Saturated fat is more metabolically harmful for the human liver than unsaturated fat or simple sugars

OBJECTIVE Nonalcoholic fatty liver disease (i.e., increased intrahepatic triglyceride [IHTG] content), predisposes to type 2 diabetes and cardiovascular disease. Adipose tissue lipolysis and hepatic de novo lipogenesis (DNL) are the main pathways contributing to IHTG. We hypothesized that dietary macronutrient composition influences the pathways, mediators, and magnitude of weight gain-induced changes in IHTG. RESEARCH DESIGN AND METHODS We overfed 38 overweight subjects (age 48 ± 2, BMI 31 ± 1 kg/m2, liver fat 4.7 ± 0.9%) 1,000 extra kcal/day of saturated (SAT) or unsaturated (UNSAT) fat or simple sugars (CARB) for 3 weeks. We measured IHTG (1H-MRS), pathways contributing to IHTG (lipolysis ([2H5]glycerol) and DNL (2H2O) basally and during euglycemic hyperinsulinemia, insulin resistance, endotoxemia, plasma ceramides, and adipose tissue gene expression at 0 and 3 weeks. RESULTS Overfeeding SAT increased IHTG more (+55%) than UNSAT (+15%, P < 0.05). CARB increased IHTG (+33%) by stimulating DNL (+98%). SAT significantly increased while UNSAT decreased lipolysis. SAT induced insulin resistance and endotoxemia and significantly increased multiple plasma ceramides. The diets had distinct effects on adipose tissue gene expression. CONCLUSIONS Macronutrient composition of excess energy influences pathways of IHTG: CARB increases DNL, while SAT increases and UNSAT decreases lipolysis. SAT induced greatest increase in IHTG, insulin resistance, and harmful ceramides. Decreased intakes of SAT could be beneficial in reducing IHTG and the associated risk of diabetes

Impairment of gut microbial biotin metabolism and host biotin status in severe obesity: effect of biotin and prebiotic supplementation on improved metabolism

Objectives Gut microbiota is a key component in obesity and type 2 diabetes, yet mechanisms and metabolites central to this interaction remain unclear. We examined the human gut microbiome\u27s functional composition in healthy metabolic state and the most severe states of obesity and type 2 diabetes within the MetaCardis cohort. We focused on the role of B vitamins and B7/B8 biotin for regulation of host metabolic state, as these vitamins influence both microbial function and host metabolism and inflammation. Design We performed metagenomic analyses in 1545 subjects from the MetaCardis cohorts and different murine experiments, including germ-free and antibiotic treated animals, faecal microbiota transfer, bariatric surgery and supplementation with biotin and prebiotics in mice. Results Severe obesity is associated with an absolute deficiency in bacterial biotin producers and transporters, whose abundances correlate with host metabolic and inflammatory phenotypes. We found suboptimal circulating biotin levels in severe obesity and altered expression of biotin-associated genes in human adipose tissue. In mice, the absence or depletion of gut microbiota by antibiotics confirmed the microbial contribution to host biotin levels. Bariatric surgery, which improves metabolism and inflammation, associates with increased bacterial biotin producers and improved host systemic biotin in humans and mice. Finally, supplementing high-fat diet-fed mice with fructo-oligosaccharides and biotin improves not only the microbiome diversity, but also the potential of bacterial production of biotin and B vitamins, while limiting weight gain and glycaemic deterioration. Conclusion Strategies combining biotin and prebiotic supplementation could help prevent the deterioration of metabolic states in severe obesity

Association of the Pro12Ala and C1431T variants of PPARgamma and their haplotypes with susceptibility to gestational diabetes.

International audienceBACKGROUND: The protective role of the Ala allele in the Pro12Ala polymorphism of PPARγ on type 2 diabetes has been well established but not confirmed in the context of pregnancy, for gestational diabetes, a known predictor of later type 2 diabetes onset. Another PPARγ polymorphism, the C1431T, is in strong linkage disequilibrium with Pro12Ala and has been shown to be associated with body weight, but its association with diabetes is controversial. RESEARCH DESIGN AND METHODS: In 1708 women of the EDEN mother-child cohort, the PPARγ Pro12Ala and C1431T polymorphisms were genotyped and analyzed in association with maternal prepregnancy body mass index, obesity before pregnancy, and gestational diabetes, separately and also combined in haplotypes. RESULTS: The prevalence of obesity was significantly higher in mothers with the Ala/Ala genotype compared with carriers of the Pro allele (35 vs. 9%, P < 0.0001), but there was no cases of gestational diabetes in Ala/Ala mothers. Mothers homozygous for the T allele of C1431T were also more obese (24 vs. 9%, P = 0.035), and three times more had gestational diabetes (18 vs. 6%, P = 0.044). Frequencies of haplotypes for these two single-nucleotide polymorphisms differed significantly in mothers with and without gestational diabetes; in comparison with the Pro-C haplotype, the Pro-T haplotype conferred the highest risk [odds ratio (95% CI) = 1.89 (1.05-3.40)], and the Ala-C the lowest risk [odds ratio (95% CI) = 0.12 (0.52-1.70)]. CONCLUSIONS: These results from a haplotype analysis, show for the first time that genetic variations in the PPARγ gene could play a role in the susceptibility to develop gestational diabetes

