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High fat intake is associated with fat mass gain through fatty acid activation of peroxisome proliferator-activated receptors ␦ and ␥ , which promote adipogenesis. We show herein that, compared to a combination of specific agonists to both receptors or to saturated, monounsaturated, and -3 polyunsaturated fatty acids, arachidonic acid (C20:4, -6) promoted substantially the differentiation of clonal preadipocytes. This effect was blocked by cyclooxygenase inhibitors and mimicked by carbacyclin, suggesting a role for the prostacyclin receptor and activation of the cyclic AMPdependent pathways that regulate the expression of the CCAAT enhancer binding proteins ␤ and ␦ implicated in adipogenesis. During the pregnancy-lactation period, mother mice were fed either a high-fat diet rich in linoleic acid, a precursor of arachidonic acid (LO diet), or the same isocaloric diet enriched in linoleic acid and ␣ -linolenic acid (LO/ LL diet). Body weight from weaning onwards, fat mass, epididymal fat pad weight, and adipocyte size at 8 weeks of age were higher with LO diet than with LO/LL diet. In contrast, prostacyclin receptor-deficient mice fed either diet were similar in this respect, indicating that the prostacyclin signaling contributes to adipose tissue development. These results raise the issue of the high content of linoleic acid of i ) ingested lipids during pregnancy and lactation, and ii ) formula milk and infant foods in relation to the epidemic of childhood obesity. -Massiera, F., P. Saint-Marc, J. Seydoux, T. Murata, T. Kobayashi, S. Narumiya, P. Guesnet, E-Z. Amri, R. Negrel, and G, Ailhaud. Obesity is associated with metabolic disorders such as dyslipidemia, diabetes, and hypertension, and fat mass excess in severe obesities is typically due to an increase in adipocyte size and number. The formation of adipocytes is a critical event, as mature adipocytes do not divide in vivo and do not undergo significant turnover under physiological conditions. The capacity for proliferation of precursor cells and their differentiation into adipocytes is highest at early age and decrease thereafter in humans and rodents. A limited number of hormones can affect the adipose tissue mass and possibly its distribution (1). High dietary fat intake is now recognized to be associated with a gain of fat mass in animals and humans at all ages (2-5). However, the lack of evidence of a general increase in energy intake as fat among youths, despite a striking increase in the prevalence of obesity in industrial and developing countries, may be due in part to decreased physical activity and nonexercise activity thermogenesis (6), but also to the composition of food intake in early life. The long-term relationship between the fatty acid composition of dietary fats and the development of adipose tissue in humans is difficult to assess in contrast to animals. When mother rats were fed a high-fat diet rich in linoleic acid (C18:2, -6) or saturated fatty acids, suckling pups at 17 days of age exhibited hyperplasia or hypertrophy of whi...

Docosahexaenoic acid (DHA, 22:6n-3) and arachidonic acid (AA, 20:4n-6) are the major polyunsaturated fatty acids in the membranes of brain and retinal cells. Animals specifically deficient in dietary n-3 fatty acids have low DHA content in their membranes, reduced visual acuity and impaired learning ability. Studies on bottle-fed human infants have shown that adding DHA and AA to milk replacer-formulas can bring their concentrations in the infant blood lipids to values as high as those produced by breast-feeding and significantly improves mental development and maturation of visual function. In older subjects, diverse neuropsychiatric and neurodegenerative diseases have been associated to decreased blood levels of n-3 PUFA. Low intakes of fish or of n-3 PUFA in populations have been associated with increased risks of depression and Alzheimer disease, and n-3 PUFA, especially eicosapentaenoic acid (EPA, 20:5n-3), have shown efficacy as adjunctive treatment-and in some cases as the only treatment-in several psychiatric disorders. The mechanisms by which polyunsaturated fatty acids have an impact on neuronal functions will be reviewed: the modulation of membrane biophysical properties, regulation of neurotransmitter release, synthesis of biologically active oxygenated derivatives, and nuclear receptor-mediated transcription of genes responsive to fatty acids or to their derivatives.

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The importance of dietary fat in human obesity remains a controversial issue as the prevalence of overweight and obesity has increased despite no dramatic change in the amount of ingested fats over the past few decades. However, qualitative changes (i.e. the fatty acid composition of fats) have been largely disregarded. In this review, we summarize experimental evidence which supports polyunsaturated fatty acids of the omega6 series as being potent promoters of both adipogenesis in vitro and adipose tissue development in vivo during the gestation/lactation period. This conclusion is also supported by epidemiological data from infant studies as well as by the assessment of the fatty acid composition of mature breast milk and formula milk. It is proposed that unnoticed changes in fatty acid composition of ingested fats over the last decades have been important determinants in the increasing prevalence of childhood overweight and obesity.

