Actions and interactions of AMPK with insulin, the peroxisomal-proliferator activated receptors and sirtuins.

AMP-activated protein kinase (AMPK) activity responds to a requirement to increase cellular ATP production and/or to conserve available ATP. AMPK is therefore central to the mechanisms of adjustment to fluctuating energy demand or metabolic substrate supply. AMPK has important actions in several insulin-responsive tissues, as well as in the pancreatic β cell, through which it can modulate glycemic control, insulin action and metabolic substrate selection and disposal.

Adipocyte pyruvate dehydrogenase kinase 4 expression is associated with augmented PPARγ upregulation in early-life programming of later obesity.

We studied adipocytes from 8-week-old control rat offspring (CON) or rat offspring subjected to maternal low (8%) protein (MLP) feeding during pregnancy/lactation, a procedure predisposing to obesity. Acute exposure to isoproterenol or adenosine enhanced PDK4 and PPARγ mRNA gene expression in CON and MLP adipocytes. Enhanced adipocyte Pdk4 expression correlated with increased PPARγ expression.

Endogenous epoxygenases are modulators of monocyte/macrophage activity.

Background: Arachidonic acid is metabolized through three major metabolic pathways, the cyclooxygenase, lipoxygenase and CYP450 enzyme systems. Unlike cyclooxygenase and lipoxygenases, the role of CYP450 epoxygenases in monocyte/macrophage-mediated responses is not known.

Methodology/principal Findings: When transfected in vitro, CYP2J2 is an efficient activator of anti-inflammatory pathways through the nuclear receptor peroxisome proliferator-activated receptor (PPAR) α.

The pyruvate carboxylase-pyruvate dehydrogenase axis in islet pyruvate metabolism: Going round in circles?

Pyruvate is the major product of glycolysis in pancreatic β-cells, and its ultimate metabolic fate depends on the relative activities of two enzymes. The first, pyruvate carboxylase (PC) replenishes oxaloacetate withdrawn from the tricarboxylic acid (TCA) cycle via the carboxylation of pyruvate to form oxaloacetate. Flux via PC is also involved in the formation of NADPH, one of several important coupling factors for insulin secretion.

Signalling satiety and starvation to β-Cell insulin secretion.

The impact of bariatric surgery on insulin sensitivity and glucose tolerance has refocused interest in the role of gut-derived factors in the regulation of insulin secretion and action. The incretins, glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1) are released from endocrine cells in the small intestinal mucosa primarily in response to oral nutrient ingestion. They have various effects, including augmentation of glucose-stimulated insulin secretion (GSIS), actions that promote the cellular assimilation and storage of dietary glucose and lipid as liver and skeletal muscle glycogen and adipocyte triacylglycerol (TAG) respectively.

PPARα-LXR as a novel metabolostatic signalling axis in skeletal muscle that acts to optimize substrate selection in response to nutrient status.

LXR (liver X receptor) and PPARα (peroxisome-proliferator-activated receptor α) are nuclear receptors that control the expression of genes involved in glucose and lipid homoeostasis. Using wild-type and PPARα-null mice fed on an LXR-agonist-supplemented diet, the present study analysed the impact of pharmacological LXR activation on the expression of metabolically important genes in skeletal muscle, testing the hypothesis that LXR activation can modulate PPAR action in skeletal muscle in a manner dependent on nutritional status. In the fed state, LXR activation promoted a gene profile favouring lipid storage and glucose oxidation, increasing SCD1 (stearoyl-CoA desaturase 1) expression and down-regulating PGC-1α (PPARγ co-activator-1α) and PDK4 (pyruvate dehydrogenase kinase 4) expression.

Acute and long-term nutrient-led modifications of gene expression: potential role of SIRT1 as a central co-ordinator of short and longer-term programming of tissue function.

Environmental factors can influence the acute and longer-term risks of developing diseases, including type 2 diabetes mellitus and cardiovascular disease; however, the underlying mechanism remains elusive. Increasing evidence suggests that these effects can be achieved by modification of metabolic gene expression. These include acute changes in histone methylation, acetylation, phosphorylation, and ubiquitination and longer-term DNA silencing elicited by DNA methylation.

The epoxygenases CYP2J2 activates the nuclear receptor PPARalpha in vitro and in vivo.

