Skin modeling is a crucial tool in dermatology, cosmetics, and pharmaceutical research. However, replicating the skin barrier function in these models remains challenging. Recent advances in lipidomics have highlighted significant differences between skin models and native human skin. Notably, self-assembled tissues exhibit an accumulation of 2-linoleoylglycerol, a monoacylglycerol containing a linoleic acid moiety. This study investigated the impact of 2-linoleoylglycerol on the skin lipidome and testosterone permeability in skin substitutes produced via the self-assembly method. The treatment of skin substitutes with 2-linoleoylglycerol resulted in higher levels of linoleic acid in epidermal phospholipids. Testosterone permeability remained largely unaffected by 2-linoleoylglycerol supplementation, and there was a modest impact on the expression of tight junction proteins. Although monoacylglycerol degradation by monoacylglycerol lipase was unchanged, its synthesis by diacylglycerol lipase β appeared to be influenced by exogenous 2-linoleoylglycerol, since the level of RNA gene transcription was decreased. In conclusion, these results show that the accumulation of 2-linoleoylglycerol in the epidermis of skin substitutes could be one of the factors that affect the lipid metabolism of the skin model.

Linoleic acid is an essential fatty acid required for skin barrier formation. However, linoleic acid-deficient media remains widely used in cell culture and reconstructed skin production, potentially contributing to suboptimal barrier function in skin models. In this study, we investigated the effects of varying linoleic acid concentrations in culture media on lipid composition, bioactive lipid mediator production, and gene expression of lipid-metabolizing enzymes in self-assembled skin substitutes. High-concentration linoleic acid significantly improved barrier function, as evidenced by reduced testosterone permeability, and enhanced incorporation into phospholipids, triacylglycerols, and diacylglycerols. Unexpectedly, ω-hydroxy-sphingosine ceramide proportions were reduced, reflective of downregulation of key enzymes in ω-O-acylceramide synthesis. These findings reveal a complex interplay between linoleic acid availability, lipid remodeling, and enzymatic regulation, offering new insights into optimizing reconstructed skin models for improved barrier function and lipid homeostasis.

There is a need to develop interventions to slow or reverse the degeneration of dopamine neurons in Parkinson’s disease after diagnosis. Given that preclinical and clinical studies suggest benefits of dietary n-3 polyunsaturated fatty acids, such as docosahexaenoic acid, and exercise in Parkinson’s disease, we investigated whether both could synergistically interact to induce recovery of the dopaminergic pathway. First, mice received a unilateral stereotactic injection of 6-hydroxydopamine into the striatum to establish an animal model of nigrostriatal denervation. Four weeks after lesion, animals were fed a docosahexaenoic acid-enriched or a control diet for the next 8 weeks. During this period, the animals had access to a running wheel, which they could use or not. Docosahexaenoic acid treatment, voluntary exercise, or the combination of both had no effect on (i) distance traveled in the open field test, (ii) the percentage of contraversive rotations in the apomorphine-induction test or (iii) the number of tyrosine-hydroxylase-positive cells in the substantia nigra pars compacta. However, the docosahexaenoic acid diet increased the number of tyrosine-hydroxylase-positive terminals and induced a rise in dopamine concentrations in the lesioned striatum. Compared to docosahexaenoic acid treatment or exercise alone, the combination of docosahexaenoic acid and exercise (i) improved forelimb balance in the stepping test, (ii) decreased the striatal DOPAC/dopamine ratio and (iii) led to increased dopamine transporter levels in the lesioned striatum. The present results suggest that the combination of exercise and docosahexaenoic acid may act synergistically in the striatum of mice with a unilateral lesion of the dopaminergic system and provide support for clinical trials combining nutrition and physical exercise in the treatment of Parkinson’s disease.

OBJECTIVES:To examine the associations of circulating very long-chain saturated fatty acids (VLSFAs) with maternal blood pressure (BP), weight gain, and incidence of gestational hypertension (GH)/preeclampsia (PE) in a retrospective longitudinal study. METHODS:Blood samples from 92 pregnant women, including normotensive (n = 64) and hypertensive pregnancies (GH/PE, n = 28), from the International Trial of Antioxidants in the Prevention of PE (INTAPP; ISRCTN 85024310) were used at 8-14 weeks (visit 1) and 20-24 weeks (visit 2). Plasma Fatty acids (FA) profiles were measured by gas chromatography with flame ionization detection. Partial correlations and mixed models assessed BP and FA associations. Logistic regression models were used to assess GH/PE risks using FAs. RESULTS:Weight gain adjusted for pre-pregnancy BMI was inversely correlated to arachidic acid at visit 1 (r = -0.364, P < 0.001). VLSFAs, arachidic acid, and tricosylic acid were negatively correlated with both systolic BP and diastolic BP (DBP) at visit 1 (r < -0.274, P < 0.03). Higher levels of VLSFAs were also associated with the lower quartile of DBP (P = 0.01). Integrating clinical parameters with FA profiles (palmitoleic acid and eicosapentaenoic acid) presented a promising predictive model for GH/PE. CONCLUSIONS:VLSFA levels in circulating phospholipids, especially arachidic acid, are associated with weight gain and BP, and with tricosylic acid, could be linked to a potentially protective role within FAs in a more complex lipid signature against hypertension in pregnancy.

