Hot off the presses! Apr 08 Cell Metab

The Apr 08 issue of the Cell Metab is now up on Pubget (About Cell Metab): if you're at a subscribing institution, just click the link in the latest link at the home page. (Note you'll only be able to get all the PDFs in the issue if your institution subscribes to Pubget.)

Latest Articles Include:

• The Insulin Receptor Talks to Glucagon?
  - Cell Metab 9(4):303-305 (2009)
  Type 2 diabetes (T2DM) is not only a disorder of impaired insulin secretion but also glucagon oversecretion. However, the link between the two remains unclear. Is it possible that the latter is a consequence of the former? In this issue, Kawamori et al. (2009) have addressed this question by generating α cell-specific insulin receptor knockout mice.
• "AcCoA"lade for Energy and Life Span
  - Cell Metab 9(4):305-306 (2009)
  Faced with changing food availability, organisms adapt metabolism to survive. In a recent issue of Cell, Lin et al. (2009) described the acetylation of an extranuclear enzyme being regulated by acetyl-CoA. This finding connects nutrient availability, energy status, and survival.
• Something Old, Something New, Something Borrowed …
  - Cell Metab 9(4):307-308 (2009)
  Two mammalian mitochondrial transcription factors (TFB1M and TFB2M) share homology with universally expressed dimethyltransferases that modify conserved adenines in the small ribosomal subunit rRNA. Work in this issue (Metodiev et al., 2009) shows that loss of TFB1M abolishes mitochondrial ribosome assembly without affecting mitochondrial transcription.
• The Worm Profits from Undercharging
  - Cell Metab 9(4):309-310 (2009)
  Hypoxia endangers the survival of cells and organisms. Mutations in an enzyme that attaches amino acids to tRNAs to supply protein synthesis confer resistance to hypoxia in C. elegans. By slowing down protein synthesis (a major consumer of energy), such mutations may save valuable energy and/or prevent accumulation of malfolded proteins.
• A Branched-Chain Amino Acid-Related Metabolic Signature that Differentiates Obese and Lean Humans and Contributes to Insulin Resistance
  - Cell Metab 9(4):311-326 (2009)
  Metabolomic profiling of obese versus lean humans reveals a branched-chain amino acid (BCAA)-related metabolite signature that is suggestive of increased catabolism of BCAA and correlated with insulin resistance. To test its impact on metabolic homeostasis, we fed rats on high-fat (HF), HF with supplemented BCAA (HF/BCAA), or standard chow (SC) diets. Despite having reduced food intake and a low rate of weight gain equivalent to the SC group, HF/BCAA rats were as insulin resistant as HF rats. Pair-feeding of HF diet to match the HF/BCAA animals or BCAA addition to SC diet did not cause insulin resistance. Insulin resistance induced by HF/BCAA feeding was accompanied by chronic phosphorylation of mTOR, JNK, and IRS1Ser307 and by accumulation of multiple acylcarnitines in muscle, and it was reversed by the mTOR inhibitor, rapamycin. Our findings show that in the context of a dietary pattern that includes high fat consumption, BCAA contributes to development of obesity-as! sociated insulin resistance.
• Hepatocyte-Specific Deletion of SIRT1 Alters Fatty Acid Metabolism and Results in Hepatic Steatosis and Inflammation
  - Cell Metab 9(4):327-338 (2009)
  Hepatic metabolic derangements are key components in the development of fatty liver, insulin resistance, and atherosclerosis. SIRT1, a NAD+-dependent protein deacetylase, is an important regulator of energy homeostasis in response to nutrient availability. Here we demonstrate that hepatic SIRT1 regulates lipid homeostasis by positively regulating peroxisome proliferators-activated receptor α (PPARα), a nuclear receptor that mediates the adaptive response to fasting and starvation. Hepatocyte-specific deletion of SIRT1 impairs PPARα signaling and decreases fatty acid β-oxidation, whereas overexpression of SIRT1 induces the expression of PPARα targets. SIRT1 interacts with PPARα and is required to activate PPARα coactivator PGC-1α. When challenged with a high-fat diet, liver-specific SIRT1 knockout mice develop hepatic steatosis, hepatic inflammation, and endoplasmic reticulum stress. Taken together, our data indicate that SIRT1 plays a vital role in the regulati! on of hepatic lipid homeostasis and that pharmacological activation of SIRT1 may be important for the prevention of obesity-associated metabolic diseases.
• CXC Ligand 5 Is an Adipose-Tissue Derived Factor that Links Obesity to Insulin Resistance
  - Cell Metab 9(4):339-349 (2009)
  We show here high levels of expression and secretion of the chemokine CXC ligand 5 (CXCL5) in the macrophage fraction of white adipose tissue (WAT). Moreover, we find that CXCL5 is dramatically increased in serum of human obese compared to lean subjects. Conversely, CXCL5 concentration is decreased in obese subjects after a weight reduction program, or in obese non-insulin-resistant, compared to insulin-resistant, subjects. Most importantly we demonstrate that treatment with recombinant CXCL5 blocks insulin-stimulated glucose uptake in muscle in mice. CXCL5 blocks insulin signaling by activating the Jak2/STAT5/SOCS2 pathway. Finally, by treating obese, insulin-resistant mice with either anti-CXCL5 neutralizing antibodies or antagonists of CXCR2, which is the CXCL5 receptor, we demonstrate that CXCL5 mediates insulin resistance. Furthermore CXCR2−/− mice are protected against obesity-induced insulin resistance. Taken together, these results show that secretion of CX! CL5 by WAT resident macrophages represents a link between obesity, inflammation, and insulin resistance.
