It is becoming increasingly clear that transcription of many of the proteins encoded in the genome is controlled by small metabolites whose concentrations vary depending upon environmental conditions. Thus consuming a diet rich in carbohydrate leads to the transcription of the genes encoding the major enzymes of glycolysis required to form the precursor acetyl CoA as well as the enzymes of the hexose monophosphate pathway producing the NADPH required for fat synthesis. The transcription factor is called ChREBP and responds to dietary carbohydrate. Combined with the effects of SREBP, the sterol responsive binding protein described by Brown and Goldstein, and responsive to insulin, these two transcription factors are of major importance in obesity, type II diabetes and vascular diseases. This elegant coordinated control of ChREBP is exerted by the simple hexose monophosphate pathway metabolite, xylulose 5-P (Veech RL, PNAC 2003;100:5578-80). Changes in the redox state of the pyridine nucleotides are the hallmark of changes in metabolic status and is known to be profoundly altered by alcohol ingestion. A number of transcription factors are now known to be controlled by the redox state of the pyridine nucleotides. These include: NPAS2, the so-called clock gene responsible for circadian rhythm (Rutter J et al, Science 2003;293:510-4) CtBP, the transcriptional co-repressor playing a role in development and transformation, (Fjeld C et al, PNAS 2003;100:9202-7) Oct-1, the transcription factor regulating expression of nuclear histones, H2B, (McKnight S, Cell 2003;114:150-2). Sir2, the gene silencer thought to play a central role in the life extending properties of caloric restriction in yeast, C. elegans, and in mammals as well. In recent work, done in colaboration with other groups as NIH, we have shown that the activity of SIR2 in myoblasts is controlled by changes in the free cytosolic [NAD+]/[NADH] (Fulco M et al, Mol Cell 2003;12:51-62). Currently it is thought that the activity of this enzyme is controlled by inhibition by nicotinamide with a Ki of over 150 micromolar. We are continuing the examination of changes induced in the amount of Sirt1 present in different dietary conditions. It is not now clear how control is related to change in the [NAD+]/[NADH] ratio. It goes without saying that changes in [NAD+]/[NADH] are characteristic of both alcohol ingestion and ketosis and would therefore be expected to alter the activity of the above listed transcription factors.? ? Reducing insulin/IGF signaling allows for organismal survival during periods of inhospitable conditions by regulating the diapause state, whereby the organism stockpiles lipids, reduces fertility, increases stress resistance, and has an increased lifespan. The Target of Rapamycin (TOR) responds to changes in growth factors, amino acids, oxygen tension, and energy status; however, it is unclear how TOR contributes to physiological homeostasis and disease conditions. Here, we show that reducing the function of Drosophila TOR results in decreased lipid stores and glucose levels. Importantly, this reduction of dTOR activity blocks the insulin resistance and metabolic syndrome phenotypes associated with increased activity of the insulin responsive transcription factor, dFOXO. Reduction in dTOR function also protects against age-dependent decline in heart function and increases longevity. Thus, the regulation of dTOR activity may be an ancient """"""""systems biological"""""""" means of regulating metabolism and senescence, that has important evolutionary, physiological, and clinical implications.? ? ? SIGNIFICANCE TO THE PROGRAMS OF THIS INSTITUTE? ? Obesity and methods to reduce it, is a major target of the NIH roadmap. Work in understanding the role of dietary carbohydrate in the genesis of obesity is of importance in understanding and correcting this problem. Our publication in this area has been well received and is now the standard reference on the metabolic control of lipogenesis in the new Lehninger?s textbook of biochemistry. In addition, the control of Sir2 activity is considered to be a key step in the life extending properties of caloric restriction. The ability of a changing [NAD+]/[NADH] ratio, which results from ethanol ingestion, is therefore of major significance to the NIAAA as well as the ability of resveratrol, a flavinoid component of red wine, which stimulates Sir2 activity.
| Burgess, Shawn C; Iizuka, Katsumi; Jeoung, Nam Ho et al. (2008) Carbohydrate-response element-binding protein deletion alters substrate utilization producing an energy-deficient liver. J Biol Chem 283:1670-8 |
| Luong, Nancy; Davies, Claire R; Wessells, Robert J et al. (2006) Activated FOXO-mediated insulin resistance is blocked by reduction of TOR activity. Cell Metab 4:133-42 |
| Veech, Richard L (2003) A humble hexose monophosphate pathway metabolite regulates short- and long-term control of lipogenesis. Proc Natl Acad Sci U S A 100:5578-80 |
| Fulco, Marcella; Schiltz, R Louis; Iezzi, Simona et al. (2003) Sir2 regulates skeletal muscle differentiation as a potential sensor of the redox state. Mol Cell 12:51-62 |
