Lipolysis: more than just a lipase

Successful adaptation to starvation in mammals depends heavily on the regulated mobilization of fatty acids from triacylglycerols stored in adipose tissue. Although it has long been recognized that cyclic AMP represents the critical second messenger and hormone-sensitive lipase (HSL)* the rate-determining enzyme for lipolysis, simple activation of the enzyme has failed to account for the robust augmentation of fatty release in response to physiological agonists. In this issue, Sztalryd et al. (2003) provide convincing support to the notion that the subcellular compartmentalization of lipase also regulates lipolysis, and, more importantly, that proteins other than HSL are localized to the lipid droplet and are indispensable for its optimal hydrolysis

Of Mice and Men: Not ExAKTly the Same?

The serine-threonine protein kinase Akt2, also known as PKBβ, has been shown to regulate glucose and lipid metabolism in animal models. In a recent study published in Science, Hussain et al. (2011) report that in human subjects an activating mutation of Akt2 leads to hypoglycemia and, unexpectedly, asymmetric overgrowth

The Polycomb protein, Bmi1, regulates insulin sensitivity

Objective: The Polycomb Repressive Complexes (PRC) 1 and 2 function to epigenetically repress target genes. The PRC1 component, Bmi1, plays a crucial role in maintenance of glucose homeostasis and beta cell mass through repression of the Ink4a/Arf locus. Here we have explored the role of Bmi1 in regulating glucose homeostasis in the adult animal, which had not been previously reported due to poor postnatal survival of Bmi1−/− mice. Methods: The metabolic phenotype of Bmi1+/− mice was characterized, both in vivo and ex vivo. Glucose and insulin tolerance tests and hyperinsulinemic-euglycemic clamps were performed. The insulin signaling pathway was assessed at the protein and transcript level. Results: Here we report a negative correlation between Bmi1 levels and insulin sensitivity in two models of insulin resistance, aging and liver-specific insulin receptor deficiency. Further, heterozygous loss of Bmi1 results in increased insulin sensitivity in adult mice, with no impact on body weight or composition. Hyperinsulinemic-euglycemic clamp reveals increased suppression of hepatic glucose production and increased glucose disposal rate, indicating elevated glucose uptake to peripheral tissues, in Bmi1+/− mice. Enhancement of insulin signaling, specifically an increase in Akt phosphorylation, in liver and, to a lesser extent, in muscle appears to contribute to this phenotype. Conclusions: Together, these data define a new role for Bmi1 in regulating insulin sensitivity via enhancement of Akt phosphorylation

Serum Concentrations of Legacy and Emerging Per- and Polyfluoroalkyl Substances in the Anniston Community Health Surveys (ACHS I and ACHS II)

Background Residents of Anniston Alabama were highly exposed to polychlorinated biphenyls (PCBs) due to longstanding manufacturing in the area. The Anniston Community Health Surveys (ACHS I-2005–2007 and II, 2014) have linked these exposures with a variety of deletereous health outcomes. In addition to PCBs, these individuals were likely simultaneously exposed to other persistent organic pollutants including per and polyfluoroalkyl substances (PFAS), which are an emerging class of ubiquitous industrial chemicals that are measurable in the blood of most individuals and have themselves been linked increased risk of some non communicable diseases. Methods To characterize PFAS exposures in ACHS I and ACHS II, we measured eight environmentally significant PFAS in serum by UPLC coupled electrospray ionization tandem mass spectrometry. Perfluorooctane sulfonate (PFOS), Perfluorooctanoic acid (PFOA), Perfluorononanoate (PFNA), Perfluorohexane sulfonate (PFHxS), Perfluoroheptanoic acid (PFHpA), Perfluorobutanesulfonic acid (PFBS), Hexafluoropropylene oxide dimer acid (HFPO-DA), and 4:2 Fluorotelomer sulfonic acid (4.2 FTS) were extracted from matched serum samples of individuals who participated in the original ACHS I (2005–2007; n = 297) and the follow up ACHS II (2014; n = 336). Data were collected in negative multiple reaction monitoring (MRM) mode with monitoring of quantitation and qualifier ions for all target PFAS analytes, surrogates and internal standards. VARCLUS procedure was used to create hierarchical clusters between PFAS and other legacy persistent organic pollutants which may share similar exposure routes. Results Overall, circulating PFAS levels decreased approximately 50% from ACHS I (2005–2007) to ACHS II (2014), but these changes varied by compound. Mean levels of PFOS were \u3e3 times higher in ACHS I subjects than in conpemporaneous NHANES subjects (2005–2006; ACHS I mean: 71.1 ng/ml; NHANES mean: 20.2 ng/mL), and this relationship persisted in ACHS II subjects (2014: ACHS II mean: 34.7 ng/ml; NHANES mean: 5.92 ng/mL). PFNA was also higher in both ACHS I and ACHS II subjects in comparision to NHANES whereas levels of PFOA and PFHxS were lower than in NHANES. Finally, cluster analysis revealed that in ACHS II, most PFAS tracked with polybrominated diphenyl ethers, except PFNA and PFHpA which clustered with industrial PCBs. In ACHS I, PFAS analytes correlated more closely with industrial PCBs and chlorinated pesticides. Conclusions Participants in the Anniston Community Health Surveys have higher levels of PFOS and PFNA than the general population with average PFOS levels \u3e3 times contemporaneous NHANES levels. Since PFAS were not known to be manufactured in the area, more work needs to be completed to determine if population demographics, proximity to a military base, or regional manufacturing can explain the elevated levels

