PAS Kinase Is a Nutrient and Energy Sensor in Hypothalamic Areas Required for the Normal Function of AMPK and mTOR/S6K1

Abstract

The complications caused by overweight, obesity and type 2 diabetes are one of the main problems that increase morbidity and mortality in developed countries. Hypothalamic metabolic sensors play an important role in the control of feeding and energy homeostasis. PAS kinase (PASK) is a nutrient sensor proposed as a regulator of glucose metabolism and cellular energy. The role of PASK might be similar to other known metabolic sensors, such as AMP-activated protein kinase (AMPK) and the mammalian target of rapamycin (mTOR). PASK-deficient mice resist diet-induced obesity.We have recently reported that AMPK and mTOR/S6K1 pathways are regulated in the ventromedial and lateral hypothalamus in response to nutritional states, being modulated by anorexigenic glucagon-like peptide-1 (GLP-1)/exendin-4 in lean and obese rats. We identified PASK in hypothalamic areas, and its expression was regulated under fasting/refeeding conditions and modulated by exendin-4. Furthermore, PASK-deficient mice have an impaired activation response of AMPK and mTOR/S6K1 pathways. Thus, hypothalamic AMPK and S6K1 were highly activated under fasted/re-fed conditions. Additionally, in this study, we have observed that the exendin-4 regulatory effect in the activity of metabolic sensors was lost in PASK-deficient mice, and the anorexigenic properties of exendin-4 were significantly reduced, suggesting that PASK could be a mediator in the GLP-1 signalling pathway. Our data indicated that the PASK function could be critical for preserving the nutrient effect on AMPK and mTOR/S6K1 pathways and maintain the regulatory role of exendin-4 in food intake. Some of the antidiabetogenic effects of exendin-4 might be modulated through these processes. Abstract The complications caused by overweight, obesity and type 2 diabetes are one of the main problems that increase morbidity and mortality in developed countries. Hypothalamic metabolic sensors play an important role in the control of feeding and energy homeostasis. PAS kinase (PASK) is a nutrient sensor proposed as a regulator of glucose metabolism and cellular energy. The role of PASK might be similar to other known metabolic sensors, such as AMP-activated protein kinase (AMPK) and the mammalian target of rapamycin (mTOR). PASK-deficient mice resist diet-induced obesity. We have recently reported that AMPK and mTOR/S6K1 pathways are regulated in the ventromedial and lateral hypothalamus in response to nutritional states, being modulated by anorexigenic glucagon-like peptide-1 (GLP-1)/exendin-4 in lean and obese rats. We identified PASK in hypothalamic areas, and its expression was regulated under fasting/refeeding conditions and modulated by exendin-4. Furthermore, PASK-deficient mice have an impaired activation response of AMPK and mTOR/S6K1 pathways. Thus, hypothalamic AMPK and S6K1 were highly activated under fasted/re-fed conditions. Additionally, in this study, we have observed that the exendin-4 regulatory effect in the activity of metabolic sensors was lost in PASK-deficient mice, and th...

Genetic Architecture of Natural Variation Underlying Adult Foraging Behavior That Is Essential for Survival of Drosophila melanogaster

“…In addition, the mammalian ortholog of fray is a Ste20-like kinase (PASK; Leiserson et al 2000, 2011), which has a role as a metabolic sensor that is required for energy balance in mice (Hao et al 2007). Importantly, the energy-sensing role of PASK has been shown to be essential for the normal function of AMPK and mTOR/S6K1 (Hurtado-Carneiro et al 2014). …”

PAS kinase is activated by direct SNF1-dependent phosphorylation and mediates inhibition of TORC1 through the phosphorylation and activation of Pbp1

“…In support of this progrowth association, PAS kinase overexpression suppresses a temperature-sensitive mutation of TOR2 in yeast ( tor2ts ; Cardon et al ., 2012 ). In addition, PAS kinase was recently shown to be required for proper activation of AMPK and mTOR in the hypothalamus, where AMPK activation by nutrient depletion and TORC1 activation by refeeding are both blunted in PASK − / − mice ( Hurtado-Carneiro et al ., 2013 , 2014 ). The converse association is found in yeast, in which AMPK/SNF1 is required for the activation of PAS kinase by non­glucose carbon sources ( Grose et al ., 2007 ).…”

PSK1 coordinates glucose metabolism and utilization and regulates energy‐metabolism oscillation in Saccharomyces cerevisiae

“…These results are consistent with the present findings. Other studies in mammals reported that PSK kinase deficiency is associated with relative decrease in insulin production, insulin resistance, triglyceride accumulation, and protects against high fat‐diet‐induced obesity (Cardon & Rutter, ; Hao et al, ; Hurtado‐Carneiro et al, ; Pape et al, ). Our results do not only provide an insight into the mechanism of biological rhythms but are also potentially useful for the design of new treatments for human metabolic syndrome and/or diabetes.…”