Enzymes for overall digestive health, brea,down SSRI, also suppresses breadkown replication of different SARS-CoV-2 variants Eco-friendly office supplies concern in Vero and AhACE2-TMPRSS2 cells, human lung slicesand human airway organoid epithelia Davison, A. Marchi, C. PubMed CAS Google Scholar Varanasi, U.

Swift lipid breakdown -

Therefore, these parameters were not adjusted in the analysis. This was consistent with previous findings by us and others [ 23 , 47 , 48 ]. During lactation however, the maternal body utilizes TAGs and glycogen to meet the increased energy demands for mammary glands to produce milk, which is achieved mainly by promoting glycogenolysis and lipolysis [ 50 , 51 ].

It has been previously shown that saturated fatty acids containing an even number of carbon atoms derive from endogenous sources including de novo lipogenesis [ 52 , 53 , 54 , 55 , 56 ]. We particularly found that long-chain fatty acids were greatly decreased in IBF women.

This could be due to the fact that long-chain fatty acids present in milk are directly transferred from plasma instead of de novo synthesized from glucose in the mammary glands [ 57 ].

The link between intensive lactation and maternal lipid metabolism was further supported by the identification of master regulons PPARA, SREBF1, FOXO1, SOX9, STAT5A, etc. via the integrative tools. These master regulons are involved in lipid metabolism associated with lactation.

In particular, PPARA encodes peroxisome proliferator-activated receptor alpha PPAR-α , which is known to regulate utilization and catabolism of fatty acids [ 58 ]. SREBF1 encodes the sterol regulatory element-binding transcription factor 1 SREBP1 , a transcription factor TF which is required for de novo biosynthesis of fatty acids, cholesterol, and triglycerides [ 59 ].

FOXO1 encodes forkhead box protein O1 FOXO1 , a TF that is involved in regulation of gluconeogenesis and glycogenolysis by insulin signaling.

FOXO1 also promotes SOX9 expression and suppresses fatty acid oxidation in response to low lipid levels [ 60 ]. STAT5A encodes signal transducer and activator of transcription 5A STAT5A , which is a TF that plays an important role in intensive breastfeeding by activating prolactin-induced transcription and regulates the expression of milk proteins during lactation [ 61 ].

In addition to the pathways that we identified from KEGG, other lactation-associated pathways were reported previously [ 63 ]. Five metabolic pathways, including gluconeogenesis, pyruvate metabolism, the tricarboxylic acid cycle TCA cycle , glycerolipid metabolism, and aspartate metabolism, were found to be involved in lactation.

Among them, the TCA cycle was the most upregulated pathway suggesting that lactation is a process with high energy demand. These three lipid classes are intimately intertwined as they share common substrates such as phosphatidate and fatty acyl-CoA [ 64 ].

These findings suggest a close relationship between these three lipid classes. Phospholipids and sphingolipids are deeply involved in cell signaling and therefore their deficiency might lead to impaired insulin receptor signaling and insulin resistance [ 66 , 67 , 68 ]. Therefore, upregulation of sphingolipids and phospholipids accompanied by downregulation of glycerolipids may lead to reduced insulin resistance [ 69 , 70 ].

Indeed, we and others reported lactating women were shown to have lower HOMA-IR than less or non-lactating women [ 71 , 72 ]. In addition to lipids, we also showed significantly decreased hexose was associated with intensive lactation. This may be explained by the increased glucose uptake in mammary glands during lactation.

In contrast, peripheral glucose uptake in other tissues such as liver and muscle is reduced during lactation, which has been suggested to occur in order to prioritize the glucose for milk production [ 50 , 73 ]. In our current study using a subset of women from SWIFT future diabetes vs.

In our previous study, intensive lactation was associated with low incident diabetes rates [ 7 , 8 ]. Additionally, expanding the sample size could also help reveal a difference. Therefore, in future studies, we could apply omics on a larger sample size of the SWIFT study whose fasting plasma samples are available at both baseline and follow-up.

Furthermore, the longer-term benefits associated with postpartum lactation may also involve other pathways including inflammatory markers or changes in lipid markers that we were unable to evaluate at follow-up in this analysis.

Importantly, the changes related to concurrent lactation intensity, such as modifications at the gene level with a more long-term and persistent effect compared to metabolic changes, should be investigated.

Interestingly, in this study, we observed a remarkable opposing lipid profile associated with IBF. Therefore, these current findings, from a standpoint of metabolism, support our previous findings that women with intensive lactation postpartum have reduced risk of developing diabetes compared to those who do not breast feed intensively [ 8 ].

We reported that metabolic dysregulation including impaired glucose metabolism was present at the early postpartum period in GDM women who would develop T2D in later years [ 36 , 75 ]. Other studies in women with obesity reported shortened breastfeeding duration, delayed onset of lactogenesis and lactation outcomes [ 76 , 77 , 78 , 79 ].