This article is available online at http://www.jlr.org able to genetic factors as it has occurred relatively recently and is observed in a wide range of human populations. High-fat diets are considered to be obesogenic in that they produce a consistent increase in fat mass that is directly related to the content of the diet and duration of feeding. However, the contribution of dietary fats compared with an excess energy intake in increasing body weight remains controversial, as no major change in the total amount of ingested fats has occurred in the last two decades ( 1, 2 ).In addition to caloric excess, a qualitative issue has emerged as a risk factor for obesity in rodents and possibly in humans; i.e., the disequilibrium in polyunsaturated fatty acid (PUFA) metabolism with a high ratio of linoleic acid (C18:2 6, LA) versus ␣ -linolenic acid (C18:3 3, LNA) ( 3 ). Notably, in rodents, reducing this ratio from 59 to 2 under isolipidic, isoenergetic conditions (40% energy as fat) by inclusion of dietary LNA counteracted the enhancing effects of LA on body weight and fat mass, which then became similar to that observed with a chow diet ( 4 ).6 PUFAs were more potent than 3 PUFAs in promoting adipogenesis ( 5-7 ). When combined with high carbohydrate content, a linoleic acid-enriched diet was found to be pro-adipogenic in vivo through cAMP-dependent signaling ( 8 ). LA acts through arachidonic acid (C20:4 6, ARA) and prostacyclin, as pups from mice invalidated for the prostacyclin receptor (IP-R) and fed a LA-rich diet exhibit reduced body weight and fat mass compared with wild-type mice fed the same diet ( 4 ). Overall, these results emphasize the importance of adipose tissue development Abstract The prevalence of obesity has steadily increased over the last few decades. During this time, populations of industrialized countries have been exposed to diets rich in fat with a high content of linoleic acid and a low content of ␣ -linolenic acid compared with recommended intake. To assess the contribution of dietary fatty acids, male and female mice fed a high-fat diet (35% energy as fat, linoleic acid: ␣ -linolenic acid ratio of 28) were mated randomly and maintained after breeding on the same diet for successive generations. Offspring showed, over four generations, a gradual enhancement in fat mass due to combined hyperplasia and hypertrophy with no change in food intake. Transgenerational alterations in adipokine levels were accompa nied by hyperinsulinemia. Gene expression analyses of the stromal vascular fraction of adipose tissue, over generations, revealed discrete and steady changes in certain important players, such as CSF3 and Nocturnin. Thus, under conditions of genome stability and with no change in the regimen over four generations, we show that a Western-like fat diet induces a gradual fat mass enhancement, in accordance with the increasing prevalence of obesity observed in humans. -Massiera, F., P. Barbry, P. Guesnet, A. Joly, S. The prevalence of obesity and the risk of developing associated diseases ha...

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Sickness behaviour is an adaptive behavioural response to the activation of the innate immune system. It is mediated by brain cytokine production and action, especially interleukin-6 (IL-6). Polyunsaturated fatty acids (PUFA) are essential fatty acids that are highly incorporated in brain cells membranes and display immunomodulating properties. We hypothesized that a decrease in n-3 PUFA brain level by dietary means impacts on lipopolysaccharide (LPS)-induced IL-6 production and sickness behaviour. Our results show that mice exposed throughout life to a diet containing n-3 PUFA (n-3/n-6 diet) display a decrease in social interaction that does not occur in mice submitted to a diet devoid of n-3 PUFA (n-6 diet). LPS induced high IL-6 plasma levels as well as expression of IL-6 mRNA in the hippocampus and cFos mRNA in the brainstem of mice fed either diet, indicating intact immune-to-brain communication. However, STAT3 and STAT1 activation, a hallmark of IL-6 signalling pathway, was lower in the hippocampus of LPS-treated n-6 mice as compared to n-3/n-6 mice. In addition, LPS did not reduce social interaction in IL-6 knock-out (IL-6 KO) mice and failed to induce STAT3 activation in the brain of IL-6 KO mice. Altogether, these findings point to alteration in brain STAT3 as a key mechanism for the lack of effect of LPS on social interaction in mice fed with the n-6 PUFA diet. The relative deficiency of Western diets in n-3 PUFA could impact on behavioural aspects of the host response to infection.