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Small molecules selectively inducing peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1α acetylation and inhibiting glucagon-dependent gluconeogenesis causing anti-diabetic effects have been identified. However, how these small molecules selectively suppress the conversion of gluconeogenic metabolites into glucose without interfering with lipogenesis is unknown. Here, we show that a small molecule SR18292 inhibits hepatic glucose production by increasing lactate and glucose oxidation. SR18292 increases phosphoenolpyruvate carboxykinase 1 (PCK1) acetylation, which reverses its gluconeogenic reaction and favors oxaloacetate (OAA) synthesis from phosphoenolpyruvate. PCK1 reverse catalytic reaction induced by SR18292 supplies OAA to tricarboxylic acid (TCA) cycle and is required for increasing glucose and lactate oxidation and suppressing gluconeogenesis. Acetylation mimetic mutant PCK1 K91Q favors anaplerotic reaction and mimics the metabolic effects of SR18292 in hepatocytes. Liver-specific expression of PCK1 K91Q mutant ameliorates hyperglycemia in obese mice. Thus, SR18292 blocks gluconeogenesis by enhancing gluconeogenic substrate oxidation through PCK1 lysine acetylation, supporting the anti-diabetic effects of these small molecules. [Display omitted] • SR18292 increases oxidation of glucose and gluconeogenic substrates • SR18292-mediated gluconeogenic inhibition does not induce de novo lipogenesis • Small molecule SR18292 enhances PCK1 acetylation, leading to OAA synthesis from PEP • Acetyl-mimetic mutation at K91 of PCK1 recapitulates the effects of SR18292 Although suppression of liver glucose production reduces hyperglycemia in diabetes, this inhibition can promote de novo lipogenesis from gluconeogenic substrates, exacerbating hepatic steatosis and compromising clinical interventions. Mutlu et al. elucidate how the small molecule SR18292 represses hepatic gluconeogenesis without perturbation of lipogenesis. [ABSTRACT FROM AUTHOR]

Cannabinoid receptor 1 (CB-1) antagonists are potential candidates for treating obesity and metabolic complications. Despite clear metabolic benefits, unwanted side effects in the brain pose issues for patients. With the hope of overcoming this obstacle, CB-1 in peripheral tissues has become a potential drug target. Previous studies had suggested that liver CB-1 would be an excellent target to prevent development of nonalcoholic steatohepatitis (NAFLD). However, in this issue of the JCI, Wang et al. showed that CB-1 was barely detectable in the liver and deletion of CB-1 in hepatocytes provided no metabolic benefits against NAFLD. These contradictory results raise substantial concerns about the potential benefits of peripheral CB-1 blockers against NAFLD. [ABSTRACT FROM AUTHOR]

During the first hours of embryogenesis, formation of higher-order heterochromatin coincides with the loss of developmental potential. Here we examine the relationship between these two events, and we probe the processes that contribute to the timing of their onset. Mutations that disrupt histone H3 lysine 9 (H3K9) methyltransferases reveal that the methyltransferase MET-2 helps terminate developmental plasticity, through mono- and di- methylation of H3K9 (me1/me2), and promotes heterochromatin formation, through H3K9me3. While loss of H3K9me3 perturbs formation of higher-order heterochromatin, embryos are still able to terminate plasticity, indicating that the two processes can be uncoupled. Methylated H3K9 appears gradually in developing embryos and depends on nuclear localization of MET- 2. We find that the timing of H3K9me2 and nuclear MET-2 is sensitive to rapid cell cycles, but not to zygotic genome activation or cell counting. These data reveal distinct roles for different H3K9 methylation states in the generation of heterochromatin and loss of developmental plasticity by MET-2 and identify the cell cycle as a critical parameter of MET-2 regulation. [ABSTRACT FROM AUTHOR]

The article offers information on a study which reveals that nuclear accumulation of 2-Mercaptoethanol (MET-2) in conjunction with LIN-65 and ARLE-14 regulates timing of heterochromatin domains during embryogenesis. It states that heterochromatin formation during early embryogenesis is timed precisely, but how this process is regulated remains elusive. It mentions that nucleus of a young embryo undergoes major reorganization as it transitions from a fertilized egg to a multicellular embryo.

