The metabolic syndrome is defined as the coexistence of 3 or more components, some of which indicate alterations in glucose and lipid metabolism. The prevalence of the metabolic syndrome is rapidly increasing in relation to obesity, and it is considered to be an important predictor of cardiovascular disease. Increased intakes or supplements of n-3 marine fatty acids may improve defects in insulin signaling and prevent alterations in glucose homeostasis and the further development of type 2 diabetes. This is largely mediated through a reduction in fatty acid accumulation in muscle and liver. n-3 Polyunsaturated fatty acids (n-3 PUFAs) reduce plasma triacylglycerols and improve the lipoprotein profile by decreasing the fraction of atherogenic small, dense LDL. However, n-3 PUFAs do not lower LDL cholesterol. These effects are likely mediated through the activity of transcription factors relating to expression of genes involved in lipid oxidation and synthesis. Other pleiotrophic effects of n-3 PUFAs may contribute to decreasing the burden of the metabolic syndrome, such as modulating inflammation, platelet activation, endothelial function, and blood pressure. Although studies comparing the effect of both major n-3 PUFAs are limited, docosahexaenoic acid appears at least as efficient as eicosapentaenoic acid in correcting several risk factors. The use of n-3 PUFAs should be considered in more global strategies including changes in lifestyle, such as adhering to a healthy Mediterranean type of diet and practicing regular physical exercise.

Patients with non-alcoholic fatty liver disease are characterised by a decreased n-3/n-6 polyunsaturated fatty acid (PUFA) ratio in hepatic phospholipids. The metabolic consequences of n-3 PUFA depletion in the liver are poorly understood. We have reproduced a drastic drop in n-3 PUFA among hepatic phospholipids by feeding C57Bl/6J mice for 3 months with an n-3 PUFA depleted diet (DEF) versus a control diet (CT), which only differed in the PUFA content. DEF mice exhibited hepatic insulin resistance (assessed by euglycemic-hyperinsulinemic clamp) and steatosis that was associated with a decrease in fatty acid oxidation and occurred despite a higher capacity for triglyceride secretion. Microarray and qPCR analysis of the liver tissue revealed higher expression of all the enzymes involved in lipogenesis in DEF mice compared to CT mice, as well as increased expression and activation of sterol regulatory element binding protein-1c (SREBP-1c). Our data suggest that the activation of the liver X receptor pathway is involved in the overexpression of SREBP-1c, and this phenomenon cannot be attributed to insulin or to endoplasmic reticulum stress responses. In conclusion, n-3 PUFA depletion in liver phospholipids leads to activation of SREBP-1c and lipogenesis, which contributes to hepatic steatosis.

In order to gain information on the determinism of the perturbation of fuel homeostasis in situations characterized by a depletion in long-chain polyunsaturated omega3 fatty acids (omega3), the metabolic and hormonal status of omega3-depleted rats (second generation) was examined. When required, these rats were injected intravenously 120 min before sacrifice with a novel medium-chain triglyceride-fish oil emulsion able to provoke a rapid and sustained increase of the omega3 content in cell phospholipids. The measurement of plasma glucose, insulin, phospholipid, triglyceride, and unesterified fatty acid concentration indicated modest insulin resistance in the omega3-depleted rats. The plasma triglyceride and phospholipid concentrations were decreased in the omega3-depleted rats with abnormally low contribution of omega3 in both circulating and pancreatic islet lipids. The protein, insulin, and lipid content of the islets, as well as their intracellular and extracellular spaces, were little affected in the omega3-depleted rats. The metabolism of D-glucose in the islets of omega3-depleted rats was characterized by a lesser increase in D-[5-3H]glucose utilization and D-[U-14C]glucose oxidation in response to a given rise in hexose concentration and an abnormally low ratio between D-glucose oxidation and utilization. These abnormalities could be linked to an increased metabolism of endogenous fatty acids with resulting alteration of glucokinase kinetics. The release of insulin evoked by D-glucose, at a close-to-physiological concentration (8.3 mM), was increased in the omega3-depleted rats, this being considered as consistent with their insulin resistance. Relative to such a release, that evoked by a further rise in D-glucose concentration or by non-glucidic nutrients was abnormally high in omega3-depleted rats, and restored to a normal level after of the intravenous injection of the omega3-rich medium-chain triglyceride-fish oil emulsion. Because the latter procedure failed to correct the perturbation of D-glucose metabolism in the islets of omega3-depleted rats, it is proposed that the anomalies in the secretory behaviour of islets in terms of their response to an increase in hexose concentration or non-nutrient secretagogues is mainly attributable to alteration in K+ and Ca2+ handling, as indeed recently documented in separate experiments.

