Cells constantly adapt their metabolism to meet their energy needs and respond to nutrient availability. Eukaryotes have evolved a very sophisticated system to sense low cellular ATP levels via the serine/threonine kinase AMP-activated protein kinase (AMPK) complex. Under conditions of low energy, AMPK phosphorylates specific enzymes and growth control nodes to increase ATP generation and decrease ATP consumption. In the past decade, the discovery of numerous new AMPK substrates has led to a more complete understanding of the minimal number of steps required to reprogramme cellular metabolism from anabolism to catabolism. This energy switch controls cell growth and several other cellular processes, including lipid and glucose metabolism and autophagy. Recent studies have revealed that one ancestral function of AMPK is to promote mitochondrial health, and multiple newly discovered targets of AMPK are involved in various aspects of mitochondrial homeostasis, including mitophagy. This Review discusses how AMPK functions as a central mediator of the cellular response to energetic stress and mitochondrial insults and coordinates multiple features of autophagy and mitochondrial biology.

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AMPK: guardian of metabolism and mitochondrial homeostasis.

Elucidating the signalling mechanisms by which obesity leads to impaired insulin action is critical in the development of therapeutic strategies for the treatment of diabetes. Recently, mice deficient for S6 Kinase 1 (S6K1), an effector of the mammalian target of rapamycin (mTOR) that acts to integrate nutrient and insulin signals, were shown to be hypoinsulinaemic, glucose intolerant and have reduced β-cell mass. However, S6K1-deficient mice maintain normal glucose levels during fasting, suggesting hypersensitivity to insulin, raising the question of their metabolic fate as a function of age and diet. Here, we report that S6K1-deficient mice are protected against obesity owing to enhanced β-oxidation. However on a high fat diet, levels of glucose and free fatty acids still rise in S6K1-deficient mice, resulting in insulin receptor desensitization. Nevertheless, S6K1-deficient mice remain sensitive to insulin owing to the apparent loss of a negative feedback loop from S6K1 to insulin receptor substrate 1 (IRS1), which blunts S307 and S636/S639 phosphorylation; sites involved in insulin resistance. Moreover, wild-type mice on a high fat diet as well as K/K Ay and ob/ob (also known as Lep/Lep) micetwo genetic models of obesityhave markedly elevated S6K1 activity and, unlike S6K1-deficient mice, increased phosphorylation of IRS1 S307 and S636/S639. Thus under conditions of nutrient satiation S6K1 negatively regulates insulin signalling.

Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity. [Erratum: 2004 Sept. 23, v. 431, no. 7007, p. 485.]

Apoptosis is a form of cell death by which the body maintains the homeostasis of the internal environment. Apoptosis is an initiative cell death process that is controlled by genes and is mainly divided into endogenous pathways (mitochondrial pathway), exogenous pathways (death receptor pathway), and apoptotic pathways induced by endoplasmic reticulum (ER) stress. The homeostasis imbalance in ER results in ER stress. Under specific conditions, ER stress can be beneficial to the body; however, if ER protein homeostasis is not restored, the prolonged activation of the unfolded protein response may initiate apoptotic cell death via the up-regulation of the C/EBP homologous protein (CHOP). CHOP plays an important role in ER stress-induced apoptosis and this review focuses on its multifunctional roles in that process, as well as its role in apoptosis during microbial infection. We summarize the upstream and downstream pathways of CHOP in ER stress induced apoptosis. We also focus on the newest discoveries in the functions of CHOP-induced apoptosis during microbial infection, including DNA and RNA viruses and some species of bacteria. Understanding how CHOP functions during microbial infection will assist with the development of antimicrobial therapies.

The C/EBP Homologous Protein (CHOP) Transcription Factor Functions in Endoplasmic Reticulum Stress-Induced Apoptosis and Microbial Infection

Nitric oxide (NO) signalling has pleiotropic roles in biology and a crucial function in cardiovascular homeostasis. Tremendous knowledge has been accumulated on the mechanisms of the nitric oxide synthase (NOS)-NO pathway, but how this highly reactive, free radical gas signals to specific targets for precise regulation of cardiovascular function remains the focus of much intense research. In this Review, we summarize the updated paradigms on NOS regulation, NO interaction with reactive oxidant species in specific subcellular compartments, and downstream effects of NO in target cardiovascular tissues, while emphasizing the latest developments of molecular tools and biomarkers to modulate and monitor NO production and bioavailability.

Nitric oxide signalling in cardiovascular health and disease

The AMP-activated protein kinase (AMPK) is a central regulator of multiple metabolic pathways and may have therapeutic importance for treating obesity, insulin resistance, type 2 diabetes (T2D), non-alcoholic fatty liver disease (NAFLD), and cardiovascular disease (CVD). Given the ubiquitous expression of AMPK, it has been a challenge to evaluate which tissue types may be most beneficially poised for mediating the positive metabolic effects of AMPK-centered treatments. In this review we evaluate the metabolic phenotypes of transgenic mouse models in which AMPK expression and function have been manipulated, and the impact this has on controlling lipid metabolism, glucose homeostasis, and inflammation. This information may be useful for guiding the development of AMPK-targeted therapeutics to treat chronic metabolic diseases.