Background: Peroxisome proliferator-activated receptors (PPARs) are a family of three (PPARalpha, -beta/delta, and -gamma) nuclear receptors. In particular, PPARalpha is involved in regulation of fatty acid metabolism, cell growth and inflammation. PPARalpha mediates the cardiac fasting response, increasing fatty acid metabolism, decreasing glucose utilisation, and is the target for the fibrate lipid-lowering class of drugs.

PPAR control: it's SIRTainly as easy as PGC.

This review describes recent advances in our knowledge of the regulatory interactions influencing the expression of peroxisome proliferator-activated receptor (PPAR)-regulated genes. We address recent advances highlighting the role of PPARgamma (PPARG) coactivator-1 (PGC-1) and lipin-1 in co-ordinating the expression of genes controlling nutrient handling. We evaluate the possibility that SIRT1 lies at the heart of a regulatory loop involving PPARalpha, PGC-1alpha (PPARA, PPARGC1A as given in the HUGO Database), and lipin-1 (LPIN1 as listed in the HUGO Database) that ultimately controls the metabolic response to varying nutrient and physiological signals via a common mechanism mediated by post-translation modifications (deacetylation) of both PPARalpha and PGC-1s.

PPARs and the orchestration of metabolic fuel selection.

This contribution describes recent advances in our knowledge of the regulatory interactions between the two major oxidative fuels glucose and lipid. It also addresses how the metabolic abnormalities associated with insulin resistance and ischemic diseases impair the ability of skeletal muscle to switch between the use of alternative metabolic fuels and the ability of adipose tissue to function appropriately in relation to the body's requirements for triglyceride mobilisation or storage, as appropriate to nutritional status. We discuss how targeting PPARs might ameliorate metabolic inflexibility in muscle through altered expression of pyruvate dehydrogenase kinase (PDK) isoforms and impact the functions of the adipocyte in lipid buffering and energy homeostasis.

The role of PPARs in modulating cardiac metabolism in diabetes.

Diabetes mellitus is an important risk factor for the development of cardiovascular disease. The impact of diabetes on the heart in part resides in the changes in metabolic fuel availability evoked by lack of insulin or resistance to its action. This review addresses how the metabolic abnormalities associated with poorly controlled diabetes impact cardiac fuel supply and handling, with emphasis on the coordinating roles of the PPARs.

PPARalpha activation and increased dietary lipid oppose thyroid hormone signaling and rescue impaired glucose-stimulated insulin secretion in hyperthyroidism.

The aim of the study was to investigate the impact of hyperthyroidism on the characteristics of the islet insulin secretory response to glucose, particularly the consequences of competition between thyroid hormone and peroxisome proliferator-activated receptor (PPAR)alpha in the regulation of islet adaptations to starvation and dietary lipid-induced insulin resistance. Rats maintained on standard (low-fat/high-carbohydrate) diet or high-fat/low-carbohydrate diet were rendered hyperthyroid (HT) by triiodothyronine (T(3)) administration (1 mg.kg body wt(-1).

Role of nuclear receptors in the modulation of insulin secretion in lipid-induced insulin resistance.

In healthy individuals, a hyperbolic relationship exists between whole-body insulin-sensitivity and insulin secretion. Thus, for any difference in insulin-sensitivity, a reciprocal proportionate change occurs in insulin secretion. Such a feedback loop is evident in healthy individuals ingesting diets high in saturated fat and in late pregnancy where, despite lipid-induced insulin resistance, glucose tolerance is maintained through augmented GSIS (glucose-stimulated insulin secretion).

PPARalpha activation reverses adverse effects induced by high-saturated-fat feeding on pancreatic beta-cell function in late pregnancy.

We examined whether the additional demand for insulin secretion imposed by dietary saturated fat-induced insulin resistance during pregnancy is accommodated at late pregnancy, already characterized by insulin resistance. We also assessed whether effects of dietary saturated fat are influenced by PPARalpha activation or substitution of 7% of dietary fatty acids (FAs) with long-chain omega-3 FA, manipulations that improve insulin action in the nonpregnant state. Glucose tolerance at day 19 of pregnancy in the rat was impaired by high-saturated-fat feeding throughout pregnancy.

Diet, obesity and diabetes: a current update.

The prevalence of obesity has been increasing at a rapid rate over the last few decades. Although the primary defect can be attributed to an imbalance of energy intake over energy expenditure, the regulation of energy balance is now recognized to be complex. Adipose-tissue factors play a central role in the control of energy balance and whole-body fuel homoeostasis.

Mechanisms underlying regulation of the expression and activities of the mammalian pyruvate dehydrogenase kinases.