Clinically, impaired glucose metabolism and insulin sensitivity may be associated with poor lactation performance and low milk supply in women [ 80 ].

These risk factors may also influence maternal circulating lipid profiles. Thus, the association between lactation and metabolic changes could differ by future T2D status. Therefore, in our case-control subsample, we stratified according to future diabetes status.

We observed that women who went on to develop T2D had far fewer lipid changes during lactation at early postpartum compared to those who did not develop T2D.

This indicates that the favorable effects of intensive lactation which are inversely associated with T2D may be attributed to significant changes in lipid metabolism during lactation. However, the IBF women whose lipid profiles were not significantly altered were more likely to develop future T2D during follow-up.

Further insight is required to address this directly. Additionally, in women with intensive breastfeeding, we identified a analyte signature panel to effectively predict future T2D risk, which is far superior to the predictive performance of non-invasive clinical parameters and standard measurements.

This signature panel included 4 major metabolite groups, including acylcarnitine, amino acid, biogenic amine, and lipid, supporting the fact that diabetes is a metabolic disorder with dysregulation of carbohydrates, lipids, and amino acids. Three of these analytes PC aa C, SM OH C and spermidine were also identified in our previous study, where we developed a analyte signature to effectively predict future T2D onset after GDM pregnancy [ 75 ], suggesting the importance of these analytes in predicting future T2D.

Moreover, the predictive performance of the analyte signature reported here does not rely on accompanying clinical variables, suggesting the significance of the metabolic signature to predict future T2D in this specific group of women with intensive breastfeeding.

Our current findings further suggested that the favorable effects of lactation on maternal metabolic health may be exerted through changes in lipid metabolism. Longitudinal studies with both lipidomics and metabolomics performed on a larger sample size and in an independent cohort would further illuminate the persistent effects of lactation on the metabolic pathways related to diabetogenesis.

Therefore, the changes in the metabolites of the plasma over the storage time should also be considered. Regardless, our study has advanced our understanding of lactation-associated biochemical pathways and their relationship with diabetes risk in women.

This study showed that intensive lactation significantly alters the circulating lipid profile at early postpartum and that women who do not respond metabolically to lactation are more likely to develop T2D. We also identified a metabolic signature that accurately predicts future onset of T2D in IBF women.

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The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada. Ziyi Zhang, Mi Lai, Anthony L. Piro, Amina Allalou, Feihan F.

Department of Endocrinology, Sir Run Run Shaw Hospital, Zhejiang University, Zhejiang, Hangzhou, China. Division of Research, Kaiser Permanente Northern California, Oakland, California, USA. Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada.

Metabolism Research Group, Division of Advanced Diagnostics, Toronto General Research Institute, Toronto, Ontario, Canada. Health Systems Science, Kaiser Permanente Bernard J.

Tyson School of Medicine, Pasadena, USA. You can also search for this author in PubMed Google Scholar. ZZ: conceptualization, data analysis, investigation, visualization, methodology, writing-original draft preparation, writing-review and editing.

LM: data curation, investigation, writing-review and editing. ALP: conceptualization, writing-original draft preparation, writing-review and editing.

SEA: data analysis, writing-review and editing. AA: conceptualization, writing-review, and editing. HLR: study design, data interpretation, writing-review and editing.

FFD: conceptualization, supervision, investigation, writing-original draft preparation and editing. MBW: conceptualization, supervision, resources, funding acquisition, methodology, investigation, writing-original draft preparation, writing-review and editing.

EPG: SWIFT cohort and study design, resources, funding, editing. All authors read and approved the final manuscript. Correspondence to Feihan F. Dai , Michael B. Wheeler or Erica P. Written informed consents were obtained from all participants before partaking in any research activities.

The study was approved by the Kaiser Permanente Northern California Institutional Review Board CNEGundH and and the Office of Research Ethics at University of Toronto Consent to publish is not applicable to this article as no details on individuals were reported in the manuscript.

The authors of this manuscript have the following competing interests: MBW has declared a research grant from Janssen Pharmaceuticals Company shared with EPG. EPG has declared the following competing interest: R01HL EPG, PI. R01DK EPG, PI. R01HD EPG, Co-I. R21HL EPG, Co-I. R01HD EPG, Consultant.

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Quality control of the final metabolomics dataset at baseline and follow-up. Figure S2. Figure S3. Quality control of the final lipidomics dataset at baseline. Figure S4. Figure S5. Effects of different lactation intensity on lipid profiling at early postpartum.

Figure S6. Metabolites associated with extreme lactation intensity at baseline. Figure S7. Generation of the predictive models.

