Fatty acids in the de novo lipogenesis pathway and incidence of type 2 diabetes: A pooled analysis of prospective cohort studies

Imamura, Fumiaki; Fretts, Amanda M.; Marklund, Matti; Korat, Andres V Ardisson; Yang, Wei-Sin; Lankinen, Maria; Qureshi, Waqas; Helmer, Catherine; Chen, Tzu-An; Virtanen, Jyrki K.; Wong, Kerry L. M.; Bassett, Julie K.; Murphy, Rachel A.; Tintle, Nathan L.; Yu, Chaoyu Ian; Brouwer, Ingeborg A.; Chien, Kuo–Liong; Chen, Yun-yu; Frazier‐Wood, Alexis C.; Gobbo, Liana C Del; Djoussé, Luc; Geleijnse, Johanna M.; Giles, Graham G.; Goede, Janette de; Gudnason, Vilmundur; Harris, William S.; Hodge, Allison; Hu, Frank B.; Koulman, Albert; Laakso, Markku; Lind, Lars; Lin, Hung‐Ju; McKnight, Barbara; Rajaobelina, Kalina; Risérus, Ulf; Robinson, Jennifer G.; Samieri, Cécilia; Senn, Mackenzie; Siscovick, David S.; Soedamah‐Muthu, Sabita S.; Sotoodehnia, Nona; Sun, Qi; Tsai, Michael Y.; Tuomainen, Tomi‐Pekka; Uusitupa, Matti; Wagenknecht, Lynne E.; Wareham, Nick; Wu, Jason; Micha, Renata; Lemaître, Rozenn N.; Mozaffarian, Dariush; Forouhi, Nita G.

doi:10.1371/journal.pmed.1003102

Cited by 42 publications

(44 citation statements)

References 53 publications

(73 reference statements)

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“…Hyperglycemia with hyperinsulinemia increases malonyl-CoA production and inhibits functional CPT1 activity, while and shunting long-chain fatty acids away from oxidation and towards storage in human muscle, as reported by Rasmussen et al [42]. Malonyl-CoA is the first reaction step for the de novo lipogenesis of palmitic acid, which is positively associated with Type 2 Diabetes, as data from Imamura et al [43] showed. But de novo lipogenesis is also positively associated with saturated fatty acid intake and is elevated in patients with non-alcoholic fatty liver and Type 2 Diabetes, as reported by Imamura et al [43].…”

Section: Bmi Is Not the Main Driver For Insulin Resistance; Insulin Resistance Drives Bmimentioning

confidence: 69%

“…Malonyl-CoA is the first reaction step for the de novo lipogenesis of palmitic acid, which is positively associated with Type 2 Diabetes, as data from Imamura et al [43] showed. But de novo lipogenesis is also positively associated with saturated fatty acid intake and is elevated in patients with non-alcoholic fatty liver and Type 2 Diabetes, as reported by Imamura et al [43]. The TyG index is significantly associated with incident NAFL, as reported by Kitae et al [44] and Jimenez-Rivera et al [45].…”

Section: Bmi Is Not the Main Driver For Insulin Resistance; Insulin Resistance Drives Bmimentioning

confidence: 91%

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Hepatic-Metabolite-Based Intermittent Fasting Enables a Sustained Reduction in Insulin Resistance in Type 2 Diabetes and Metabolic Syndrome

Rohner¹,

Heiz

Feldhaus³

et al. 2021

Horm Metab Res

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Insulin resistance is the hallmark of Type 2 Diabetes and is still an unmet medical need. Insulin resistance lies at the crossroads of non-alcoholic fatty liver disease, obesity, weight loss and exercise resistance, heart disease, stroke, depression, and brain health. Insulin resistance is purely nutrition related, with a typical molecular disease food intake pattern. The insulin resistant state is accessible by TyG as the appropriate surrogate marker, which is found to lead the personalized molecular hepatic nutrition system for highly efficient insulin resistance remission. Treating insulin resistance with a molecular nutrition-centered approach shifts the treatment paradigm of Type 2 Diabetes from management to cure. This allows remission within five months, with a high efficiency rate of 85%. With molecular intermittent fasting a very efficient treatment for prediabetes and metabolic syndrome is possible, improving the non-alcoholic fatty liver disease (NAFL) state and enabling the body to lose weight in a sustainable manner.

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Section: Bmi Is Not the Main Driver For Insulin Resistance; Insulin Resistance Drives Bmimentioning

confidence: 69%

Section: Bmi Is Not the Main Driver For Insulin Resistance; Insulin Resistance Drives Bmimentioning

confidence: 91%

Hepatic-Metabolite-Based Intermittent Fasting Enables a Sustained Reduction in Insulin Resistance in Type 2 Diabetes and Metabolic Syndrome

Rohner¹,

Heiz

Feldhaus³

et al. 2021

Horm Metab Res

View full text Add to dashboard Cite

show abstract

“…These lipid species may represent an essential pathway of ARA utilization to meet increasing demands for neuronal growth and development in early childhood [17][18][19] . Additionally, several triacylglycerol species containing long chain saturated and monounsaturated fatty acids were also higher in child plasma, suggesting an increase in de novo fatty acid synthesis with possible implications on metabolism in children 32,33 . As is evident from our analyses (birth to 6 years of age, and child to adult comparisons), levels of more than half of the profiled lipid species increased in circulation with age.…”