Introduction High prostate eicosapentaenoic fatty acid (EPA) levels have been associated with a significant reduction of prostate cancer upgrading to grade group (GG) ≥2 in men with GG1 prostate cancer on active surveillance. The current phase IIb randomized pre-prostatectomy placebo-controlled trial assessed the effect of a monoacylglyceride-EPA (MAG-EPA) supplement on prostate cancer aggressiveness in 130 men diagnosed with prostate cancer. Methods Men diagnosed with GG ≥2 prostate cancer and undergoing radical prostatectomy between 2015-2017 were randomized to either 3g/day of MAG-EPA (n=65) or placebo (n=65) for seven weeks prior to radical prostatectomy and for up to one year after surgery (NCT02333435). The primary outcome was the cancer proliferation index quantified by automated image analysis of tumor nuclear Ki-67 expression using standardized prostatectomy tissue microarrays. One exploratory clinical outcome was grade reclassification from baseline biopsy at prostatectomy. Stool samples were collected in a sub-group of consent patients (n=42) for gut microbiome and fecal short-chain fatty acid analyses, using 16srRNA sequencing and targeted metabolomics, respectively. Results Men randomized to MAG-EPA had four-fold higher EPA levels in prostate tissues compared to those on placebo. The primary outcome was the cancer proliferation index measured by Ki-67 expression which was not statistically different between intervention (3.10%) and placebo (2.85%) groups. In the per protocol analyses, the adjusted estimated effect of MAG-EPA was greater but remained non-significant. However, there was a significant increase in size and proliferative index of tumor lymphoid aggregates in MAG-EPA treated prostate cancer, suggesting an immune mediated effect. In exploratory analyses, the MAG-EPA group had more cancer pathological downgrade and less cancer upgrade at prostatectomy, compared to the placebo group (p=0.024). Gut microbiota analysis revealed that the cancer up-grading reduction in pre-prostatectomy prostate cancer patients taking MAG-EPA was associated with a reduction of gut Ruminococaceae and fecal butyrate levels. Conclusions Our results suggest that lowering gut butyrate, a known immune modulator, may partly explain the beneficial effect of MAG-EPA on prostate cancer aggressiveness. More studies are needed to better understand the biological and clinical outcomes following this concentrated EPA supplementation and determine if and how it can benefit prostate cancer patients.

Abstract Background High prostate eicosapentaenoic fatty acid (EPA) levels were associated with a significant reduction of upgrading to grade group (GG) ≥ 2 prostate cancer in men under active surveillance. We aimed to evaluate the effect of MAG-EPA long-chain omega-3 fatty acid dietary supplement on prostate cancer proliferation. Methods A phase II double-blind randomized placebo-controlled trial was conducted in 130 men diagnosed with GG ≥ 2 prostate cancer and undergoing radical prostatectomy between 2015–2017 (Clinicaltrials.gov: NCT02333435). Participants were randomized to receive 3 g daily of either MAG-EPA (n = 65) or placebo (n = 65) for 7 weeks (range 4–10) prior to radical prostatectomy. The primary outcome was the cancer proliferation index quantified by automated image analysis of tumor nuclear Ki-67 expression using standardized prostatectomy tissue microarrays. Additional planned outcomes at surgery are reported including plasma levels of 27 inflammatory cytokines and fatty acid profiles in circulating red blood cells membranes and prostate tissue. Results Cancer proliferation index measured by Ki-67 expression was not statistically different between the intervention (3.10%) and placebo (2.85%) groups (p = 0.64). In the per protocol analyses, the adjusted estimated effect of MAG-EPA was greater but remained non-significant. Secondary outcome was the changes in plasma levels of 27 cytokines, of which only IL-7 was higher in MAG-EPA group compared to placebo (p = 0.026). Men randomized to MAG-EPA prior to surgery had four-fold higher EPA levels in prostate tissue compared to those on placebo. Conclusions This MAG-EPA intervention did not affect the primary outcome of prostate cancer proliferation according to nuclear Ki-67 expression. More studies are needed to decipher the effects of long-chain omega-3 fatty acid dietary supplementation in men with prostate cancer.