Table S1. Table S2. Table S3. Table S4. Relationship between lactation intensity and fatty acid composition in lipids. Table S5. Reduction of total cholesterol and LDL level are each well known to be associated with a decrease in the risk of adverse cardiovascular events Overall, the data suggests a fundamental improvement in lipid metabolism in our clinical cohort, a finding which is consistent with previous studies Following the conversion of plasma NEFAs to fatty acid methyl esters FAMEs , NEFA concentrations in plasma samples taken from participants before and 9 months after Roux-en-Y surgery were measured.

An example GC-MS chromatogram showing the retention times of individual NEFA peaks is shown in Fig. The resultant quantitative data for the respective NEFA species in each of the samples is presented Fig. The other five major NEFA species measured exhibited no difference in concentration 9 months after surgery compared to pre-surgery levels.

These were α-linolenate , cis-vaccenate c11 , eicosapentaenoate , dihomo-γ-linoleate and docosahexaenoate Example GC:MS chromatogram showing points of separation of individual FAMEs. The retention times of peaks corresponding to individual NEFA species are shown in the table.

Mean plasma NEFA concentrations in participants before Pre-Op and 9 months after Post-Op bariatric surgery. Mean plasma NEFA indices and ratios in participants before Pre-Op and 9 months after Post-Op bariatric surgery. Different plasma NEFA indices were then calculated and levels before and after surgery were compared.

The de novo lipogenesis index was calculated as the ratio of palmitate , the main product of lipogenesis with linoleate , an essential NEFA only found in the diet.

Several other studies that have examined plasma NEFA profiles in patients after various types of bariatric surgery have found such interventions to lead to significant reductions in total NEFA concentrations and groups of fatty acids in the months following surgery 28 , 29 , 30 , 31 , 32 , 33 , in a manner similar to that observed in this study.

A meta-analysis published in found that serum NEFA levels were decreased at 6 and 12 months but did not differ from preoperative levels at 3 months post-surgery However, this analysis also found that serum NEFAs did not differ significantly from pre-operative levels at 18 and 24 months after surgery.

This work and the data presented here suggests that the greatest reduction in circulatory NEFA concentration is observed between 6 and 12 months after bariatric surgery. It is worth noting that Roux-en-Y surgery is also known to alter the gut microbiota 35 , which has the potential to influence circulating NEFA levels.

The effect of Roux-en-Y surgery on NEFA composition in the plasma has not been extensively studied. Of particular interest is the effect of the surgery on the two essential fatty acids, linoleate n-6, an omega-6 fatty acid and α-linolenate n-3, an omega-3 fatty acid , and also their polyunsaturated fatty acid derivatives.

Specifically, linoleate is converted to arachidonic acid n-6 and α-linolenate is converted to eicosapentaenoic n-3 acid and docosahexaenoic acid n All four NEFAs were measured in our study.

Of these, linoleate was found to be present in plasma at reduced levels at 9 months following surgery. This NEFA has been shown to be associated with a lower incidence of type 2 diabetes 36 , and coronary heart disease mortality This observed decrease in linoleate concentration suggests that the reduction in the effective size of the stomach may lead to reduced absorption of this essential fatty acid.

The concentration of arachidonate was also reduced at 9 months after surgery. Arachidonate has essential roles in the brain and serves as a precursor for eicosanoid biosynthesis Our study found no significant difference in eicosapentaenoic acid and docosahexaenoic acid between pre and post-surgery.

Our study however does report a reduction in both total omega-3 and omega-6 fatty acids. A recent systematic review has analyzed the effect of different obesity surgeries on blood polyunsaturated NEFAs.

There are some conflicting data in the current literature both increases and decreases in polyunsaturated NEFAs have been reported following obesity surgery Our own analysis of the current literature confirms this Table 4.

Overall, however, the authors concluded that both the essential fatty acids and eicosapentaenoic acid decrease in the months following surgery. Interestingly, the effect of Roux-en-Y on levels of saturated NEFAs also appears to vary depending on the study. To fully understand changes in lipid metabolism following Roux-en-Y surgery, different fatty acid indices were calculated to indicate the activities of various enzyme classes involved in fatty acid metabolism.

The increase in de novo lipogenesis index at 9 months following surgery might suggest an increase in fatty acid synthesis. This is supported by a study that found that bariatric weight loss increased de novo lipogenesis in white adipose tissue However, it is more likely this result is due to lower consumption and reduced absorption of dietary fat after surgery given that palmitate concentrations the major product of de novo lipogenesis did not increase post-surgery and the essential linoleic acid found only in the diet was lower following surgery.

The elongase index and the D6D index increased following surgery. The D5D index was unchanged between the groups. The increased elongase activity is consistent with reports demonstrating that weight loss, induced by bariatric surgery, leads to increased expression of various genes involved in fatty acid metabolism in adipose tissue including fatty acid elongase-6 and fatty acid synthase The D6D index can reflect an increased production of polyunsaturated fatty acids.