Essential Regulation of Cell Bioenergetics by Constitutive InsP3 Receptor Ca2+ Transfer to Mitochondria

SummaryMechanisms that regulate cellular metabolism are a fundamental requirement of all cells. Most eukaryotic cells rely on aerobic mitochondrial metabolism to generate ATP. Nevertheless, regulation of mitochondrial activity is incompletely understood. Here we identified an unexpected and essential role for constitutive InsP3R-mediated Ca2+ release in maintaining cellular bioenergetics. Macroautophagy provides eukaryotes with an adaptive response to nutrient deprivation that prolongs survival. Constitutive InsP3R Ca2+ signaling is required for macroautophagy suppression in cells in nutrient-replete media. In its absence, cells become metabolically compromised due to diminished mitochondrial Ca2+ uptake. Mitochondrial uptake of InsP3R-released Ca2+ is fundamentally required to provide optimal bioenergetics by providing sufficient reducing equivalents to support oxidative phosphorylation. Absence of this Ca2+ transfer results in enhanced phosphorylation of pyruvate dehydrogenase and activation of AMPK, which activates prosurvival macroautophagy. Thus, constitutive InsP3R Ca2+ release to mitochondria is an essential cellular process that is required for efficient mitochondrial respiration and maintenance of normal cell bioenergetics

SREBP1c-CRY1 signalling represses hepatic glucose production by promoting FOXO1 degradation during refeeding

SREBP1c is a key lipogenic transcription factor activated by insulin in the postprandial state. Although SREBP1c appears to be involved in suppression of hepatic gluconeogenesis, the molecular mechanism is not thoroughly understood. Here we show that CRY1 is activated by insulin-induced SREBP1c and decreases hepatic gluconeogenesis through FOXO1 degradation, at least, at specific circadian time points. SREBP1c−/− and CRY1−/− mice show higher blood glucose than wild-type (WT) mice in pyruvate tolerance tests, accompanied with enhanced expression of PEPCK and G6Pase genes. CRY1 promotes degradation of nuclear FOXO1 by promoting its binding to the ubiquitin E3 ligase MDM2. Although SREBP1c fails to upregulate CRY1 expression in db/db mice, overexpression of CRY1 attenuates hyperglycaemia through reduction of hepatic FOXO1 protein and gluconeogenic gene expression. These data suggest that insulin-activated SREBP1c downregulates gluconeogenesis through CRY1-mediated FOXO1 degradation and that dysregulation of hepatic SREBP1c-CRY1 signalling may contribute to hyperglycaemia in diabetic animals

Isoform-specific requirement for Akt1 in the developmental regulation of cellular metabolism during lactation

SummaryThe metabolic demands and synthetic capacity of the lactating mammary gland exceed that of any other tissue, thereby providing a useful paradigm for understanding the developmental regulation of cellular metabolism. By evaluating mice bearing targeted deletions in Akt1 or Akt2, we demonstrate that Akt1 is specifically required for lactating mice to synthesize sufficient quantities of milk to support their offspring. Whereas cellular proliferation, differentiation, and apoptosis are unaffected, loss of Akt1 disrupts the coordinate regulation of metabolic pathways that normally occurs at the onset of lactation. This results in a failure to upregulate glucose uptake, Glut1 surface localization, lipid synthesis, and multiple lipogenic enzymes, as well as a failure to downregulate lipid catabolic enzymes. These findings demonstrate that Akt1 is required in an isoform-specific manner for orchestrating many of the developmental changes in cellular metabolism that occur at the onset of lactation and establish a role for Akt1 in glucose metabolism

PPARγ contributes to PKM2 and HK2 expression in fatty liver

Rapidly proliferating cells promote glycolysis in aerobic conditions, to increase growth rate. Expression of specific glycolytic enzymes, namely pyruvate kinase M2 and hexokinase 2, concurs to this metabolic adaptation, as their kinetics and intracellular localization favour biosynthetic processes required for cell proliferation. Intracellular factors regulating their selective expression remain largely unknown. Here we show that the peroxisome proliferator-activated receptor gamma transcription factor and nuclear hormone receptor contributes to selective pyruvate kinase M2 and hexokinase 2 gene expression in PTEN-null fatty liver. Peroxisome proliferator-activated receptor gamma expression, liver steatosis, shift to aerobic glycolysis and tumorigenesis are under the control of the Akt2 kinase in PTEN-null mouse livers. Peroxisome proliferator-activated receptor gamma binds to hexokinase 2 and pyruvate kinase M promoters to activate transcription. In vivo rescue of peroxisome proliferator-activated receptor gamma activity causes liver steatosis, hypertrophy and hyperplasia. Our data suggest that therapies with the insulin-sensitizing agents and peroxisome proliferator-activated receptor gamma agonists, thiazolidinediones, may have opposite outcomes depending on the nutritional or genetic origins of liver steatosis