The mechanisms that control mammalian pyruvate dehydrogenase complex (PDC) activity include its phosphorylation (inactivation) by a family of pyruvate dehydrogenase kinases (PDKs 1 - 4). Here we review new developments in the regulation of the activities and expression of the PDKs, in particular PDK2 and PDK4, in relation to glucose and lipid homeostasis. This review describes recent advances relating to the acute and long-term modes of regulation of the PDKs, with particular emphasis on the regulatory roles of nuclear receptors including peroxisome proliferator-activated receptor (PPAR) alpha and Liver X receptor (LXR), PPAR gamma coactivator alpha (PGC-1alpha) and insulin, and the impact of changes in PDK activity and expression in glucose and lipid homeostasis.

Peroxisome proliferator-activated receptor-alpha and glucocorticoids interactively regulate insulin secretion during pregnancy.

We evaluated the impact of peroxisome proliferator-activated receptor (PPAR)alpha activation and dexamethasone treatment on islet adaptations to the distinct metabolic challenges of fasting and pregnancy, situations where lipid handling is modified to conserve glucose. PPARalpha activation (24 h) in vivo did not affect glucose-stimulated insulin secretion (GSIS) in nonpregnant female rats in the fasted state, although fasting suppressed GSIS. Dexamethasone treatment (5 days) of nonpregnant rats lowered the glucose threshold and augmented GSIS at high glucose; the former effect was selectively opposed by PPARalpha activation.

Epigenetic regulation of metabolism in children born small for gestational age.

Purpose Of Review: Epigenetic alterations are responsible for modulation of tissue-specific gene expression and genomic imprinting. Mechanisms include posttranslational modifications of core histones and DNA methylation. The review focuses on emerging data highlighting the potential for epigenetic modulation of gene expression in mediating early-life programming of increased risk of adult-onset disease.

Acute omega-3 fatty acid enrichment selectively reverses high-saturated fat feeding-induced insulin hypersecretion but does not improve peripheral insulin resistance.

In rats fed a high-saturated fat diet, replacement of a small percentage of total fatty acids with long-chain omega-3 fatty acids from fish oil for the duration of high-fat feeding prevents the development of insulin resistance. We investigated the effect of acute (24-h) modulation of dietary fat composition on glucose-stimulated insulin secretion (GSIS) in rats made insulin resistant by high-saturated fat feeding for 4 weeks. Insulin secretion after an intravenous glucose challenge was greatly increased by high-saturated fat feeding.

Potential role of peroxisome proliferator-activated receptor-alpha in the modulation of glucose-stimulated insulin secretion.

In this review, we discuss the influence of peroxisome proliferator-activated receptor (PPAR)-alpha on islet insulin secretion and develop the hypothesis that modulation of PPAR-alpha function may be important for the regulation of compensatory insulin secretion. We have attempted to analyze the role of PPAR-alpha-linked fatty acid metabolism in islet function in health and in insulin-resistant states linked to lifestyle factors, in particular pregnancy and a diet inappropriately high in saturated fat. We have emphasized the potential for both actions of PPAR-alpha on insulin sensitivity that may be relayed systemically to the islet, leading to modulation of the insulin response in accordance with changes in insulin sensitivity, and direct effects of PPAR-alpha action on the islet itself.

Trials, tribulations and finally, a transporter: the identification of the mitochondrial pyruvate transporter.

Pyruvate occupies a central role in energy homoeostasis, and dysregulation of its cellular disposition underlies many metabolic disturbances. Although the mitochondrial membrane pyruvate transporter has been characterized, its molecular identity has proved elusive. Recent work has now identified a single candidate protein for the mitochondrial pyruvate carrier in yeast, opening the way for further studies in mammalian systems, which may have important therapeutic applications within the context of metabolic disease.

Diabetogenic impact of long-chain omega-3 fatty acids on pancreatic beta-cell function and the regulation of endogenous glucose production.

In healthy individuals, peripheral insulin resistance evoked by dietary saturated lipid can be accompanied by increased insulin secretion such that glucose tolerance is maintained. Substitution of long-chain omega-3 fatty acids for a small percentage of dietary saturated fat prevents insulin resistance in response to high-saturated fat feeding. We substituted a small amount (7%) of dietary lipid with long-chain omega-3 fatty acids during 4 wk of high-saturated fat feeding to investigate the relationship between amelioration of insulin resistance and glucose-stimulated insulin secretion (GSIS).