However, in our case, this parameter most likely increased because of a much-reduced level of plasma linoleate after surgery due to restricted dietary intake.

The fact that the D5D index did not change which can also reflect polyunsaturated fatty acid synthesis supports this. The SCD1 index 1 was found to be significantly decreased after surgery.

However, SCD1 index 2 was unchanged. These indices are reflective of stearoyl-CoA desaturase 1 activity, an enzyme known to exhibit increased expression in obesity This enzyme has been shown to exhibit decreased activity following weight loss, but the decrease in activity at least regarding palmitoleate to palmitate conversion can also potentially be attributable to decreased carbohydrate intake In summary, we show that Roux-en-Y gastric surgery leads to substantive weight loss and corresponding changes in anthropometric parameters in obese patients 9 months following surgery.

The intervention additionally led to the normalization of dysglycemia in several participants. The total and LDL cholesterol concentrations were markedly reduced following surgery. The study identified reductions in the plasma concentrations of most of the NEFA species examined, including saturated, monounsaturated and polyunsaturated species.

Measurement of individual NEFAs revealed specific changes in lipid metabolism 9 months after surgery that included increased lipogenesis in addition to increased elongase and decreased stearoyl-CoA desaturase 1 activity.

The novel findings presented here further illuminate the metabolic changes that take place following gastric bypass surgery in severely obese patients. All research protocols were performed in accordance with the Declaration of Helsinki.

Briefly, a total of 25 Roux-en-Y surgical patients 17 females and 8 males were recruited from York Hospital, York, United Kingdom. Male or female participants over 18 years of age and referred to the hospital for bariatric surgery for obesity were included in this study.

Exclusion criteria included if participants were under 18 years old, were diagnosed with an endocrine disorder other than type 2 diabetes, had a history of alcohol or drug abuse, had a significant psychological history, had a history of deep vein thrombotic disease, were taking warfarin, were pregnant, had a history of active malignancy or if they developed post-operative complications.

Blood samples were collected in both lithium heparin and EDTA tubes prior to surgery within 48 h of the procedure and at a 9-month follow-up appointment after surgery. Blood was collected after patients had fasted for at least 6 h.

EDTA-treated whole-blood was used to measure HbA1c by the Laboratory Medicine Service at York Hospital using a boronate affinity chromatography-based method HbA1c concentrations are expressed as a percentage of total haemoglobin.

Cholesterol, triglycerides, HDL and LDL cholesterol concentrations were measured in plasma collected in lithium heparin tubes also by the Laboratory Medicine service at York Hospital using standard methods.

To measure individual NEFA species present in each sample, NEFAs were converted to fatty acid methyl esters FAMEs and analysed by gas chromatography-mass spectrometry GC- MS analysis as previously described 51 , Plasma samples were spiked with pmol of a heptadecanoate internal standard to allow normalisation.

Samples were evaporated to dryness using nitrogen. The FAME mixtures were then dissolved in 1 ml of water:hexane ratio and the hexane phase was collected and evaporated to dryness in a fume hood. FAMEs were then dissolved in 30 µl dichloromethane and 1—2 µl of the resultant samples were analysed by GC—MS.

Mass spectra were acquired from 50— amu. FAMEs were identified by comparison of retention times and fragmentation patterns of the samples with various FAME standard mixtures Supelco, Bellefonte, PA, USA.

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Thank you lipir visiting nature. Enzymes for overall digestive health are using a browser version Swifh limited support for CSS. To obtain breakeown Swift lipid breakdown liipid, we recommend you Motivational strategies a more up to date browser or turn off compatibility mode in Internet Explorer. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. A common feature is dyslipidemia characterized by increased levels of plasma lipids, which include non-esterified fatty acids NEFAs. Moreover, lipids store energy and breakxown as secondary messengers whose breakxown is tightly breakdwon. Disruption of Weight gain progress metabolism is associated with many Swift lipid breakdown, including those caused by viruses. In contrast, Sdift can counteract viruses using lipids as weapons. In this review, we discuss the available data on how coronaviruses profit from cellular lipid compartments and why targeting lipid metabolism may be a powerful strategy to fight these cellular parasites. We also provide a formidable collection of data on the pharmacological approaches targeting lipid metabolism to impair and treat coronavirus infection.

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Some lipoproteins have protective effects, while others have AD enhancing properties. For example, HDL has been shown to be protective by improving Aβ clearance, delaying Aβ fibrillization, suppressing vascular inflammation, and inducing endothelial nitric oxide production Button et al.

Since cholesterol metabolism altered at several stages of AD, modulation of its metabolism may have beneficial effects on disease progression. Modification of cholesterol homeostasis can be influenced during its consumption, at the level of its biosynthesis, and during its transport into the brain.

