RESUMEN
Obesity-induced metabolic disease involves functional integration among several organs via circulating factors, but little is known about crosstalk between liver and visceral adipose tissue (VAT). In obesity, VAT becomes populated with inflammatory adipose tissue macrophages (ATMs). In obese humans, there is a close correlation between adipose tissue inflammation and insulin resistance, and in obese mice, blocking systemic or ATM inflammation improves insulin sensitivity. However, processes that promote pathological adipose tissue inflammation in obesity are incompletely understood. Here we show that obesity in mice stimulates hepatocytes to synthesize and secrete dipeptidyl peptidase 4 (DPP4), which acts with plasma factor Xa to inflame ATMs. Silencing expression of DPP4 in hepatocytes suppresses inflammation of VAT and insulin resistance; however, a similar effect is not seen with the orally administered DPP4 inhibitor sitagliptin. Inflammation and insulin resistance are also suppressed by silencing expression of caveolin-1 or PAR2 in ATMs; these proteins mediate the actions of DPP4 and factor Xa, respectively. Thus, hepatocyte DPP4 promotes VAT inflammation and insulin resistance in obesity, and targeting this pathway may have metabolic benefits that are distinct from those observed with oral DPP4 inhibitors.
Asunto(s)
Dipeptidil Peptidasa 4/metabolismo , Hepatocitos/metabolismo , Inflamación/enzimología , Resistencia a la Insulina , Grasa Intraabdominal/patología , Obesidad/enzimología , Administración Oral , Animales , Caveolina 1/deficiencia , Caveolina 1/genética , Caveolina 1/metabolismo , Dipeptidil Peptidasa 4/deficiencia , Dipeptidil Peptidasa 4/genética , Factor Xa/metabolismo , Hepatocitos/efectos de los fármacos , Hepatocitos/enzimología , Humanos , Inflamación/genética , Inflamación/metabolismo , Resistencia a la Insulina/genética , Grasa Intraabdominal/metabolismo , Macrófagos/metabolismo , Masculino , Ratones , Ratones Obesos , Obesidad/genética , Obesidad/metabolismo , Receptor PAR-2/deficiencia , Receptor PAR-2/genética , Receptor PAR-2/metabolismo , Fosfato de Sitagliptina/administración & dosificación , Fosfato de Sitagliptina/farmacologíaRESUMEN
Defective insulin signaling in hepatocytes is a key factor in type 2 diabetes. In obesity, activation of calcium/calmodulin-dependent protein kinase II (CaMKII) in hepatocytes suppresses ATF6, which triggers a PERK-ATF4-TRB3 pathway that disrupts insulin signaling. Elucidating how CaMKII suppresses ATF6 is therefore essential to understanding this insulin resistance pathway. We show that CaMKII phosphorylates and blocks nuclear translocation of histone deacetylase 4 (HDAC4). As a result, HDAC4-mediated SUMOylation of the corepressor DACH1 is decreased, which protects DACH1 from proteasomal degradation. DACH1, together with nuclear receptor corepressor (NCOR), represses Atf6 transcription, leading to activation of the PERK-TRB3 pathway and defective insulin signaling. DACH1 is increased in the livers of obese mice and humans, and treatment of obese mice with liver-targeted constitutively nuclear HDAC4 or DACH1 small hairpin RNA (shRNA) increases ATF6, improves hepatocyte insulin signaling, and protects against hyperglycemia and hyperinsulinemia. Thus, DACH1-mediated corepression in hepatocytes emerges as an important link between obesity and insulin resistance.
Asunto(s)
Núcleo Celular/metabolismo , Proteínas del Ojo/metabolismo , Hepatocitos/metabolismo , Histona Desacetilasas/metabolismo , Resistencia a la Insulina , Hígado/metabolismo , Hígado/patología , Obesidad/metabolismo , Factor de Transcripción Activador 6/genética , Factor de Transcripción Activador 6/metabolismo , Animales , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Dieta Alta en Grasa , Silenciador del Gen , Glucosa/metabolismo , Homeostasis , Ratones Obesos , Co-Represor 1 de Receptor Nuclear/metabolismo , Obesidad/patología , Fosforilación , Complejo de la Endopetidasa Proteasomal/metabolismo , Transporte de Proteínas , Proteolisis , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Transducción de Señal , SumoilaciónRESUMEN
The prevalence of obesity-induced type 2 diabetes (T2D) is increasing worldwide, and new treatment strategies are needed. We recently discovered that obesity activates a previously unknown pathway that promotes both excessive hepatic glucose production (HGP) and defective insulin signaling in hepatocytes, leading to exacerbation of hyperglycemia and insulin resistance in obesity. At the hub of this new pathway is a kinase cascade involving calcium/calmodulin-dependent protein kinase II (CaMKII), p38α mitogen-activated protein kinase (MAPK), and MAPKAPK2/3 (MK2/3). Genetic-based inhibition of these kinases improves metabolism in obese mice. Here, we report that treatment of obese insulin-resistant mice with an allosteric MK2/3 inhibitor, compound (cmpd) 28, ameliorates glucose homeostasis by suppressing excessive HGP and enhancing insulin signaling. The metabolic improvement seen with cmpd 28 is additive with the leading T2D drug, metformin, but it is not additive with dominant-negative MK2, suggesting an on-target mechanism of action. Allosteric MK2/3 inhibitors represent a potentially new approach to T2D that is highly mechanism based, has links to human T2D, and is predicted to avoid certain adverse effects seen with current T2D drugs.