Section: Discussionmentioning

confidence: 99%

Developmental and Intergenerational Landscape of Human Circulatory Lipidome and its Association with Obesity Risk

Chen

Burugupalli

et al. 2021

Preprint

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Lipids play a vital role in human health and development, but changes to their circulatory levels during gestation and in early life are poorly understood. Here we present the first developmental and intergenerational landscape of the human circulatory lipidome, derived by profiling of 480 lipid species representing 25 lipid classes, in mothers and their offspring (n=2491). Levels of 66% of the profiled lipids increased in maternal circulation during gestation, while cord blood had higher concentrations of acylcarnitines and lysophospholipids. The offspring lipidome at age six years revealed striking similarities with postnatal maternal lipidome (adult) in its lipid composition and concentrations. Comparison of lipids associated with child and maternal adiposity identified a 92% overlap, implying intergenerational similarities in the lipid signatures of obesity risk. We also catalogued lipid signatures linked with maternal adiposity during gestation and offspring birthweight, and validated (>70% overlap) the findings in an independent birth-cohort (n=1935).

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“…Overall, total fatty acids and subclasses of fatty acids (SFAs, MUFAs, n-6 PUFAs and trans-FAs) were higher in HepG2 cells in low B12. Recently, the Fatty Acids and Outcomes Research Consortium (FORCE) study involving 17 global cohorts (n=65, 225) reported that higher concentrations of SFA (16:0 -palmitate, 18:0 -stearate) and MUFA (16:1 n-7 -palmitoleate, 18:1 n-9 -oleate) was associated with higher incidence of T2D [42]. We found higher levels of 16:0 and 18:0, de novo lipogenesis related fatty acids in low B12 status.…”

Section: Discussionmentioning

confidence: 99%

Vitamin B12 Induces Hepatic Fatty Infiltration through Altered Fatty Acid Metabolism

Boachie

Adaikalakoteswari

Gázquez

et al. 2021

Cell Physiol Biochem

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Background/Aims: Rise in global incidence of obesity impacts metabolic health. Evidence from human and animal models show association of vitamin B12 (B12) deficiency with elevated BMI and lipids. Human adipocytes demonstrated dysregulation of lipogenesis by low B12 via hypomethylation and altered microRNAs. It is known de novo hepatic lipogenesis plays a key role towards dyslipidaemia, however, whether low B12 affects hepatic metabolism of lipids is not explored. Methods: HepG2 was cultured in B12-deficient EMEM medium and seeded in different B12 media: 500nM(control), 1000pM(1nM), 100pM and 25pM(low) B12. Lipid droplets were examined by Oil Red O (ORO) staining using microscopy and then quantified by elution assay. Gene expression were assessed with real-time quantitative polymerase chain reaction (qRT-PCR) and intracellular triglycerides were quantified using commercial kit (Abcam, UK) and radiochemical assay. Fatty acid composition was measured by gas chromatography and mitochondrial function by seahorse XF24 flux assay. Results: HepG2 cells in low B12 had more lipid droplets that were intensely stained with ORO compared with control. The total intracellular triglyceride and incorporation of radio-labelled-fatty acid in triglyceride synthesis were increased. Expression of genes regulating fatty acid, triglyceride and cholesterol biosynthesis were upregulated. Absolute concentrations of total fatty acids, saturated fatty acids (SFAs), monounsaturated fatty acids (MUFAs), trans-fatty acids and individual even-chain and odd-chain fatty acids were significantly increased. Also, low B12 impaired fatty acid oxidation and mitochondrial functional integrity in HepG2 compared with control. Conclusion: Our data provide novel evidence that low B12 increases fatty acid synthesis and levels of individual fatty acids, and decreases fatty acid oxidation and mitochondrial respiration, thus resulting in dysregulation of lipid metabolism in HepG2. This highlights the potential significance of de novo lipogenesis and warrants possible epigenetic mechanisms of low B12.

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Fatty acids in the de novo lipogenesis pathway and incidence of type 2 diabetes: A pooled analysis of prospective cohort studies

Abstract: Background De novo lipogenesis (DNL) is the primary metabolic pathway synthesizing fatty acids from carbohydrates, protein, or alcohol. Our aim was to examine associations of in vivo levels of selected fatty acids (16:0, 16:1n7, 18:0, 18:1n9) in DNL with incidence of type 2 diabetes (T2D).

Cited by 42 publications

References 53 publications

Hepatic-Metabolite-Based Intermittent Fasting Enables a Sustained Reduction in Insulin Resistance in Type 2 Diabetes and Metabolic Syndrome

Hepatic-Metabolite-Based Intermittent Fasting Enables a Sustained Reduction in Insulin Resistance in Type 2 Diabetes and Metabolic Syndrome

Developmental and Intergenerational Landscape of Human Circulatory Lipidome and its Association with Obesity Risk

Vitamin B12 Induces Hepatic Fatty Infiltration through Altered Fatty Acid Metabolism

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