The use of statin to alter cholesterol biosynthesis is proposed to be insightful in AD pathophysiology and therapy Wolozin et al. Gene therapy targeting cholesterol hydroxylase reduces the amyloid pathology before or after the onset of amyloid plaques in mouse AD models Hudry et al.

Studies in mouse models show that blocking the conversion of cholesterol to cholesterol esters has beneficial effects on AD Shibuya et al. The relationship between hypercholesterolemia, cholesterol-lowering therapies, and the role of oxysterols in AD pathology have led to the proposition that cholesterol metabolites are valuable targets for alternative AD treatments or prevention Loera-Valencia et al.

Neuroinflammatory pathways mediated by toll-like receptor 4 TLR4 -mediated signaling can aggravate AD symptoms. In a rodent AD model, treatment with an anti-inflammatory steroid atorvastatin regulates this inflammatory process and results in the amelioration of cognitive deficits Wang et al. The activity or expression of several lipolytic enzymes are altered in AD.

Phospholipase A 2 PLA 2 is associated with amyloid plaques, and reduction of its activity and expression ameliorates AD. Plasmalogen selective PLA 2 is also altered in AD.

Our studies show an increase in PLA 2 activity of CSF of AD participants accompanied by an increase in lysophosphatidylcholine LPC. LPC is known to disrupt the BBB, and changes in PLA 2 are associated with inflammation.

The association of PLA 2 with AD pathology suggests that inhibitors of PLA 2 activity or expression may be an effective means of preventing AD. Ong et al. Since PLA 2 isoforms may have divergent effects on membrane remodeling and function, there is a need for isoform-specific inhibitors in order to avoid toxicity encountered with non-selective inhibitors.

In addition to PLA 2 , phospholipase D PLD and phospholipase C PLC expression and activities are associated with AD pathology. These lipases that are linked with neurite growth and signaling, respectively, offer other avenues for exploring AD treatments.

There is convincing evidence for the importance of oxidative stress on AD pathology Sun et al. The most important brain fatty acid, DHA, is a polyunsaturated fatty that is easily susceptible to oxidative damage. While HDL is protective against oxidative damage, VLDL is easily oxidized.

Oxidatively damaged lipids contribute to AD pathology by their highly neurotoxic properties Bassett et al. Approaches that reduce oxidation are expected to reduce AD progression. These include the use of natural antioxidants, carnosine, lipoic acid, Ginkgo biloba flavonoids, soybean isoflavones, vitamin K, homocysteine, curcumin Rutten et al.

A limitation of natural antioxidant is the lack of demonstration of efficacy. Given that oxidative stress destroys mitochondrial function, an objective measure of any antioxidant can be their ability to restore mitochondrial function Kumar and Singh, ; Kwon et al. The role of endogenous lipids in oxidative stress can be exploited when there is an uncontrolled formation of ROS and RNS or when the antioxidants contribute to disease pathology Leuti et al.

Also, the source of ROS determines the effects on cellular physiology and manipulation of the ubiquinone redox state is proposed to be a viable approach of delaying aging and therapy Scialo et al. Biochemical, physiological, and genetic analyses show that lipid metabolism interphases with all the major facets of AD pathology Figure 1.

In normal aging, lipid metabolic homeostasis ensures that the basic functions of the brain are met. In AD, there is dyshomeostasis of lipid metabolism, and this results in abnormal functions of the brain that characterize disease progression.

This underscores the need for detailed analyses of brain lipid homeostasis in order to unravel more comprehensive mechanisms, specific biomarkers, and novel therapies of AD. AF contributed to the conceptualization and study design, supervised the data, and carried out the project administration and funding acquisition.

HC, VS, and AF contributed to writing of the original draft and manuscript preparation. HC and AF contributed to the manuscript review and editing. VS and AF prepared the figures and illustrations. AF was supported by funds from the L. Whittier Foundation and HMRI.

VS is supported by R01 AG and R01 AG to Dr. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. We thank HMRI and Dr. Harrington for providing support and a scholarly environment for the summer student program.

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To further explore these findings, we utilized lipidomics covering a wide-spectrum of lipid species lipid species from 15 classes along with fatty acids as previously described [ 36 ] to assess the lipid changes associated with lactation intensity at baseline among women IBF vs.

A total of lipid species were included in the final bioinformatic analysis. Normality of dataset was checked Additional file 1 : Figure S3A.

PCA and PLS-DA analyses showed a distinct separation between the two groups which was not due to a random effect Additional file 1 : Figure S3B to S3D. These differentially expressed lipids were composed of neutral lipids, phospholipids, and 47 sphingolipids Fig. Of the downregulated lipids, were from TAG class while 45 were from diacylglycerol DAG class Fig.

