cAMP-dependent Signaling Regulates the Adipogenic Effect of n-6 Polyunsaturated Fatty Acids

Madsen, Lise; Pedersen, Lone Møller; Liaset, Bjørn; Ma, Tao; Petersen, Rasmus Koefoed; Berg, Sjoerd van den; Pan, Jie; Müller‐Decker, Karin; Dülsner, Erik; Kleemann, Robert; Kooistra, Teake; Døskeland, Stein Ove; Kristiansen, Karsten

doi:10.1074/jbc.m707775200

Cited by 76 publications

(139 citation statements)

References 41 publications

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“…Clearly, a progressive decrease in energy expenditure cannot be excluded, although the resistance of C57BL/6J mice to diet-induced thermogenesis has been reported ( 8 ). Actually, we observed a trend (not statistically significant) toward higher expression of UCP1 in brown adipose tissue, suggesting an increase in energy expenditure over generations.…”

Section: Genes Regulated By Regimenmentioning

confidence: 36%

A Western-like fat diet is sufficient to induce a gradual enhancement in fat mass over generations

Massiéra

Barbry

Guesnet

et al. 2010

Journal of Lipid Research

166

128

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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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Section: Genes Regulated By Regimenmentioning

confidence: 36%

A Western-like fat diet is sufficient to induce a gradual enhancement in fat mass over generations

Massiéra

Barbry

Guesnet

et al. 2010

Journal of Lipid Research

166

128

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“…However, in the mouse experiment by Alvheim et al (2) increasing 18 : 2n-6 from 1 % to 8 % of energy in the feed was sufficient to promote obesity. In the mouse experiment by Madsen et al (9) , the intake of carbohydrates constituted 8 % of the energy intake in the low-carbohydrate group and 37 % in the high-carbohydrate group; intakes below the 10th percentile intake in the present study. The finding of the importance of the carbohydrate:protein ratio in the mouse experiment (9) is in line with the results from a large European human trial on weight-loss maintenance (16) .…”

Section: Discussioncontrasting

confidence: 52%

“…This may be due to lower levels of intake of n-6 PUFA (80 % central range: 3·4, 6·9 % of energy), higher levels of intake of carbohydrates (80 % central range: 38·5, 52·5 % of energy) and/or limited exposure contrasts. Generally, animal experiments used high doses of n-6 PUFA (5)(6)(7)(8) , such as 22 % of energy from n-6 PUFA in the mouse experiment by Madsen et al (9) (Lise Madsen, personal communication, 2013), but did not provide information on lower intakes compatible with intakes in the general population. However, in the mouse experiment by Alvheim et al (2) increasing 18 : 2n-6 from 1 % to 8 % of energy in the feed was sufficient to promote obesity.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, other animal experiments have reported that feed high in n-6 PUFA decreased adipose tissue mass (7,8) . In animals, the apparent conflicting findings may be explained by different background diets, as Madsen et al (9) have shown that the effect of n-6 PUFA on adipose tissue mass is determined by the balance between carbohydrates and proteins. In mice, when the carbohydrate:protein ratio was high, also the plasma insulin:glucagon ratio was high and high n-6 PUFA intake increased adipose tissue mass.…”

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confidence: 99%

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Dietary n-6 PUFA, carbohydrate:protein ratio and change in body weight and waist circumference: a follow-up study

Jakobsen

Madsen

Dethlefsen

et al. 2014

Public Health Nutr.

