β‐Aminoisobutyric Acid Prevents Diet‐induced Obesity in Mice With Partial Leptin Deficiency

Begriche, Karima; Massart, Julie; Abbey-Toby, Adjé; Igoudjil, Anissa; Lettéron, Philippe; Fromenty, Bernard

doi:10.1038/oby.2008.337

Cited by 84 publications

(126 citation statements)

References 60 publications

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“…Plasma ALT was higher in obese mice compared with their lean counterparts (Fig. 1A), reflecting liver damage as reported previously (Robin et al, 2005;Begriche et al, 2008b). However, ethanol administration did not change ALT values in both groups of mice (Fig.…”

Section: Resultssupporting

confidence: 62%

“…Indeed, phosphorylation of ACC leads to the inactivation of its activity, reducing hepatic levels of malonyl-CoA, the only endogenous inhibitor of CPT-1 (Begriche et al, 2008b(Begriche et al, , 2009. In this study, hepatic phospho-ACC was significantly augmented in ethanol-treated ob/ob mice, and this was associ- .…”

supporting

confidence: 53%

“…Indeed, none of the ethanol-treated ob/ob mice presented microvesicular steatosis, whereas this liver lesion was predominant in half of the naive obese mice. It is noteworthy that microvesicular steatosis reflects mitochondrial dysfunction (Fromenty and Pessayre, 1995) and that ob/ob mice present some mitochondrial alterations (Melia et al, 1999;García-Ruiz et al, 2006), although different studies have shown several metabolic and mitochondrial adaptations in ob/ob liver such as increased PPAR␣ expression, cytochrome c, and mitochondrial DNA levels (Robin et al, 2005;Begriche et al, 2008bBegriche et al, , 2009. Thus, the lack of microvesicular steatosis in ethanoltreated ob/ob mice could reflect improved mitochondrial function although further investigations will be necessary to confirm this hypothesis.…”

mentioning

confidence: 89%

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Chronic Ethanol Consumption Lessens the Gain of Body Weight, Liver Triglycerides, and Diabetes in Obese ob/ob Mice

Fromenty

Vadrot²,

Massart³

et al. 2009

J Pharmacol Exp Ther

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Clinical studies suggest that moderate alcohol consumption can have beneficial effects, in particular regarding cardiovascular events, insulin resistance, and type 2 diabetes. In this study, lean and obese diabetic ob/ob mice were submitted or not to chronic ethanol intake via the drinking water for 6 months, which was associated with moderate levels of plasma ethanol. Plasma levels of alanine aminotransferase and aspartate aminotransferase were not increased by alcohol intake. Ethanol consumption progressively reduced the gain of body weight in ob/ob mice, but not in lean mice, and this was observed despite higher calorie intake. Increased plasma free fatty acids and glycerol in ethanol-treated ob/ob mice suggested peripheral lipolysis. Glycemia and insulinemia were significantly reduced, whereas adiponectinemia was increased in ethanol-treated ob/ob mice. Liver weight and triglycerides were significantly decreased in ethanol-treated ob/ob mice, and this was associated with less microvesicular steatosis. Hepatic levels of AMP-activated protein kinase and the phosphorylated form of acetyl-CoA carboxylase were higher in ethanol-treated ob/ob mice, suggesting better fatty acid oxidation. However, hepatic mRNA expression of several lipogenic genes was not reduced by ethanol consumption. Finally, mild oxidative stress was noticed in the liver of ethanol-treated mice, regardless of their genotype. Hence, our data are in keeping with clinical studies suggesting that moderate ethanol intake can have beneficial effects on type 2 diabetes and insulin sensitivity, at least in part through increased levels of plasma adiponectin. However, further studies are needed to determine whether longterm drinking of light-to-moderate amounts of ethanol is safe for the liver.

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Section: Resultssupporting

confidence: 62%

supporting

confidence: 53%

mentioning

confidence: 89%

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Chronic Ethanol Consumption Lessens the Gain of Body Weight, Liver Triglycerides, and Diabetes in Obese ob/ob Mice

Fromenty

Vadrot²,

Massart³

et al. 2009

J Pharmacol Exp Ther

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“…One of the major advantages of these genetic murine models of obesity is the rapid and consistent occurrence of insulin resistance, hyperglycemia, and NAFLD (Lindström, 2007;Trak-Smayra et al, 2011;Massart et al, 2012), whereas high-fat diet-induced obesity is not always associated with these secondary metabolic disorders, even after several months of feeding (Burcelin et al, 2002;Begriche et al, 2008a). It is noteworthy that both ob/ob and db/db mice are characterized by "borderline NASH," because fatty liver is associated with moderate hepatic necroinflammation and mild fibrosis Begriche et al, 2008b;Trak-Smayra et al, 2011). Moreover, this study and previous investigations (Trak-Smayra et al, 2011) showed comparable basal levels of plasma transaminases between ob/ob and db/db mice, indicating a similar degree of hepatic cytolysis.…”

