RESUMEN
The benefits of endurance exercise on general health make it desirable to identify orally active agents that would mimic or potentiate the effects of exercise to treat metabolic diseases. Although certain natural compounds, such as reseveratrol, have endurance-enhancing activities, their exact metabolic targets remain elusive. We therefore tested the effect of pathway-specific drugs on endurance capacities of mice in a treadmill running test. We found that PPARbeta/delta agonist and exercise training synergistically increase oxidative myofibers and running endurance in adult mice. Because training activates AMPK and PGC1alpha, we then tested whether the orally active AMPK agonist AICAR might be sufficient to overcome the exercise requirement. Unexpectedly, even in sedentary mice, 4 weeks of AICAR treatment alone induced metabolic genes and enhanced running endurance by 44%. These results demonstrate that AMPK-PPARdelta pathway can be targeted by orally active drugs to enhance training adaptation or even to increase endurance without exercise.
Asunto(s)
Aminoimidazol Carboxamida/análogos & derivados , Complejos Multienzimáticos/metabolismo , Músculo Esquelético/metabolismo , PPAR delta/agonistas , Resistencia Física/efectos de los fármacos , Proteínas Serina-Treonina Quinasas/metabolismo , Ribonucleótidos/farmacología , Tiazoles/farmacología , Proteínas Quinasas Activadas por AMP , Administración Oral , Aminoimidazol Carboxamida/administración & dosificación , Aminoimidazol Carboxamida/farmacología , Animales , Biomimética , Masculino , Ratones , Ratones Endogámicos C57BL , Condicionamiento Físico Animal , Ribonucleótidos/administración & dosificaciónRESUMEN
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.
Asunto(s)
Factor 1 de Crecimiento de Fibroblastos/genética , Factor 1 de Crecimiento de Fibroblastos/metabolismo , Homeostasis , Grasa Intraabdominal/metabolismo , PPAR gamma/metabolismo , Adipocitos/efectos de los fármacos , Adipocitos/metabolismo , Adipocitos/patología , Animales , Secuencia de Bases , Tamaño de la Célula/efectos de los fármacos , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patología , Dieta Alta en Grasa/efectos adversos , Factor 1 de Crecimiento de Fibroblastos/deficiencia , Homeostasis/efectos de los fármacos , Humanos , Inflamación/genética , Insulina/metabolismo , Resistencia a la Insulina , Grasa Intraabdominal/efectos de los fármacos , Grasa Intraabdominal/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Necrosis/enzimología , Regiones Promotoras Genéticas/genética , Elementos de Respuesta/genéticaRESUMEN
Circadian clocks coordinate behavioral and physiological processes with daily light-dark cycles by driving rhythmic transcription of thousands of genes. Whereas the master clock in the brain is set by light, pacemakers in peripheral organs, such as the liver, are reset by food availability, although the setting, or "entrainment," mechanisms remain mysterious. Studying mouse fibroblasts, we demonstrated that the nutrient-responsive adenosine monophosphate-activated protein kinase (AMPK) phosphorylates and destabilizes the clock component cryptochrome 1 (CRY1). In mouse livers, AMPK activity and nuclear localization were rhythmic and inversely correlated with CRY1 nuclear protein abundance. Stimulation of AMPK destabilized cryptochromes and altered circadian rhythms, and mice in which the AMPK pathway was genetically disrupted showed alterations in peripheral clocks. Thus, phosphorylation by AMPK enables cryptochrome to transduce nutrient signals to circadian clocks in mammalian peripheral organs.