Insulin resistance is often associated with obesity and can precipitate type 2 diabetes. To date, most known approaches that improve insulin resistance must be preceded by the amelioration of obesity and hepatosteatosis. Here, we show that this provision is not mandatory; insulin resistance and hyperglycemia are improved by the modification of hepatic fatty acid composition, even in the presence of persistent obesity and hepatosteatosis. Mice deficient for Elovl6, the gene encoding the elongase that catalyzes the conversion of palmitate to stearate, were generated and shown to become obese and develop hepatosteatosis when fed a high-fat diet or mated to leptin-deficient ob/ob mice. However, they showed marked protection from hyperinsulinemia, hyperglycemia and hyperleptinemia. Amelioration of insulin resistance was associated with restoration of hepatic insulin receptor substrate-2 and suppression of hepatic protein kinase C epsilon activity resulting in restoration of Akt phosphorylation. Collectively, these data show that hepatic fatty acid composition is a new determinant for insulin sensitivity that acts independently of cellular energy balance and stress. Inhibition of this elongase could be a new therapeutic approach for ameliorating insulin resistance, diabetes and cardiovascular risks, even in the presence of a continuing state of obesity.

Since the first scientific article about "fairy rings" in 1675 and subsequent studies reviewed in 1884, this phenomenon has been a mystery attributed to "fairies". [1] The tendency of all fungi to grow outward from the point of germination of the spore results in circular colonies in a widely varying group of fungi. Fairy rings are zones of stimulated grass growth. They appear as more or less continuous, circular bands of turfgrass that are darker green and faster growing than adjacent plants of the same species (Figure 1 A). These belts of greener plants can range from 10 to 30 cm wide, and the diameter of the circles they form is generally between 0.9 and 3.7 m. Fungi are responsible for this growth stimulation; presumably through the saprophytic action of the fungus mycelium, the protein portion of nonliving organic matter in the soil is decomposed to ammonia. The ammonia combines with other compounds, or is used as a substrate by successive bacteria to generate nitrites and nitrates. The resulting accumulation of nitrogen in the soil in a form readily available to higher plants causes the typical growth pattern of conspicuous bands of taller, darker green plants. [1,2] We questioned this accepted notion, even if it is partially true, and thus investigated the possibility of a specific plantgrowth-regulating substance(s) being produced by the fungi. We cultured a fairy-ring-forming fungus, Lepista sordida, examined the effect of the culture on the growth of turfgrass, and found that the culture supernatant promoted plant growth. L. sordida is widespread in northern temperate zones throughout the world, [3] including the campus of our university where this study was conducted ( Figure S1 in the Supporting Information).First, to confirm that our L. sordida strain exhibits growthpromoting activity, the cultivated mycelia were placed under bentgrass seedlings (Agrostis palustris) in a deep petri dish and incubated for three weeks. Grass treated with the fungus grew taller than untreated grass (Figure 1 B). Isolation of the active compound from the fungus was guided by its growth-regulating activity on bentgrass. The liquid-cultured fungus was filtered, the filtrate was fractionated by repeated chromatography, and the fractions were tested for their growth-regulating activity. This lead to the isolation and purification of the active compound, 2-azahypoxanthine (AHX; Figures 2 A, B, S2 and S3). Although AHX has been reported as a photolytic degradation product from an antitumor drug, dacarbazine (5-(3,3-dimethyltriazeno)imidazole-4-carboxamide) [4] and has been synthesized, [5] this is the first reported isolation of AHX from a natural source.AHX elongated the shoots and roots of bentgrass seedlings (Figure 2 B). The effect of AHX on shoots was observed at 0.2 and 1 mm and on roots at 0.05 and 0.2 mm. In order to confirm the presence of AHX in the interaction between the fungus and bentgrass (Figure 1 B and Figure S4)

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1. The metabolic fate of midaglizole, 2-[2-(4,5-dihydro-1H-imidazole-2-yl)-1-phenylethyl]pyridine dihydrochloride sesquihydrate, was studied in rats after a single oral dose of 10 mg/kg. 2. After oral administration of 14C-midaglizole to rats, 63% of the dose was excreted in the urine and 41% in the faeces within 72 h. The major radioactive compound in the urine was unchanged midaglizole and accounted for 38.1% of the dose. In the faeces, two major radioactive compounds, M-VII and unchanged midaglizole, were present. These accounted for 17.2 and 14.1% of the dose, respectively. M-VII is a new metabolite, identified as 2-[2-(4,5-dihydro-1H-imidazole-2-yl)-1-(4-hydroxyphenyl)ethyl]pyridine by n.m.r. and mass spectrometry. 3. The biliary excretion of the radioactivity after oral administration of 14C-midaglizole to bile-duct cannulated rats amounted to 53% of the dose. Of the total amount of radioactivity excreted in the bile, 48% was calculated to be subject to enterohepatic recycling. 4. Four biliary metabolites were new metabolites and were identified by n.m.r., mass spectrometry and enzymic hydrolysis. These compounds are 2-[2-(4,5-dihydro-1H-imidazole-2-yl)-1-(4-hydroxyphenyl)-ethyl]pyridine O-glucuronide (M-XI), 2-[2-(4-hydroxyphenyl)-2-(2-pyridyl)]ethyl-2-imidazole O-glucuronide (M-XII),3-(4-hydroxyphenyl)-3-(2-pyridyl)propioimidamide O-glucuronide (M-XIII) and 2-[2-(4,5-dihydro-1H-imidazole-2-yl)-1-(4-hydroxy- 3-methoxyphenyl)ethyl]pyridine O-glucuronide (M-XIV). These glucuronides accounted for 35.4% of the dose. 5. Midaglizole was metabolized in rats mainly via phenyl ring para-hydroxylation followed by glucuronidation, with or without the biotransformation of the imidazoline ring moiety.