Section: Discussionmentioning

confidence: 99%

Differences in Early Acetaminophen Hepatotoxicity between Obeseob/obanddb/dbMice

Aubert

Begriche

Delannoy

et al. 2012

J Pharmacol Exp Ther

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Clinical investigations suggest that hepatotoxicity after acetaminophen (APAP) overdose could be more severe in the context of obesity and nonalcoholic fatty liver disease. The preexistence of fat accumulation and CYP2E1 induction could be major mechanisms accounting for such hepatic susceptibility. To explore this issue, experiments were performed in obese diabetic ob/ob and db/db mice. Preliminary investigations performed in male and female wild-type, ob/ob, and db/db mice showed a selective increase in hepatic CYP2E1 activity in female db/db mice. However, liver triglycerides in these animals were significantly lower compared with ob/ob mice. Next, APAP (500 mg/kg) was administered in female wild-type, ob/ ob, and db/db mice, and investigations were carried out 0.5, 2, 4, and 8 h after APAP intoxication. Liver injury 8 h after APAP intoxication was higher in db/db mice, as assessed by plasma transaminases, liver histology, and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay. In db/db mice, however, the extent of hepatic glutathione depletion, levels of APAP-protein adducts, c-Jun N-terminal kinase activation, changes in gene expression, and mitochondrial DNA levels were not greater compared with the other genotypes. Furthermore, in the db/db genotype plasma lactate and ␤-hydroxybutyrate were not specifically altered, whereas the plasma levels of APAP-glucuronide were intermediary between wild-type and ob/ob mice. Thus, early APAP-induced hepatotoxicity was greater in db/db than ob/ob mice, despite less severe fatty liver and similar basal levels of transaminases. Hepatic CYP2E1 induction could have an important pathogenic role when APAP-induced liver injury occurs in the context of obesity and related metabolic disorders.

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“…Begriche et al demonstrated that β-aminoisobutyric acid (BAIBA), a natural catabolite of thymine, reduced body fat percentage through increased fatty acid oxidation and decreased de novo lipogenesis in mice [2]. Recently, Roberts et al identified BAIBA as a small molecule myokine secreted from myocytes with forced expression of peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α).…”

Section: Introductionmentioning

confidence: 99%

BAIBA attenuates insulin resistance and inflammation induced by palmitate or a high fat diet via an AMPK–PPARδ-dependent pathway in mice

et al. 2015

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Aims/hypothesis We explored the effects of β-aminoisobutyric acid (BAIBA) on hyperlipidaemic-condition-induced insulin resistance and inflammation as mediated through a signalling pathway involving AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor δ (PPARδ). Methods Mouse skeletal muscle C2C12 cells and C57BL/6J mice were treated with palmitate or a high-fat diet (HFD) and BAIBA. Inflammation and the expression of genes associated with insulin signalling were determined by western blot and quantitative real-time PCR. Selected genes from candidate pathways were evaluated by small interfering (si)RNA knockdown and specific inhibitors. Results BAIBA treatment ameliorated impairment of insulin receptor substrate (IRS)-1/Akt-mediated insulin signalling in palmitate-treated C2C12 myocytes and in skeletal muscle of HFD-fed mice. In addition, BAIBA treatment reversed HFDinduced increases in body weight and improved impaired glucose tolerance in mice. In vitro and in vivo, inhibitory κBα (IκBα) phosphorylation, nuclear factor κB (NFκB) nuclear translocation and downstream inflammatory cytokines were significantly suppressed by BAIBA. Furthermore, BAIBA treatment significantly induced AMPK phosphorylation and expression of PPARδ in C2C12 myocytes and in skeletal muscle of mice. Both compound C, an AMPK inhibitor, and Pparδ (also known as Ppard) siRNA abrogated the inhibitory effects of BAIBA on palmitate-induced inflammation and insulin resistance. BAIBA significantly induced the expression of genes associated with fatty acid oxidation, such as carnitine palmitoyltransferase 1 (Cpt1), acyl-CoA oxidase (Aco; also known as Acox1) and fatty acid binding protein 3 (Fabp3); this effect of BAIBA was significantly reduced by compound C and Pparδ siRNA. Conclusions/interpretation These results are the first to demonstrate that BAIBA attenuates insulin resistance, suppresses inflammation and induces fatty acid oxidation via the AMPK-PPARδ pathway in skeletal muscle.

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β‐Aminoisobutyric Acid Prevents Diet‐induced Obesity in Mice With Partial Leptin Deficiency

Cited by 84 publications

References 60 publications

Chronic Ethanol Consumption Lessens the Gain of Body Weight, Liver Triglycerides, and Diabetes in Obese ob/ob Mice

Chronic Ethanol Consumption Lessens the Gain of Body Weight, Liver Triglycerides, and Diabetes in Obese ob/ob Mice

Differences in Early Acetaminophen Hepatotoxicity between Obeseob/obanddb/dbMice

BAIBA attenuates insulin resistance and inflammation induced by palmitate or a high fat diet via an AMPK–PPARδ-dependent pathway in mice

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