Furan fatty acid extracted from Hevea brasiliensis latex increases muscle mass in mice.

Skeletal muscle is essential for locomotion and plays a crucial role in energy homeostasis. It is regulated by nutrition, genetic factors, physical activity and hormones. Furan fatty acids (FuFAs) are minor fatty acids present in small quantities in food from plants and animals origin. Recently, we showed that a preventive nutritional supplementation with furan fatty acid in a DIO mouse model reduces metabolic disorders. The present study was designed to determine the influence of FuFA-F2 extracted from Hevea brasiliensis latex on skeletal muscle phenotype. In C2C12 myotubes we found that FuFA-F2 whatever the concentration used increased protein content. We revealed that in C2C12 myotubes FuFA-F2 (10 µM) increases protein synthesis as shown by the stimulation of mTOR phosphorylation. Next, to confirm in vivo our results C57Bl6 mice were supplemented by oral gavage with vehicle or FuFA-F2 (20 mg/kg) for 3 and a half weeks. We found that mice supplemented with FuFA-F2 had a greater lean mass than the control mice. In line with this observation, we revealed that FuFA-F2 increased muscle mass and promoted more oxidative muscle metabolism in mice as attested by cytochrome c oxidase activity. In conclusion, we demonstrated that FuFA-F2 stimulates muscle anabolism in mice in vitro and in vivo, mimicking in part physical activity. This study highlights that in vivo FuFA-F2 may have health benefits by increasing muscle mass and oxidative metabolism.

Preventive nutritional supplementation with furan fatty acid in a DIO mouse model increases muscle mass and reduces metabolic disorders.

The increase in obesity has become a major global health problem and is associated with numerous metabolic dysfunctions. Furan fatty acids (FuFAs) are minor lipids present in our diet. Recently we showed that FuFA-F2 extracted from Hevea brasiliensis latex stimulates muscle anabolism in mice in vitro and in vivo, mimicking in part physical activity. While skeletal muscle is essential for energy metabolism and is the predominant site of insulin-mediated glucose uptake in the post prandial state, our results suggested that FuFA-F2 could have favorable effects against obesity. The aim of this work was therefore to study whether a preventive nutritional supplementation with FuFA-F2 (40 mg or 110 mg/day/kg of body weight) in a diet-induced obesity (DIO) mouse model may have beneficial effects against obesity and liver and skeletal muscle metabolic dysfunction. We showed that 12 weeks of FuFA-F2 supplementation in DIO mice decreased fat mass, increased lean mass and restored normal energy expenditure. In addition, we found that FuFA-F2 improved insulin sensitivity. We revealed that FuFA-F2 increased muscle mass but had no effect on mitochondrial function and oxidative stress in skeletal muscle. Furthermore, we observed that FuFA-F2 supplementation reduced liver steatosis without impact on mitochondrial function and oxidative stress in liver. Our findings demonstrated for the first time that a preventive nutritional supplementation with a furan fatty acid in DIO mice reduced metabolic disorders and was able to mimic partly the positive effects of physical activity. This study highlights that nutritional FuFA-F2 supplementation could be an effective approach to treat obesity and metabolic syndrome.

9-PAHPA long term intake in DIO and db/db mice ameliorates insulin sensitivity but has few effects on obesity and associated metabolic disorders.

Branched fatty acid esters of hydroxy fatty acids are endogenous lipids reported to have antidiabetic and anti-inflammatory effects. Recently, we showed that 9-palmitic acid esters of hydroxypalmitic acid (9-PAHPA) and 9-oleic acid esters of hydroxypalmitic acid increased insulin sensitivity in mice when incorporated to a chow diet or to a high fat and high sucrose diet. However, preventive supplementation with 9-PAHPA and 9-oleic acid esters of hydroxypalmitic acid in high fat and high sucrose diet mice did not impair significant weight gain or the development of hyperglycemia. The aim of this work was therefore to study whether in two animal models of obesity, namely the classical diet-induced obesity (DIO) and the db/db mice, 9-PAHPA may have beneficial effects against obesity and liver and skeletal muscle metabolic dysfunction. In DIO mice, we observed that 9-PAHPA increased body weight and fat mass. In line with this observation, we found that 9-PAHPA supplementation decreased energy expenditure. In liver and in skeletal muscle, mitochondrial activities and oxidative stress parameters were not modified by 9-PAHPA supplementation. In db/db mice, 9-PAHPA had no effect on the dramatic weight gain and hyperglycemia. In addition, 9-PAHPA supplementation did not correct either the hepatomegaly and hepatic steatosis or the severe muscle atrophy recorded compared with db/+ animals. Likewise, supplementation with 9-PAHPA did not impact the different metabolic parameters analyzed, either in the liver or in the skeletal muscles. However, it decreased insulin resistance in DIO and db/db mice. In conclusion, our study indicated that a long-term intake of 9-PAHPA in DIO and db/db mice improved insulin sensitivity but had only few effects on obesity and associated metabolic disorders.

FAHFAs Regulate the Proliferation of C2C12 Myoblasts and Induce a Shift toward a More Oxidative Phenotype in Mouse Skeletal Muscle.