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Objective: To investigate the association between the intake of n-6 PUFA and subsequent change in body weight and waist circumference at different levels of the carbohydrate:protein ratio. Design: Follow-up study with anthropometric measurements at recruitment and on average 5·3 years later. Dietary intake was determined at recruitment by using an FFQ that was designed for the study and validated. We applied linear regression models with 5-year change in weight or waist circumference as outcome and including a two-way interaction term between n-6 PUFA and carbohydrate intakes, lower-order terms, protein intake, long-chain n-3 PUFA intake and other potential confounders. Due to adjustment for intake of protein, levels of carbohydrate indirectly reflect levels of the carbohydrate:protein ratio. Setting: Diet, Cancer and Health follow-up study, Denmark. Subjects: Women and men (n 29 152) aged 55 years. Results: For a high intake of n-6 PUFA (6·9 % of energy) v. a low intake of n-6 PUFA (3·4 % of energy), the difference in 5-year weight change was − 189·7 g (95 % CI − 636·8, 257·4 g) at a low carbohydrate:protein ratio and − 86·7 g (95 % CI − 502·9, 329·6 g) at a high carbohydrate:protein ratio; the differences in 5-year waist circumference change were 0·26 cm (95 % CI − 0·47, 0·98 cm) and − 0·52 cm (95 % CI − 1·19, 0·15 cm), respectively. Inclusion of the dietary glycaemic index did not change the results. Conclusions: No consistent associations between the intake of n-6 PUFA and change in body weight or waist circumference at different levels of the carbohydrate:protein ratio were observed. Keywords Dietary carbohydrates Dietary fats Dietary proteins ObesityBMI and waist circumference are proxy measures of overall body fat mass and abdominal fat mass, respectively, and strong predictors of obesity-related mortality (1) . Studies on the evolutionary aspects of diet indicate that major changes have taken place in the Western diet, particularly during the last 100 years; changes that correlate with the increasing prevalence of obesity (2) . Today, more than 85 % of the total intake of n-6 and n-3 PUFA is n-6 PUFA (3) . In the USA, the estimated per capita consumption of soyabean oil, the major source of the n-6 PUFA linoleic acid (18 : 2n-6), has increased more than 1000-fold from 1909 to 1999 (4) ; thus, the availability of 18 : 2n-6 increased from 2·8 % to 7·2 % of energy during the 20th century. Interesting, the increase in the availability of soyabean oil paralleled the increase in the prevalence of obesity (2) . Likewise, the availability of sugars was also positively correlated with obesity whereas energy was not (2) . Of note, in mice, increasing 18 : 2n-6 from 1 % to 8 % of energy in the feed, reflecting the 20th century increase in availability of 18 : 2n-6, promoted obesity (2) . Still, in man, the effect of n-6 PUFA on obesity development has not been investigated in detail. The findings from the mouse experiment by Alvheim et al. (2) are in line with other animal experiments which

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“…Under conditions with increased intracellular cAMP signaling, studies in mice suggest that induced expression of Ucp1 in white adipose tissues is associated with a lean and healthy phenotype (40,(52)(53)(54). As BAs are known to increase intracellular cAMP levels, we speculated whether the increased plasma BA concentrations could also alter the phenotype of WAT.…”

Section: Nutritional Regulation Of Endogenous Ba Metabolism Modulatesmentioning

confidence: 99%

Nutritional Regulation of Bile Acid Metabolism Is Associated with Improved Pathological Characteristics of the Metabolic Syndrome

Liaset¹,

Qin

Jørgensen

et al. 2011

Journal of Biological Chemistry

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Bile acids (BAs) are powerful regulators of metabolism, and mice treated orally with cholic acid are protected from dietinduced obesity, hepatic lipid accumulation, and increased plasma triacylglycerol (TAG) and glucose levels. Here, we show that plasma BA concentration in rats was elevated by exchanging the dietary protein source from casein to salmon protein hydrolysate (SPH). Importantly, the SPH-treated rats were resistant to diet-induced obesity. SPH-treated rats had reduced fed state plasma glucose and TAG levels and lower TAG in liver. The elevated plasma BA concentration was associated with induction of genes involved in energy metabolism and uncoupling, Dio2, Pgc-1␣, and Ucp1, in interscapular brown adipose tissue. Interestingly, the same transcriptional pattern was found in white adipose tissue depots of both abdominal and subcutaneous origin. Accordingly, rats fed SPH-based diet exhibited increased whole body energy expenditure and heat dissipation. In skeletal muscle, expressions of the peroxisome proliferatoractivated receptor ␤/␦ target genes (Cpt-1b, Angptl4, Adrp, and Ucp3) were induced. Pharmacological removal of BAs by inclusion of 0.5 weight % cholestyramine to the high fat SPH diet attenuated the reduction in abdominal obesity, the reduction in liver TAG, and the decrease in nonfasted plasma TAG and glucose levels. Induction of Ucp3 gene expression in muscle by SPH treatment was completely abolished by cholestyramine inclusion. Taken together, our data provide evidence that bile acid metabolism can be modulated by diet and that such modulation may prevent/ameliorate the characteristic features of the metabolic syndrome.

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cAMP-dependent Signaling Regulates the Adipogenic Effect of n-6 Polyunsaturated Fatty Acids

Cited by 76 publications

References 41 publications

A Western-like fat diet is sufficient to induce a gradual enhancement in fat mass over generations

A Western-like fat diet is sufficient to induce a gradual enhancement in fat mass over generations

Dietary n-6 PUFA, carbohydrate:protein ratio and change in body weight and waist circumference: a follow-up study

Nutritional Regulation of Bile Acid Metabolism Is Associated with Improved Pathological Characteristics of the Metabolic Syndrome

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