The changes in gut microbiota composition by n-3 PUFA-depletion and prebiotics modulate hepatic steatosis by changing gene expression in the liver, a phenomenon that could implicate micro-RNA and gut-derived hormones. Our data underline the advantage of targeting the gut microbiota by colonic nutrients in the management of liver disease.

We cloned the 5 upstream region of the rat glucagon receptor gene, demonstrating that the 5 noncoding domain of the glucagon receptor mRNA contained two untranslated exons of 131 and 166 nucleotides (nt), respectively, separated by two introns of 0.6 and 3.2 kilobase pairs. We also observed an alternative splicing involving the 166-base pair exon. Cloning of up to 2 kilobase pairs of the newly identified genomic domain and transfection of various constructs driving a reporter gene, in pancreatic islet cell line INS-1, uncovered a strong glucose regulation of the promoter activity of plasmids containing up to nucleotide ؊868, or more, upstream from the transcriptional start point. This promoter activity displayed threshold-like behavior, with low activity of the promoter below 5 mM glucose, and maximal activation as of 10 mM glucose. This glucose regulation was mapped to a highly palindromic 19-nucleotide region between nt ؊545 and ؊527. Indeed, deletion or mutation of this sequence abolished the glucose regulation. This domain contained two palindromic "E-boxes" CACGTG and CAGCTG separated by 3 nt, a feature similar to the "L4 box" found in the pyruvate kinase L gene promoter. This is the first description of a G protein-coupled receptor gene promoter regulated by glucose.The primary physiological role of glucagon, together with insulin, is maintenance of normal glycemia. The liver has a central role in handling absorbed nutrients and in the regulation of hepatic glycogen disposability; this requires high density of glucagon receptors in the liver (for review see Refs. 1 and 2). The glucagon receptor mRNA has also been detected at variable levels in other tissues such as heart, kidney, adrenal gland, and adipose tissue (3-5), as well as in pancreatic islets, especially in B cells (6, 7). The expression of the glucagon receptor mRNA is stimulated by glucose and inhibited by cyclic AMP, both in liver (8) and in cultured endocrine cells (9). Consequently, the promoter of the glucagon receptor gene could contain regulatory elements for these factors. It has been recently suggested by Burcelin et al. (10) that the glucose regulation of the glucagon receptor mRNA level differs from the glucose regulation of other genes such as Glut2, and might be mediated by triose metabolites, suggesting the existence of new enhancer sequences. To address this question, a prerequisite is the precise knowledge of the complete 5Ј mRNA sequence. For the glucagon receptor mRNA, there was an ambiguity; the glucagon receptor cDNA has been first cloned (from rat) simultaneously by us (11, 12) and by Jelinek et al. (13). Our sequence (GenBank accession number L04796) was almost identical to that of Jelinek (GenBank accession number M96674) except for the 5Ј end; the first 25 nt 1 in our sequence (corresponding to positions Ϫ105 to Ϫ80 from the ATG codon) differed from the sequence published by Jelinek (13). The coding domain of the rat glucagon receptor gene is highly fragmented; it contains 12 introns with uneven splicing maturation (14) t...