PAS kinase is required for normal cellular energy balance

Abstract

The metabolic syndrome, a complex set of phenotypes typically associated with obesity and diabetes, is an increasing threat to global public health. Fundamentally, the metabolic syndrome is caused by a failure to properly sense and respond to cellular metabolic cues. We studied the role of the cellular metabolic sensor PAS kinase (PASK) in the pathogenesis of metabolic disease by using PASK ؊/؊ mice. We identified tissue-specific metabolic phenotypes caused by PASK deletion consistent with its role as a metabolic sensor. Specifically, PASK ؊/؊ mice exhibited impaired glucose-stimulated insulin secretion in pancreatic ␤-cells, altered triglyceride storage in liver, and increased metabolic rate in skeletal muscle. Further, PASK deletion caused nearly complete protection from the deleterious effects of a high-fat diet including obesity and insulin resistance. We also demonstrate that these cellular effects, increased rate of oxidative metabolism and ATP production, occur in cultured cells. We therefore hypothesize that PASK acts in a cell-autonomous manner to maintain cellular energy homeostasis and is a potential therapeutic target for metabolic disease.metabolism ͉ PAS domain ͉ nutrient sensing ͉ obesity B ecause of changes in diet and lifestyle, the incidence of obesity and type 2 diabetes is increasing dramatically worldwide. Type 2 diabetes arises when pancreatic ␤-cells fail to secrete sufficient insulin to compensate for peripheral insulin resistance, a condition severely aggravated by obesity (1, 2). Type 2 diabetes is now widely viewed as a manifestation of a broader underlying metabolic disorder called the metabolic syndrome, which is characterized by hyperglycemia, hyperinsulinemia, dyslipidemia, hypertension, visceral obesity, and cardiovascular disease (3). The World Health Organization estimates that the current decade will witness a 46% increase in diabetes incidence worldwide (from 151 million to 221 million), with the vast majority of this increase being due to metabolic syndrome-related type 2 diabetes (4).Cellular energy and nutrient sensors determine how cells respond to excessive nutrients, and aberrant nutrient and energy sensing is a contributing factor to metabolic syndrome development (5, 6). AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) are two well studied and evolutionarily conserved cellular energy and nutrient sensors. AMPK is activated in response to intracellular ATP depletion and acts to switch the cellular metabolic program from ATP consumption to ATP production (7). In contrast to AMPK, mTOR is activated by sufficient cellular energy or nutrients, particularly amino acids (8). Activation of mTOR stimulates cell growth by increasing protein synthesis through phosphorylation of ribosomal S6 kinase (S6K) and eIF4E-binding protein (9). Decreased AMPK activity and elevated mTOR activity have been linked with obesity, diabetes, and cancer (10-12).Like AMPK and mTOR, PAS kinase (PASK) is a nutrientresponsive protein kinase conserved from yeast to humans. Th...

Orchestrated downregulation of genes involved in oxidative metabolic pathways in obese vs. lean high-fat young male consumers

“…Therefore, all the observed changes suggest that a decrease in both mitochondrial oxidative activity and mitochondrial adenosin triphosphate (ATP) synthesis could underlie the susceptibility to HFD-induced obesity. This hypothesis is in agreement with the results obtained by Hao et al (12), which showed that mice with deleted PAS kinase (a cellular metabolic sensor) are resistant to high fat diet-induced obesity and insulin resistance, partly due to an increase in the rate of oxidative metabolism and ATP production. This finding could explain why after a high fat load of 50% of their energy requirements, obese-susceptible subjects were not able to increase their rates of fat oxidation more than the lean subjects, despite their higher metabolic mass (25).…”

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

“…However, an analysis of pancreatic beta cells from mice in which the kinase domain has been removed (PASK knockout) showed that Pask mRNA expression did not respond to elevated glucose concentrations, and no differences in glucose-stimulated insulin production were found between both types of mice [31]. Later studies indicated that PASK-deficient mice are resistant to diet-induced obesity, with this effect being related to an increase in the metabolic rate in skeletal muscle, although there was no effect on the function of other metabolic sensors (AMPK, mTOR) [7].…”

“…PASK Expression Responds to Fasting and Re-feeding in VMH and LH from Wild-Type Mice PASK has already been proposed as a nutrient sensor [7], so we analysed PASK mRNA expression under fasting and refeeding conditions in VMH and LH from wild-type and PASK-deficient mice. In order to ensure the purity of these hypothalamic nuclei obtained by micropunching from mouse hypothalamus, Sf-1 and prepro-orexin genes were used as markers of these specific nuclei, respectively.…”

“…Initially, PASK-deficient mice showed no developmental, growth, or reproductive defects [6]. Later investigation indicated that PASK-deficient mice are resistant to dietinduced obesity, and PASK knockdown by RNAi in cultured myoblasts causes increased glucose and palmitate oxidation and elevated cellular ATP levels [7]. Additionally, PASK is also implicated in the regulation of glucagon secretion by glucose, and PASK expression was lower in pancreatic islets from human with type 2 diabetes [8].…”

Per-arnt-sim (PAS) domain kinase (PASK) as a regulator of glucagon secretion

“…The da Silva Xavier study focuses on the per-arnt-sim (PAS) domain kinase (PASK), another serine/threonine kinase [18] implicated in the sensing of cellular energy homeostasis, the control of insulin gene expression [19] and the modulation of insulin gene expression under pathophysiological cell culture conditions [20]. However, while Pask -/-mice displayed reduced plasma insulin responses to glucose they showed normal glucose [21,22] and insulin [21] tolerance. da Silva Xavier et al now examine whether PASK may function as a metabolic sensor in alpha cells.…”