In contrast, of the upregulated lipids, 91 were phospholipids 11 from lysophosphatidylcholine LPC class, 6 from lysophosphatidylethanolamine LPE class, 39 from phosphatidylcholine PC class, 22 from phosphatidylethanolamine PE class, 13 from phosphatidylinositol PI class , 43 were sphingolipids 8 from ceramide CER class, 7 from dihydroceramide DCER class, 9 from hexosylceramide HCER class, 10 from lactosylceramide LCER class and 9 from sphingomyelin SM class , and 49 were neutral lipids 21 were from cholesterol ester CE class, one from DAG class, 11 from free fatty acid FFA class, 2 from monoacylglycerol MAG class, and 14 from TAG class Fig.

More strictly, we showed the top most significantly differentially expressed lipid species Fig. Among these lipid species, 81 TAGs and 23 DAGs were consistently negatively associated with lactation intensity at baseline. In contrast, 15 sphingolipids, 20 phospholipids, and 11 CEs were consistently positively correlated with intensive lactation Fig.

Lipid species associated with intensive lactation at baseline. Blue points indicate significantly differentially expressed neutral lipids, red denotes phospholipids, and yellow indicates sphingolipids.

Grey points indicate no significant change. B Number of lactation intensity-associated metabolites in 15 lipid classes. Red indicates upregulated metabolites whereas blue indicates downregulated, and grey denotes no significant change. C Bubble plot showing the top organized by FDR value most significantly differentially expressed lipid species associated with lactation intensity.

A total of lipid species were significantly differentially expressed among the four groups. Moreover, there was a dosage effect of lactation intensity associated with lipid changes.

Additional file 1 : Figure S5. Additionally, we performed an extreme analysis by comparing the exclusive BF group with the exclusive FF group. A total of lipid species were found to be significantly changed between the two groups. In addition to lipid species, we also examined number of carbon atoms and double bonds in lipidomic profiling to gain insight into whether intensive lactation affected composition and configuration of lipids.

The TAGs measured in this study possessed carbon atoms ranging from 35 to 60, and double bonds ranging from 0 to Significantly downregulated TAGs in IBF women were clustered in the range of carbon atoms 50—56, especially those with even carbon atoms 50, 52, 54, and 60 Fig.

Similarly, DAGs with an even number of carbon atoms 32, 34, 36, 38, and 40 were significantly negatively associated with intensive lactation at baseline Fig. We did not identify specific patterns in other lipid classes Fig.

As for the total FAs, most long-chain fatty acid FA , FA , FA , FA , FA , FA , FA , and FA were significantly downregulated in IBF women, whereas most very long-chain fatty acids FA , FA , FA , FA , and FA were upregulated.

No changes were observed in medium-chain fatty acids Fig. Characterization of lipid structure associated with intensive lactation at baseline.

A Association between lactation intensity groups and lipid structure including the number of carbon atoms and double bonds in each lipid species from 15 lipid classes. Log2 FC of each lipid species are indicated with dots, with color of dots indicating log2 FC value, and dot size denoting significance by FDR value.

B Association between lactation intensity and fatty acid composition in 15 lipid classes. To identify metabolic pathways associated with lactation intensity at baseline, we performed Kyoto Encyclopedia of Genes and Genomes KEGG pathway analysis. These three significantly regulated pathways glycerolipid, sphingolipid, and glycerophospholipid metabolism are closely linked as they share common substrates such as phosphatidate and fatty acyl-CoA, suggesting a pathway switch and flux of carbon from TAG and DAG sources towards phospholipids and sphingolipids Fig.

Metabolic pathways associated with intensive lactation at baseline. Blue indicates downregulated pathway whereas red indicates upregulated pathway. B Integrated metabolic pathway of synthesis of 15 lipid classes from neutral lipids, phospholipids, and sphingolipids.

Red indicates upregulation, and blue denotes downregulation with p value indicated. Our findings suggested lactation intensity was associated with alterations in lipid metabolism. To further examine this biological change at the gene level, we used MetaBridge to cross-link genes with the differential lipids that were associated with lactation intensity [ 39 ].

iRegulon was then applied to detect master regulons from the set of genes and establish a regulatory network [ 40 ]. We found upregulated lipids mainly phospholipids and sphingolipids were linked to genes including ACSL, CERS, CPT, ELOVL, and G6PC Additional file 1 : Table S6 that participate in the biosynthesis of fatty acids, phospholipids, and sphingolipids [ 41 , 42 , 43 , 44 , 45 ].

By using iRegulon analysis, these genes were matched to 21 master regulons such as PPARA, SREBF1, FOXO1, SOX9, STAT5A , majority of which are involved in lipid metabolism Fig.