AMPK as a Therapeutic Target for Treating Metabolic Diseases

Cigarette smoking promotes body weight reduction in humans while paradoxically also promoting insulin resistance (IR) and hyperinsulinemia. However, the mechanisms behind these effects are unclear. Here we show that nicotine, a major constituent of cigarette smoke, selectively activates AMP-activated protein kinase α2 (AMPKα2) in adipocytes, which in turn phosphorylates MAP kinase phosphatase-1 (MKP1) at serine 334, initiating its proteasome-dependent degradation. The nicotine-dependent reduction of MKP1 induces the aberrant activation of both p38 mitogen-activated protein kinase and c-Jun N-terminal kinase, leading to increased phosphorylation of insulin receptor substrate 1 (IRS1) at serine 307. Phosphorylation of IRS1 leads to its degradation, protein kinase B inhibition, and the loss of insulin-mediated inhibition of lipolysis. Consequently, nicotine increases lipolysis, which results in body weight reduction, but this increase also elevates the levels of circulating free fatty acids and thus causes IR in insulin-sensitive tissues. These results establish AMPKα2 as an essential mediator of nicotine-induced whole-body IR in spite of reductions in adiposity.

Activation of AMPKα2 in adipocytes is essential for nicotine-induced insulin resistance in vivo.

Background— This study tested the hypothesis whether endoplasmic reticulum (ER) stress/C/EBP homologous protein (CHOP) signaling is linked with coxsackievirus B3 (CVB3)–induced acute viral myocarditis (AVMC) in vivo.

Methods and Results— AVMC was induced by intraperitoneal injection of 1000 tissue culture infectious dose (TCID50) of CVB3 virus in mice. In AVMC mouse hearts (n=11), ER stress and CHOP were significantly activated, and were linked to the induction of proapoptotic signaling including reduction of Bcl-2, activation of Bax and caspase 3, compared with the controls (n=10), whereas these could be markedly blocked by ER stress inhibitor tauroursodeoxycholic acid administration (n=11). Moreover, chemical inhibition of ER stress significantly attenuated cardiomyocytes apoptosis, and prevented cardiac troponin I elevation, ameliorated cardiac dysfunction assessed by both hemodynamic and echocardiographic analysis, reduced viral replication, and increased survival rate after CVB3 inoculation. We further discovered that genetic ablation of CHOP (n=10) suppressed cardiac Bcl-2/Bax ratio reduction and caspase 3 activation, and prevented cardiomyotes apoptosis in vivo, compared with wild-type receiving CVB3 inoculation (n=10). Strikingly, CHOP deficiency exhibited dramatic protective effects on cardiac damage, cardiac dysfunction, viral replication, and promoted survival in CVB3-caused AVMC.

Conclusions— Our data imply the involvement of ER stress/CHOP signaling in CVB3-induced AVMC via proapoptotic pathways, and provide a novel strategy for AVMC treatment.

Involvement of Endoplasmic Reticulum Stress Mediated C/EBP Homologous Protein Activation in Coxsackievirus B3-Induced Acute Viral Myocarditis

Objective—Dihydrofolate reductase (DHFR) is a key protein involved in tetrahydrobiopterin (BH4) regeneration from 7,8-dihydrobiopterin (BH2). Dysfunctional DHFR may induce endothelial nitric oxide (NO) synthase (eNOS) uncoupling resulting in enzyme production of superoxide anions instead of NO. The mechanism by which DHFR is regulated is unknown. Here, we investigate whether eNOS-derived NO maintains DHFR stability. Approach and Results—DHFR activity, BH4 content, eNOS activity, and S-nitrosylation were assessed in human umbilical vein endothelial cells and in aortas isolated from wild-type and eNOS knockout mice. In human umbilical vein endothelial cells, depletion of intracellular NO by transfection with eNOS-specific siRNA or by the NO scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (PTIO)—both of which had no effect on DHFR mRNA levels—markedly reduced DHFR protein levels in parallel with increased DHFR polyubiquitination. Supplementation of S-nitroso-l-glutathione (GSNO), ...

Endothelial Nitric Oxide Synthase–Derived Nitric Oxide Prevents Dihydrofolate Reductase Degradation via Promoting S-Nitrosylation

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Activation of AMPKα2 in adipocytes is essential for nicotine-induced insulin resistance in vivo.

Involvement of Endoplasmic Reticulum Stress Mediated C/EBP Homologous Protein Activation in Coxsackievirus B3-Induced Acute Viral Myocarditis

Endothelial Nitric Oxide Synthase–Derived Nitric Oxide Prevents Dihydrofolate Reductase Degradation via Promoting S-Nitrosylation