Branched fatty acid esters of hydroxy fatty acids (FAHFAs) are endogenous lipids reported to have antidiabetic and anti-inflammatory effects. Since skeletal muscle is a major target for insulin, the aim of this study is to explore for the first time the influence of several FAHFAs in C2C12 myoblasts and in skeletal muscle phenotype in mice. Here, we show that eleven FAHFAs belonging to different families inhibit C2C12 myoblast proliferation. In addition, all FAHFAs decreased mitochondrial cytochrome c oxidase activity without affecting reactive oxygen species production and the mitochondrial network. During C2C12 myoblasts differentiation, we found that two of the most active lipids, 9-PAHPA and 9-OAHPA, did not significantly affect the fusion index and the expression of myosin heavy chains. However, we found that three months' intake of 9-PAHPA or 9-OAHPA in mice increased the expression of more oxidative myosin in skeletal muscle without affecting skeletal muscle mass, number, and mean fiber area, mitochondrial activity, and oxidative stress parameters. In conclusion, our study indicated that the eleven FAHFAs tested decreased the proliferation rate of C2C12 myoblasts, probably through the inhibition of mitochondrial activity. In addition, we found that 9-PAHPA or 9-OAHPA supplementation in mice induced a switch toward a more oxidative contractile phenotype of skeletal muscle. These data suggest that the increase in insulin sensitivity previously described for these two FAHFAs is of muscular origin.

Long-term high intake of 9-PAHPA or 9-OAHPA increases basal metabolism and insulin sensitivity but disrupts liver homeostasis in healthy mice.

Branched fatty acid esters of hydroxy fatty acids (FAHFAs) are a new family of endogenous lipids recently discovered. Several studies reported that some FAHFAs have antidiabetic and anti-inflammatory effects. The objective of this study was to explore the impact of two FAHFAs, 9-PAHPA or 9-OAHPA, on the metabolism of mice. C57Bl/6J male mice, 6 weeks old, were divided into 3 groups of 10 mice each. One group received a control diet and the two others groups received the control diet supplemented with 9-PAHPA or 9-OAHPA for 12 weeks. Mouse weight and body composition were monitored throughout the study. Some days before euthanasia, energy expenditure, glucose tolerance and insulin sensitivity were also determined. After sacrifice, blood and organs were collected for relevant molecular, biochemical and histological analyses. Although high intake of 9-PAHPA or 9-OAHPA increased basal metabolism, it had no direct effect on body weight. Interestingly, the 9-PAHPA or 9-OAHPA intake increased insulin sensitivity but without modifying glucose tolerance. Nevertheless, 9-PAHPA intake induced a loss of glucose-stimulated insulin secretion. Surprisingly, both studied FAHFAs induced hepatic steatosis and fibrosis in some mice, which were more marked with 9-PAHPA. Finally, a slight remodeling of white adipose tissue was also observed with 9-PAHPA intake. In conclusion, the long-term high intake of 9-PAHPA or 9-OAHPA increased basal metabolism and insulin sensitivity in healthy mice. However, this effect, highly likely beneficial in a diabetic state, was accompanied by manifest liver damage in certain mice that should deserve special attention in both healthy and pathological studies.

Protective Activity of Total Polyphenols from Genista quadriflora Munby and Teucrium polium geyrii Maire in Acetaminophen-Induced Hepatotoxicity in Rats.

Oxidative stress is a major cause of drug-induced hepatic diseases and several studies have demonstrated that diet supplementation with plants rich in antioxidant compounds provides a variety of health benefits in these circumstances. Genista quadriflora Munby (Gq) and Teucrium polium geyrii Maire (Tp) are known to possess antioxidant and numerous biological properties and these endemic plants are often used for dietary or medicinal applications. Herein, we evaluated the beneficial effect of rich-polyphenol fractions of Gq and Tp to prevent Acetaminophen-induced liver injury and investigated the mechanisms involved in this protective action. Rats were orally administered polyphenolic extracts from Gq or Tp (300 mg/kg) or N-acetylcysteine (NAC: 200 mg/kg) once daily for ten days prior to the single oral administration of Acetaminophen (APAP: 1 g/kg). The results show that preventive administration of polyphenolic extracts from Gq or Tp exerts a hepatoprotective influence during APAP treatment by improving transaminases leakage and liver histology and stimulating antioxidant defenses. Besides, suppression of liver CYP2E1, GSTpi and TNF-α mRNA levels, with enhancement of mitochondrial bioenergetics may contribute to the observed hepatoprotection induced by Gq and Tp extracts. The effect of Tp extract is significantly higher (1.5-2 fold) than that of Gq extract and NAC regarding the enhancement of mitochondrial functionality. Overall, this study brings the first evidence that pretreatment with these natural extracts display in vivo protective activity against APAP hepatotoxicity through improving mitochondrial bioenergetics, oxidant status, phase I and II enzymes expression and inflammatory processes probably by virtue of their high total polyphenols content.

Characterization of a novel thyroid hormone receptor alpha variant involved in the regulation of myoblast differentiation.

The regulation of gene expression by thyroid hormone (T3) involves binding of the hormone to nuclear receptors [thyroid hormone receptor (TR)] acting as T3-dependent transcription factors encoded by TRalpha (NR1A1) and TRbeta (NR1A2) genes. Several TRalpha variants have already been characterized, but only some of them display T3 binding activity. In this study, we have identified another transcript, TRalpha-DeltaE6, produced by alternative splicing with microexon 6b instead of exon 6. This splicing leads to the synthesis of a protein devoid of a hinge domain. The TRalpha-DeltaE6 transcript is detected in all mouse tissues tested. Although TRalpha-DeltaE6 did not bind DNA, its expression induced a TRalpha1 sequestration in the cytoplasm. Functional studies demonstrated that TRalpha-DeltaE6 inhibits the transcriptional activity of TRalpha1 and retinoic X receptor-alpha, but not of retinoic acid receptor-alpha. We also found that TRalpha-DeltaE6 efficiently decreased the ability of TRalpha to inhibit MyoD transcriptional activity during myoblast proliferation. Consequently, when overexpressed in myoblasts, it stimulated terminal differentiation. We suggest that this novel TRalpha variant may act as down regulator of overall T3 receptor activity, including its ability to repress MyoD transcriptional activity during myoblast proliferation.