• Insulin Signaling in α Cells Modulates Glucagon Secretion In Vivo
  - Cell Metab 9(4):350-361 (2009)
  Glucagon plays an important role in glucose homeostasis by regulating hepatic glucose output in both normo- and hypoglycemic conditions. In this study, we created and characterized α cell-specific insulin receptor knockout (αIRKO) mice to directly explore the role of insulin signaling in the regulation of glucagon secretion in vivo. Adult male αIRKO mice exhibited mild glucose intolerance, hyperglycemia, and hyperglucagonemia in the fed state and enhanced glucagon secretion in response to L-arginine stimulation. Hyperinsulinemic-hypoglycemic clamp studies revealed an enhanced glucagon secretory response and an abnormal norepinephrine response to hypoglycemia in αIRKO mice. The mutants also exhibited an age-dependent increase in β cell mass. Furthermore, siRNA-mediated knockdown of insulin receptor in glucagon-secreting InR1G cells promoted enhanced glucagon secretion and complemented our in vivo findings. Together, these data indicate a significant role for intrai! slet insulin signaling in the regulation of α cell function in both normo- and hypoglycemic conditions.
• Critical Role for Hypothalamic mTOR Activity in Energy Balance
  - Cell Metab 9(4):362-374 (2009)
  The mammalian target of rapamycin (mTOR) promotes anabolic cellular processes in response to growth factors and metabolic cues. The TSC1 and TSC2 tumor suppressors are major upstream inhibitory regulators of mTOR signaling. Mice with Rip2/Cre-mediated deletion of Tsc1 (Rip-Tsc1cKO mice) developed hyperphagia and obesity, suggesting that hypothalamic disruption (for which Rip2/Cre is well known) of Tsc1 may dysregulate feeding circuits via mTOR activation. Indeed, Rip-Tsc1cKO mice displayed increased mTOR signaling and enlarged neuron cell size in a number of hypothalamic populations, including Pomc neurons. Furthermore, Tsc1 deletion with Pomc/Cre (Pomc-Tsc1cKO mice) resulted in dysregulation of Pomc neurons and hyperphagic obesity. Treatment with the mTOR inhibitor, rapamycin, ameliorated the hyperphagia, obesity, and the altered Pomc neuronal morphology in developing or adult Pomc-Tsc1cKO mice, and cessation of treatment reinstated these phenotypes. Thus, ongoing mTO! R activation in Pomc neurons blocks the catabolic function of these neurons to promote nutrient intake and increased adiposity.
• Coordinated Regulation of Foraging and Metabolism in C. elegans by RFamide Neuropeptide Signaling
  - Cell Metab 9(4):375-385 (2009)
  Animals modify food-seeking behavior and metabolism according to perceived food availability. Here we show that, in the roundworm C. elegans, release of neuropeptides from interneurons that are directly postsynaptic to olfactory, gustatory, and thermosensory neurons coordinately regulates behavior and metabolism. Animals lacking these neuropeptides, encoded by the flp-18 gene, are defective in chemosensation and foraging, accumulate excess fat, and exhibit reduced oxygen consumption. Two G protein-coupled receptors of the NPY/RFamide family, NPR-4 and NPR-5, are activated by FLP-18 peptides in vitro and exhibit mutant phenotypes that recapitulate those of flp-18 mutants. Our data suggest that sensory input can coordinately regulate behavior and metabolism via NPY/RFamide-like receptors. They suggest that peptidergic feedback from interneurons regulates sensory neuron activity, and that at least some of this communication occurs extrasynaptically. Extrasynaptic neuropep! tide signaling may greatly increase the computational capacity of neural circuits.
• Methylation of 12S rRNA Is Necessary for In Vivo Stability of the Small Subunit of the Mammalian Mitochondrial Ribosome
  - Cell Metab 9(4):386-397 (2009)
  The 3′ end of the rRNA of the small ribosomal subunit contains two extremely highly conserved dimethylated adenines. This modification and the responsible methyltransferases are present in all three domains of life, but its function has remained elusive. We have disrupted the mouse Tfb1m gene encoding a mitochondrial protein homologous to bacterial dimethyltransferases and demonstrate here that loss of TFB1M is embryonic lethal. Disruption of Tfb1m in heart leads to complete loss of adenine dimethylation of the rRNA of the small mitochondrial ribosomal subunit, impaired assembly of the mitochondrial ribosome, and abolished mitochondrial translation. In addition, we present biochemical evidence that TFB1M does not activate or repress transcription in the presence of TFB2M. Our results thus show that TFB1M is a nonredundant dimethyltransferase in mammalian mitochondria. In addition, we provide a possible explanation for the universal conservation of adenine dimethylati! on of rRNA by showing a critical role in ribosome maintenance.