¯=â¯0.3, ΔFsp3â¯=â¯0.24). Although active in OGTT, 10 also displayed similar activity in the FFA2-knockout mice. Given this off-target OGTT effect, we discontinued development of this FFA2 agonist scaffold.
Asunto(s)
Diabetes Mellitus Experimental/tratamiento farmacológico , Modelos Animales de Enfermedad , Descubrimiento de Drogas , Receptores de Superficie Celular/agonistas , Tiazoles/farmacología , Animales , Relación Dosis-Respuesta a Droga , Humanos , Ratones , Ratones Noqueados , Estructura Molecular , Ratas , Receptores de Superficie Celular/deficiencia , Receptores de Superficie Celular/metabolismo , Relación Estructura-Actividad , Tiazoles/químicaRESUMEN
Although feast and famine cycles illustrate that remodelling of adipose tissue in response to fluctuations in nutrient availability is essential for maintaining metabolic homeostasis, the underlying mechanisms remain poorly understood. Here we identify fibroblast growth factor 1 (FGF1) as a critical transducer in this process in mice, and link its regulation to the nuclear receptor PPARγ (peroxisome proliferator activated receptor γ), which is the adipocyte master regulator and the target of the thiazolidinedione class of insulin sensitizing drugs. FGF1 is the prototype of the 22-member FGF family of proteins and has been implicated in a range of physiological processes, including development, wound healing and cardiovascular changes. Surprisingly, FGF1 knockout mice display no significant phenotype under standard laboratory conditions. We show that FGF1 is highly induced in adipose tissue in response to a high-fat diet and that mice lacking FGF1 develop an aggressive diabetic phenotype coupled to aberrant adipose expansion when challenged with a high-fat diet. Further analysis of adipose depots in FGF1-deficient mice revealed multiple histopathologies in the vasculature network, an accentuated inflammatory response, aberrant adipocyte size distribution and ectopic expression of pancreatic lipases. On withdrawal of the high-fat diet, this inflamed adipose tissue fails to properly resolve, resulting in extensive fat necrosis. In terms of mechanisms, we show that adipose induction of FGF1 in the fed state is regulated by PPARγ acting through an evolutionarily conserved promoter proximal PPAR response element within the FGF1 gene. The discovery of a phenotype for the FGF1 knockout mouse establishes the PPARγFGF1 axis as critical for maintaining metabolic homeostasis and insulin sensitization.