Mitochondria provide essential metabolites and adenosine triphosphate (ATP) for the regulation of energy homeostasis. For instance, liver mitochondria are a vital source of gluconeogenic precursors under a fasted state. However, the regulatory mechanisms at the level of mitochondrial membrane transport are not fully understood. Here, we report that a liver-specific mitochondrial inner-membrane carrier SLC25A47 is required for hepatic gluconeogenesis and energy homeostasis. Genome-wide association studies found significant associations between SLC25A47 and fasting glucose, HbA1c, and cholesterol levels in humans. In mice, we demonstrated that liver-specific depletion of SLC25A47 impaired hepatic gluconeogenesis selectively from lactate, while significantly enhancing whole-body energy expenditure and the hepatic expression of FGF21. These metabolic changes were not a consequence of general liver dysfunction because acute SLC25A47 depletion in adult mice was sufficient to enhance hepatic FGF21 production, pyruvate tolerance, and insulin tolerance independent of liver damage and mitochondrial dysfunction. Mechanistically, SLC25A47 depletion leads to impaired hepatic pyruvate flux and malate accumulation in the mitochondria, thereby restricting hepatic gluconeogenesis. Together, the present study identified a crucial node in the liver mitochondria that regulates fasting-induced gluconeogenesis and energy homeostasis. [ABSTRACT FROM AUTHOR]

The peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1a) is a transcriptional coactivator that controls expression of metabolic/energetic genes, programming cellular responses to nutrient and environmental adaptations such as fasting, cold, or exercise. Unlike other coactivators, PGC-1a contains protein domains involved in RNA regulation such as serine/arginine (SR) and RNA recognition motifs (RRMs). However, the RNA targets of PGC-1a and how they pertain to metabolism are unknown. To address this, we performed enhanced ultraviolet (UV) cross-linking and immunoprecipitation followed by sequencing (eCLIP-seq) in primary hepatocytes induced with glucagon. A large fraction of RNAs bound to PGC-1a were intronic sequences of genes involved in transcriptional, signaling, or metabolic function linked to glucagon and fasting responses, but were not the canonical direct transcriptional PGC-1a targets such as OXPHOS or gluconeogenic genes. Among the top-scoring RNA sequences bound to PGC-1a were Foxo1, Camk1d, Per1, Klf15, Pln4, Cluh, Trpc5, Gfra1, and Slc25a25. PGC-1a depletion decreased a fraction of these glucagon-induced messenger RNA (mRNA) transcript levels. Importantly, knockdown of several of these genes affected glucagon-dependent glucose production, a PGC-1a-regulated metabolic pathway. These studies show that PGC-1a binds to intronic RNA sequences, some of them controlling transcript levels associated with glucagon action. [ABSTRACT FROM AUTHOR]

Summary: One drug may suppress the effects of another. Although knowledge of drug suppression is vital to avoid efficacy-reducing drug interactions or discover countermeasures for chemical toxins, drug-drug suppression relationships have not been systematically mapped. Here, we analyze the growth response of Saccharomyces cerevisiae to anti-fungal compound (“drug”) pairs. Among 440 ordered drug pairs, we identified 94 suppressive drug interactions. Using only pairs not selected on the basis of their suppression behavior, we provide an estimate of the prevalence of suppressive interactions between anti-fungal compounds as 17%. Analysis of the drug suppression network suggested that Bromopyruvate is a frequently suppressive drug and Staurosporine is a frequently suppressed drug. We investigated potential explanations for suppressive drug interactions, including chemogenomic analysis, coaggregation, and pH effects, allowing us to explain the interaction tendencies of Bromopyruvate. [Copyright &y& Elsevier]

Drug synergy allows a therapeutic effect to be achieved with lower doses of component drugs. Drug synergy can result when drugs target the products of genes that act in parallel pathways (‘specific synergy’). Such cases of drug synergy should tend to correspond to synergistic genetic interaction between the corresponding target genes. Alternatively, ‘promiscuous synergy’ can arise when one drug non-specifically increases the effects of many other drugs, for example, by increased bioavailability. To assess the relative abundance of these drug synergy types,we examined 200 pairs of antifungal drugs in S. cerevisiae.We found 38 antifungal synergies, 37 of which were novel. While 14 cases of drug synergy corresponded to genetic interaction, 92% of the synergies we discovered involved only six frequently synergistic drugs. Although promiscuity of four drugs can be explained under the bioavailability model, the promiscuity of Tacrolimus and Pentamidine was completely unexpected. While many drug synergies correspond to genetic interactions, the majority of drug synergies appear to result from non-specific promiscuous synergy. [ABSTRACT FROM AUTHOR]