Omega-3-polyunsaturated fatty acids (ω-3-PUFAs) have well-documented protective effects that are attributed not only to eicosanoid inhibition but also to the formation of novel biologically active lipid mediators (i.e., resolvins and protectins). In this study, we examined their effects on ob/ob mice, an obesity model of insulin resistance and fatty liver disease. Dietary intake of ω-3-PUFAs had insulin-sensitizing actions in adipose tissue and liver and improved insulin tolerance in obese mice. Genes involved in insulin sensitivity (PPARγ), glucose transport (GLUT-2/GLUT-4), and insulin receptor signaling (IRS-1/IRS-2) were up-regulated by ω-3-PUFAs. Moreover, ω-3-PUFAs increased adiponectin, an anti-inflammatory and insulin-sensitizing adipokine, and induced AMPK phosphorylation, a fuel-sensing enzyme and a gatekeeper of the energy balance. Concomitantly, hepatic steatosis was alleviated by ω-3-PUFAs. A lipidomic analysis with liquid chromatography/mass spectrometry/mass spectrometry revealed that ω-3-PUFAs inhibited the formation of ω-6-PUFA-derived eicosanoids, while triggering the formation of ω-3-PUFA-derived resolvins and protectins. Moreover, representative members of these lipid mediators, namely resolvin E1 and protectin D1, mimicked the insulin-sensitizing and antisteatotic effects of ω-3-PUFAs and induced adiponectin expression to a similar extent that of rosiglitazone, a member of the thiazolidinedione family of antidiabetic drugs. Taken together, these findings uncover beneficial actions of ω-3-PUFAs and their bioactive lipid autacoids in preventing obesity-induced insulin resistance and hepatic steatosis.—Gonzalez-Periz, A., Horrillo, R., Ferre, N., Gronert, K., Dong, B., Moran-Salvador, E., Titos, E., Martinez-Clemente, M., Lopez-Parra, M., Arroyo, V., Claria, J. Obesity-induced insulin resistance and hepatic steatosis are alleviated by ω-3 fatty acids: a role for resolvins and protectins.

Obesity-induced insulin resistance and hepatic steatosis are alleviated by ω-3 fatty acids: a role for resolvins and protectins

Essential polyunsaturated fatty acids (PUFAs) are critical nutritional lipids that must be obtained from the diet to sustain homeostasis. Omega-3 and -6 PUFAs are key components of biomembranes and play important roles in cell integrity, development, maintenance, and function. The essential omega-3 fatty acid family member docosahexaenoic acid (DHA) is avidly retained and uniquely concentrated in the nervous system, particularly in photoreceptors and synaptic membranes. DHA plays a key role in vision, neuroprotection, successful aging, memory, and other functions. In addition, DHA displays anti-inflammatory and inflammatory resolving properties in contrast to the proinflammatory actions of several members of the omega-6 PUFAs family. This review discusses DHA signalolipidomics, comprising the cellular/tissue organization of DHA uptake, its distribution among cellular compartments, the organization and function of membrane domains rich in DHA-containing phospholipids, and the cellular and molecular events revealed by the uncovering of signaling pathways regulated by DHA and docosanoids, the DHA-derived bioactive lipids, which include neuroprotectin D1 (NPD1), a novel DHA-derived stereoselective mediator. NPD1 synthesis agonists include neurotrophins and oxidative stress; NPD1 elicits potent anti-inflammatory actions and prohomeostatic bioactivity, is anti-angiogenic, promotes corneal nerve regeneration, and induces cell survival. In the context of DHA signalolipidomics, this review highlights aging and the evolving studies on the significance of DHA in Alzheimer's disease, macular degeneration, Parkinson's disease, and other brain disorders. DHA signalolipidomics in the nervous system offers emerging targets for pharmaceutical intervention and clinical translation.

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Docosahexaenoic Acid Signalolipidomics in Nutrition: Significance in Aging, Neuroinflammation, Macular Degeneration, Alzheimer's, and Other Neurodegenerative Diseases

It is desirable to minimize the use of rare or toxic metals for oxidative reactions in the synthesis of pharmaceutical products. Hypervalent iodine compounds are environmentally benign alternatives, but their catalytic use, particularly for asymmetric transformations, has been quite limited. We report here an enantioselective oxidative cycloetherification of ketophenols to 2-acyl-2,3-dihydrobenzofuran derivatives, catalyzed by in situ-generated chiral quaternary ammonium (hypo)iodite salts, with hydrogen peroxide as an environmentally benign oxidant. The optically active 2-acyl 2,3-dihydrobenzofuran skeleton is a key structure in several biologically active compounds.

http://science.sciencemag.org/content/sci/328/5984/1376.full.pdf

Quaternary Ammonium (Hypo)iodite Catalysis for Enantioselective Oxidative Cycloetherification

PPARγ is a nuclear receptor that regulates metabolic homeostasis and whose physiological ligands are nitrated and oxidized fatty acids. The crystal structures of the ligand binding domain of PPARγ in complex with several oxidized fatty acids are now described, showing differences with synthetic agonists that may have physiological relevance.

Structural basis for the activation of PPARγ by oxidized fatty acids

Peroxisome proliferator-activated receptor structures: ligand specificity, molecular switch and interactions with regulators.

Mild oxidation of aldehydes to the corresponding carboxylic acids and esters: alkaline iodine oxidation revisited

Identification of putative metabolites of docosahexaenoic acid as potent PPARγ agonists and antidiabetic agents

Synthesis of a reagent for fluorescence-labeling of vitamin D and its use in assaying vitamin D metabolites

Fluorometric assay of 25-hydroxyvitamin D3 and 24R,25-dihydroxyvitamin D3 in plasma.

Fluorigenic dienophiles, 1,2,4-triazoline-3,5-dione derivatives with a highly fluorescent substituent at the 4-position 1a, b, were synthesized as reagents for detecting biological compounds with a conjugated diene group.

Sachiko Yamada

Papers

Mild oxidation of aldehydes to the corresponding carboxylic acids and esters: alkaline iodine oxidation revisited

Identification of putative metabolites of docosahexaenoic acid as potent PPARγ agonists and antidiabetic agents

Synthesis of a reagent for fluorescence-labeling of vitamin D and its use in assaying vitamin D metabolites

Fluorometric assay of 25-hydroxyvitamin D3 and 24R,25-dihydroxyvitamin D3 in plasma.

Synthesis of highly fluorescent dienophiles for detecting conjugated dienes in biological fluid