Fatty acid desaturases introduce a double bond in a specific position of long-chain fatty acids, and are conserved across kingdoms. Degree of unsaturation of fatty acids affects physical properties of membrane phospholipids and stored triglycerides. In addition, metabolites of polyunsaturated fatty acids are used as signaling molecules in many organisms. Three desaturases, Delta9, Delta6, and Delta5, are present in humans. Delta-9 catalyzes synthesis of monounsaturated fatty acids. Oleic acid, a main product of Delta9 desaturase, is the major fatty acid in mammalian adipose triglycerides, and is also used for phospholipid and cholesteryl ester synthesis. Delta-6 and Delta5 desaturases are required for the synthesis of highly unsaturated fatty acids (HUFAs), which are mainly esterified into phospholipids and contribute to maintaining membrane fluidity. While HUFAs may be required for cold tolerance in plants and fish, the primary role of HUFAs in mammals is cell signaling. Arachidonic acid is required as substrates for eicosanoid synthesis, while docosahexaenoic acid is required in visual and neuronal functions. Desaturases in mammals are regulated at the transcriptional level. Reflecting overlapping functions, three desaturases share a common mechanism of a feedback regulation to maintain products in membrane phospholipids. At the same time, regulation of Delta9 desaturase differs from Delta6 and Delta5 desaturases because its products are incorporated into more diverse lipid groups. Combinations of multiple transcription factors achieve this sophisticated differential regulation.

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This article is available online at http://www.jlr.org identifi ed as essential fatty acids that must be consumed in the diet. Once consumed, however, LA and ALA can both be desaturated and elongated into more highly unsaturated fatty acids (HUFA) such as arachidonic (AA), docosapentaenoic (DPA n-6), and docosahexaenoic (DHA) acids via the pathway shown in Fig. 1A . Delta-6 desaturase (D6D) performs the fi rst and rate-limiting step in this process, as well as the last step of desaturation for DHA and DPA n-6 synthesis. The D6D gene FADS2 was cloned in 1999 ( 2 ), and subsequently, a human case of D6D deficiency was identifi ed ( 3 ). The patient exhibited growth retardation accompanied by skin abnormalities, corneal ulceration, and feeding intolerance. Treatment with dietary AA and DHA restored normal growth and eliminated most other symptoms, underscoring the importance of the endogenous synthesis of these HUFAs.AA is a precursor to a host of signaling molecules known as eicosanoids, which include thromboxanes, leukotrienes, prostacyclins, and prostaglandins produced from the oxygenation of AA by cyclooxygenase and lipoxygenase enzymes. However, the symptoms of classic essential fatty acid defi ciency, growth retardation and dermatitis ( 1 ), are attributed to a loss of LA, not AA or eicosanoids. Because LA is an essential component of skin ceramides, LA defi ciency results in the disruption of the skin's water barrier function ( 4 ) and heat loss from skin ( 5 ). These side effects make investigation of AA defi ciency impossible by dietary manipulation without complications from LA defi ciency.DHA is found in large amounts in the retina, brain, and testes ( 6, 7 ). The role of DHA has been largely thought to be structural, increasing the fl uidity of cellular memAbstract Delta-6 desaturase (D6D) catalyzes the fi rst step in the synthesis of highly unsaturated fatty acids (HUFA) such as arachidonic (AA), docosapentaenoic (DPAn-6), and docosahexaenoic (DHA) acids, as well as the last desaturation of DPAn-6 and DHA. We created D6D-null mice ( ؊ / ؊ ), which enabled us to study HUFA defi ciency without depleting their precursors. In ؊ / ؊ , no in vivo AA synthesis was detected after administration of [U-

Fatty acids (FA) regulate the expression of genes involved in lipid and energy metabolism. In particular, two transcription factors, sterol regulatory element binding protein-1c (SREBP-1c) and peroxisome proliferator activated receptor alpha (PPARalpha), have emerged as key mediators of gene regulation by FA. SREBP-1c induces a set of lipogenic enzymes in liver. Polyunsaturated fatty acids (PUFA), but not saturated or monounsaturated FA, suppress the induction of lipogenic genes by inhibiting the expression and processing of SREBP-1c. This unique effect of PUFA suggests that SREBP-1c may regulate the synthesis of unsaturated FA for incorporation into glycerolipids and cholesteryl esters. PPARalpha plays an essential role in metabolic adaptation to fasting by inducing the genes for mitochondrial and peroxisomal FA oxidation as well as those for ketogenesis in mitochondria. FA released from adipose tissue during fasting are considered as ligands of PPARalpha. Dietary PUFA, except for 18:2 n-6, are likely to induce FA oxidation enzymes via PPARalpha as a "feed-forward " mechanism. PPARalpha is also required for regulating the synthesis of highly unsaturated FA, indicating pleiotropic functions of PPARalpha in the regulation of lipid metabolic pathways. It is yet to be determined whether FA regulate other transcription factors such as liver-X receptor, hepatocyte nuclear factor 4, and carbohydrate response element binding protein.