The cluster of targeted genes regulated by the master regulons involved in lipid metabolism during lactation was summarized in Fig. In contrast, downregulated lipids mainly TAG and DAG were linked to only one gene CEPT1 Fig.

No master regulon was identified due to only one gene being linked to the downregulated lipid species. Regulatory network analysis of master regulons and genes that participate in metabolism of lipids associated with intensive lactation.

A Flow chart of the identification of co-expressed genes and the master regulons from altered lipids by using MetaBridge and iRegulon.

B iRegulon analysis depicting the regulatory network between the master regulons associated with lipid metabolism and their downstream target genes. We further stratified the subset of women with recent GDM by future T2D status and examined whether intensive lactation affected lipid profiles in each subgroup.

In the future T2D group, 98 In the no T2D group, However, the amount of significantly differentially expressed lipids in the future T2D subgroup was much less than those in women with no T2D.

The same trend was also observed in the metabolomic profiling. This indicates that women who do not respond metabolically to lactation would be very likely to progress to future T2D after GDM pregnancy. The effect of postpartum lactation on lipid profiling in future T2D and no T2D women at baseline.

Solid dots represent significance, empty dots indicate non-significance. Moreover, at early postpartum, the non-responders exhibited higher FPG, fasting insulin, HOMA-IR, and higher proportion of glucose intolerance compared to responders.

To further identify who is more likely to develop future T2D even with intensive breastfeeding, we established a distinct predictive model with 10 analytes-1 acylcarnitine, 2 biogenic amines, 3 amino acids, and 4 lipids Fig. Notably, after combining the clinical variables with the analyte signature, the predictive performance was slightly improved median AUC 0.

These data suggest that the metabolic changes appeared years before the real onset of T2D in women with intensive breastfeeding, which allows us to predict T2D in this specific group of women and further investigate the underlying mechanisms associated with T2D pathogenesis. Metabolic signature to predict future T2D in IBF women at early postpartum.

A Variable selection using random forest identified a set of 10 analytes with high predictive power. B ROC of the predictive models generated by analyte signature and traditional clinical variables fasting glucose and 2-h glucose in the testing set. We showed that high lactation intensity was associated with substantial effects on maternal lipid profiles in women with recent GDM.

Interestingly, these changes were not observed at follow-up or in a longitudinal analysis, indicating a convergence in the metabolome at this point. We further revealed that women who later progressed to T2D had fewer lipid changes associated with lactation intensity compared to no T2D women.

Several prenatal parameters could affect the changes in lipids observed in IBF women. Therefore, in the following statistical analyses, we adjusted pre-pregnancy BMI. Since baseline measures of glucose FPG, 2-h PG, HOMA-IR, HOMA-β, etc.

Therefore, these parameters were not adjusted in the analysis. This was consistent with previous findings by us and others [ 23 , 47 , 48 ]. During lactation however, the maternal body utilizes TAGs and glycogen to meet the increased energy demands for mammary glands to produce milk, which is achieved mainly by promoting glycogenolysis and lipolysis [ 50 , 51 ].

It has been previously shown that saturated fatty acids containing an even number of carbon atoms derive from endogenous sources including de novo lipogenesis [ 52 , 53 , 54 , 55 , 56 ]. We particularly found that long-chain fatty acids were greatly decreased in IBF women.

This could be due to the fact that long-chain fatty acids present in milk are directly transferred from plasma instead of de novo synthesized from glucose in the mammary glands [ 57 ].

The link between intensive lactation and maternal lipid metabolism was further supported by the identification of master regulons PPARA, SREBF1, FOXO1, SOX9, STAT5A, etc.

via the integrative tools. These master regulons are involved in lipid metabolism associated with lactation. In particular, PPARA encodes peroxisome proliferator-activated receptor alpha PPAR-α , which is known to regulate utilization and catabolism of fatty acids [ 58 ].

SREBF1 encodes the sterol regulatory element-binding transcription factor 1 SREBP1 , a transcription factor TF which is required for de novo biosynthesis of fatty acids, cholesterol, and triglycerides [ 59 ]. FOXO1 encodes forkhead box protein O1 FOXO1 , a TF that is involved in regulation of gluconeogenesis and glycogenolysis by insulin signaling.

FOXO1 also promotes SOX9 expression and suppresses fatty acid oxidation in response to low lipid levels [ 60 ]. STAT5A encodes signal transducer and activator of transcription 5A STAT5A , which is a TF that plays an important role in intensive breastfeeding by activating prolactin-induced transcription and regulates the expression of milk proteins during lactation [ 61 ].

In addition to the pathways that we identified from KEGG, other lactation-associated pathways were reported previously [ 63 ]. Five metabolic pathways, including gluconeogenesis, pyruvate metabolism, the tricarboxylic acid cycle TCA cycle , glycerolipid metabolism, and aspartate metabolism, were found to be involved in lactation.