Association between CST3 rs2424577 polymorphism and corpulence related phenotypes during lifetime in populations of European ancestry

Objective: Cystatin C, a protein coded by CST3 gene, is implicated in adipose tissue biology. Our hypothesis is that common variants in CST3 gene could play a role in the development of corpulence during lifetime. Methods: Two tag SNPs were selected to capture all SNPs in the CST3 region. We first investigated the association of the two tag SNPs individually and combined into haplotypes with corpulence related phenotypes in 4,288 French subjects (BMI = 24.31 +/- 3.74 kg/m(2)). Significant findings were replicated in five independent populations 790 Danish lean men (BMI = 24.63 +/- 2.30 kg/m(2)), 672 Danish obese men (BMI = 33.23 +/- 2.34 kg/m(2)), 763 Swedish women (BMI = 21.73 +/- 2.87 kg/m(2)), 1,848 Danish lean women (BMI = 22.66 +/- 2.85 kg/m(2)) and 2,061 Danish obese women (BMI = 37.01 +/- 3.59 kg/m(2)). Results: Rs2424577 was associated with BMI in three independent populations - G/G carriers were less corpulent than A/A carriers in the French individuals (p = 0.045) and in the Danish lean men (p = 0.021), and they were more corpulent in the group of Swedish women (p = 0.004). This phenomenon has been described as a flip-flop phenomenon, probably caused by a multi-locus effect. Conclusion: CST3 rs2424577 is associated with BMI in a complex fashion. This association is probably caused by the interaction between several functional variants

Intermittent Hypoxia Rewires the Liver Transcriptome and Fires up Fatty Acids Usage for Mitochondrial Respiration

International audienceSleep Apnea Syndrome (SAS) is one of the most common chronic diseases, affecting nearly one billion people worldwide. The repetitive occurrence of abnormal respiratory events generates cyclical desaturation-reoxygenation sequences known as intermittent hypoxia (IH). Among SAS metabolic sequelae, it has been established by experimental and clinical studies that SAS is an independent risk factor for the development and progression of non-alcoholic fatty liver disease (NAFLD). The principal goal of this study was to decrypt the molecular mechanisms at the onset of IH-mediated liver injury. To address this question, we used a unique mouse model of SAS exposed to IH, employed unbiased high-throughput transcriptomics and computed network analysis. This led us to examine hepatic mitochondrial ultrastructure and function using electron microscopy, high-resolution respirometry and flux analysis in isolated mitochondria. Transcriptomics and network analysis revealed that IH reprograms Nuclear Respiratory Factor- (NRF-) dependent gene expression and showed that mitochondria play a central role. We thus demonstrated that IH boosts the oxidative capacity from fatty acids of liver mitochondria. Lastly, the unbalance between oxidative stress and antioxidant defense is tied to an increase in hepatic ROS production and DNA damage during IH. We provide a comprehensive analysis of liver metabolism during IH and reveal the key role of the mitochondria at the origin of development of liver disease. These findings contribute to the understanding of the mechanisms underlying NAFLD development and progression during SAS and provide a rationale for novel therapeutic targets and biomarker discovery

A distinct adipose tissue gene expression response to caloric restriction predicts 6-mo weight maintenance in obese subjects.

International audienceBACKGROUND: Weight loss has been shown to reduce risk factors associated with cardiovascular disease and diabetes; however, successful maintenance of weight loss continues to pose a challenge. OBJECTIVE: The present study was designed to assess whether changes in subcutaneous adipose tissue (scAT) gene expression during a low-calorie diet (LCD) could be used to differentiate and predict subjects who experience successful short-term weight maintenance from subjects who experience weight regain. DESIGN: Forty white women followed a dietary protocol consisting of an 8-wk LCD phase followed by a 6-mo weight-maintenance phase. Participants were classified as weight maintainers (WMs; 0-10% weight regain) and weight regainers (WRs; 50-100% weight regain) by considering changes in body weight during the 2 phases. Anthropometric measurements, bioclinical variables, and scAT gene expression were studied in all individuals before and after the LCD. Energy intake was estimated by using 3-d dietary records. RESULTS: No differences in body weight and fasting insulin were observed between WMs and WRs at baseline or after the LCD period. The LCD resulted in significant decreases in body weight and in several plasma variables in both groups. WMs experienced a significant reduction in insulin secretion in response to an oral-glucose-tolerance test after the LCD; in contrast, no changes in insulin secretion were observed in WRs after the LCD. An ANOVA of scAT gene expression showed that genes regulating fatty acid metabolism, citric acid cycle, oxidative phosphorylation, and apoptosis were regulated differently by the LCD in WM and WR subjects. CONCLUSION: This study suggests that LCD-induced changes in insulin secretion and scAT gene expression may have the potential to predict successful short-term weight maintenance. This trial was registered at clinicaltrials.gov as NCT00390637