Dietary fructose has been suspected to contribute to development of metabolic syndrome. However, underlying mechanisms of fructose effects are not well characterized. We investigated metabolic outcomes and hepatic expression of key regulatory genes upon fructose feeding under well defined conditions. Rats were fed a 63% (w/w) glucose or fructose diet for 4 h/day for 2 weeks, and were killed after feeding or 24-hour fasting. Liver glycogen was higher in the fructose-fed rats, indicating robust conversion of fructose to glycogen through gluconeogenesis despite simultaneous induction of genes for de novo lipogenesis and increased liver triglycerides. Fructose feeding increased mRNA of previously unidentified genes involved in macronutrient metabolism including fructokinase, aldolase B, phosphofructokinase-1, fructose-1,6-bisphosphatase and carbohydrate response element binding protein (ChREBP). Activity of glucose-6-phosphate dehydrogenase, a key enzyme for ChREBP activation, remained elevated in both fed and fasted fructose groups. In the fasted liver, the fructose group showed lower non-esterified fatty acids, triglycerides and microsomal triglyceride transfer protein mRNA, suggesting low VLDL synthesis even though plasma VLDL triglycerides were higher. In conclusion, fructose feeding induced a broader range of genes than previously identified with simultaneous increase in glycogen and triglycerides in liver. The induction may be in part mediated by ChREBP.

Peroxisome proliferator-activated receptor alpha (PPARalpha), a key regulator of fatty acid oxidation, is essential for adaptation to fasting in rats and mice. However, physiological functions of PPARalpha in other species, including humans, are controversial. A group of PPARalpha ligands called peroxisome proliferators (PPs) causes peroxisome proliferation and hepatocarcinogenesis only in rats and mice. To elucidate the role of PPARalpha in adaptation to fasting in nonproliferating species, we compared gene expressions in pig liver from fasted and clofibric acid (a PP)-fed groups against a control diet-fed group. As in rats and mice, fasting induced genes involved with mitochondrial fatty acid oxidation and ketogenesis in pigs. Those genes were also induced by clofibric acid feeding, indicating that PPARalpha mediates the induction of these genes. In contrast to rats and mice, little or no induction of genes for peroxisomal or microsomal fatty acid oxidation was observed in clofibric acid-fed pigs. Histology showed no significant hyperplasia or hepatomegaly in the clofibric acid-fed pigs, whereas it showed a reduction of glycogen by clofibric acid, an effect of PPs also observed in rats. Copy number of PPARalpha mRNA was higher in pigs than in mice and rats, suggesting that peroxisomal proliferation and hyperresponse of several genes to PPs seen only in rats and mice are unrelated to the abundance of PPARalpha. In conclusion, PPARalpha is likely to play a central role in adaptation to fasting in pig liver as in rats and mice.

There are two types of brown adipocytes: classical brown adipocytes that form the brown fat depots and beige adipocytes that emerge in the white fat depots. Beige adipocytes have a low level of uncoupling protein 1 (Ucp1) expression in the basal state, but Ucp1 expression is increased in response to β adrenergic receptor activation. The present study explored the factors responsible for the differentiation of 3T3-L1 white preadipocytes to beige adipocytes. Significant expression of Ucp1 was not detected under any tested conditions in the absence of isoproterenol (Iso), an agonist of β adrenergic receptor. Iso-induced Ucp1 expression was significantly higher in the cells treated with a mixture of triiodothyronine (T3) and 3-isobutyl-1-methylxanthine (IBMX) for days 0–8 than in the control cells. Chronic IBMX treatment was indispensable for the enhanced Iso-induced Ucp1 expression, and treatment with additional rosiglitazone (Rosi) for days 0–8 further increased the Ucp1 expression. Recently, genes were identified that are predominantly expressed in beige adipocytes, which were induced from stromal vascular cells in white fat depots. However, the expression levels of the beige adipocyte-selective genes in the adipocytes induced by the mixture of T3, IBMX and Rosi did not differ from those in the control adipocytes. The present study indicates that 3T3-L1 cells can differentiate to beige-like adipocytes by prolonged treatment with the mixture of T3, IBMX and Rosi and that the gene expression profile of the adipocytes is distinct from those previously induced from white fat depots.

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