Among them, the TCA cycle was the most upregulated pathway suggesting that lactation is a process with high energy demand. These three lipid classes are intimately intertwined as they share common substrates such as phosphatidate and fatty acyl-CoA [ 64 ]. These findings suggest a close relationship between these three lipid classes.

Phospholipids and sphingolipids are deeply involved in cell signaling and therefore their deficiency might lead to impaired insulin receptor signaling and insulin resistance [ 66 , 67 , 68 ].

Therefore, upregulation of sphingolipids and phospholipids accompanied by downregulation of glycerolipids may lead to reduced insulin resistance [ 69 , 70 ]. Indeed, we and others reported lactating women were shown to have lower HOMA-IR than less or non-lactating women [ 71 , 72 ]. In addition to lipids, we also showed significantly decreased hexose was associated with intensive lactation.

This may be explained by the increased glucose uptake in mammary glands during lactation. In contrast, peripheral glucose uptake in other tissues such as liver and muscle is reduced during lactation, which has been suggested to occur in order to prioritize the glucose for milk production [ 50 , 73 ].

In our current study using a subset of women from SWIFT future diabetes vs. In our previous study, intensive lactation was associated with low incident diabetes rates [ 7 , 8 ]. Additionally, expanding the sample size could also help reveal a difference.

Therefore, in future studies, we could apply omics on a larger sample size of the SWIFT study whose fasting plasma samples are available at both baseline and follow-up.

Furthermore, the longer-term benefits associated with postpartum lactation may also involve other pathways including inflammatory markers or changes in lipid markers that we were unable to evaluate at follow-up in this analysis.

Importantly, the changes related to concurrent lactation intensity, such as modifications at the gene level with a more long-term and persistent effect compared to metabolic changes, should be investigated.

Interestingly, in this study, we observed a remarkable opposing lipid profile associated with IBF. Therefore, these current findings, from a standpoint of metabolism, support our previous findings that women with intensive lactation postpartum have reduced risk of developing diabetes compared to those who do not breast feed intensively [ 8 ].

We reported that metabolic dysregulation including impaired glucose metabolism was present at the early postpartum period in GDM women who would develop T2D in later years [ 36 , 75 ]. Other studies in women with obesity reported shortened breastfeeding duration, delayed onset of lactogenesis and lactation outcomes [ 76 , 77 , 78 , 79 ].

Clinically, impaired glucose metabolism and insulin sensitivity may be associated with poor lactation performance and low milk supply in women [ 80 ]. These risk factors may also influence maternal circulating lipid profiles. Thus, the association between lactation and metabolic changes could differ by future T2D status.

Therefore, in our case-control subsample, we stratified according to future diabetes status. We observed that women who went on to develop T2D had far fewer lipid changes during lactation at early postpartum compared to those who did not develop T2D.

This indicates that the favorable effects of intensive lactation which are inversely associated with T2D may be attributed to significant changes in lipid metabolism during lactation. However, the IBF women whose lipid profiles were not significantly altered were more likely to develop future T2D during follow-up.

Further insight is required to address this directly. Additionally, in women with intensive breastfeeding, we identified a analyte signature panel to effectively predict future T2D risk, which is far superior to the predictive performance of non-invasive clinical parameters and standard measurements.

This signature panel included 4 major metabolite groups, including acylcarnitine, amino acid, biogenic amine, and lipid, supporting the fact that diabetes is a metabolic disorder with dysregulation of carbohydrates, lipids, and amino acids. Three of these analytes PC aa C, SM OH C and spermidine were also identified in our previous study, where we developed a analyte signature to effectively predict future T2D onset after GDM pregnancy [ 75 ], suggesting the importance of these analytes in predicting future T2D.

Moreover, the predictive performance of the analyte signature reported here does not rely on accompanying clinical variables, suggesting the significance of the metabolic signature to predict future T2D in this specific group of women with intensive breastfeeding.

Our current findings further suggested that the favorable effects of lactation on maternal metabolic health may be exerted through changes in lipid metabolism. Longitudinal studies with both lipidomics and metabolomics performed on a larger sample size and in an independent cohort would further illuminate the persistent effects of lactation on the metabolic pathways related to diabetogenesis.

Therefore, the changes in the metabolites of the plasma over the storage time should also be considered. Regardless, our study has advanced our understanding of lactation-associated biochemical pathways and their relationship with diabetes risk in women.

This study showed that intensive lactation significantly alters the circulating lipid profile at early postpartum and that women who do not respond metabolically to lactation are more likely to develop T2D. We also identified a metabolic signature that accurately predicts future onset of T2D in IBF women.

Our findings provide novel insight into how lactation influences maternal metabolism and its link to future diabetes onset.

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