Fatty acids play many critical roles in brain function but have not been investigated in essential tremor (ET), a frequent movement disorder suspected to involve cerebellar dysfunction. Here, we report a postmortem comparative analysis of fatty acid profiles by gas chromatography in the cerebellar cortex from ET patients (n = 15), Parkinson’s disease (PD) patients (n = 15) and Controls (n = 17). Phosphatidylcholine (PC), phosphatidylethanolamine (PE) and phosphatidylinositol (PI)/ phosphatidylserine (PS) were separated by thin-layer chromatography and analyzed separately. First, the total amounts of fatty acids retrieved from the cerebellar cortex were lower in ET patients compared with PD patients, including monounsaturated (MUFA) and polyunsaturated fatty acids (PUFA). The diagnosis of ET was associated with lower cerebellar levels of saturated fatty acids (SFA) and PUFA (DHA and ARA) in the PE fraction specifically, but with a higher relative content of dihomo-γ-linolenic acid (DGLA; 20:3 ω-6) in the PC fraction. In contrast, a diagnosis of PD was associated with higher absolute concentrations of SFA, MUFA and ω-6 PUFA in the PI + PS fractions. However, relative PI + PS contents of ω-6 PUFA were lower in both PD and ET patients. Finally, linear regression analyses showed that the ω-3:ω-6 PUFA ratio was positively associated with age of death, but inversely associated with insoluble α-synuclein. Although it remains unclear how these FA changes in the cerebellum are implicated in ET or PD pathophysiology, they may be related to an ongoing neurodegenerative process or to dietary intake differences. The present findings provide a window of opportunity for lipid-based therapeutic nutritional intervention.

S1. Chronic long-chain omega-3 (LCω3) treatment blocks prostate cancer cell growth. S2. Tables of differentially expressed genes in tumors of MAG-EPA-supplemented mice. S3. Twenty men supplemented for 4-10 weeks with MAG-EPA or placebo before radical prostatectomy. S4. Stable expression of the ω3 fatty acid desaturase 1 (FAT-1) from c. elegans, which convert ω6 into ω3 fatty acids, hinders prostate cancer cell growth. S5. Cytokine profiling of mouse tumors.

Prostate cancer (PCa) and associated treatments incur symptoms that may impact patients’ quality of life. Studies have shown beneficial relationships between diet, especially omega-3 fatty acids, and these symptoms. Unfortunately, only few data describing the relationship between long-chain omega-3 fatty acids (LCn3) and PCa-related symptoms in patients are available. The purpose of this study was to evaluate the effects of LCn3 supplementation on PCa-specific quality of life in 130 men treated by radical prostatectomy. Men were randomized to receive a daily dose of either 3.75 g of fish oil or a placebo starting 7 weeks before surgery and for up to one-year post-surgery. Quality of life was assessed using the validated EPIC-26 and IPSS questionnaires at randomization, at surgery, and every 3 months following surgery. Between-group differences were assessed using linear mixed models. Intention-to-treat analyses showed no significant difference between the two groups. However, at 12-month follow-up, per-protocol analyses showed a significantly greater increase in the urinary irritation function score (better urinary function) (MD = 5.5, p = 0.03) for the LCn3 group compared to placebo. These results suggest that LCn3 supplementation may improve the urinary irritation function in men with PCa treated by radical prostatectomy and support to conduct of larger-scale studies.

Aim: To assess whether small-for-gestational-age (SGA) -an indicator of poor fetal growth, may affect metabolic health biomarkers in infancy and explore the predictors. Methods: This was a nested matched (1:2) prospective observational study of 65 SGA (birth weight < 10th percentile) and 130 optimal-for-gestational-age (OGA, birth weight 25th-75th percentiles, control) infants in the 3D birth cohort with subjects recruited in Canada from 1 May 2010 to 31 August 2012. The outcomes included homeostasis model assessment of insulin resistance (HOMA-IR) and beta-cell function (HOMA-eta), circulating leptin and adiponectin concentrations at age 2 years. Results: HOMA-IR, HOMA-beta, leptin and adiponectin concentrations were similar in SGA versus OGA infants. Female sex and accelerated growth in length during mid-infancy (3-12 months) were associated with higher HOMA-IR. Caucasian ethnicity and decelerated growth in weight during late infancy (12-24 months) were associated with lower HOMA-IR. Current BMI was positively associated with circulating adiponectin in SGA infants only (+13.4% [4.0%-23.7%] per BMI z score increment). Conclusion: Insulin resistance and secretion, circulating leptin and adiponectin levels were normal in SGA subjects in infancy at age 2 years. The novel observation in SGA-specific positive association between current BMI and circulating adiponectin suggests dysfunctional adiposity-adiponectin negative feedback loop development during infancy in SGA subjects.

PDF file - 68K, Supplementary Table S1. Daily food groups intake assessed by the web-based food frequency questionnaire stratified by prostate cancer progression status.

PDF file - 76K, Supplementary Table S2. Mean of calculated coefficient of variation between duplicate prostate biopsies determined for specific fatty acids.

To assess whether small-for-gestational-age (SGA) – an indicator of poor fetal growth, may affect metabolic health biomarkers in infancy and explore the predictors. This was a nested matched (1:2) prospective observational study of 65 SGA (birth weight < 10th percentile) and 130 optimal-for-gestational-age (OGA, birth weight 25th-75th percentiles, control) infants in the 3D birth cohort with subjects recruited in Canada from 1 May 2010 to 31 August 2012. The outcomes included homeostasis model assessment of insulin resistance (HOMA-IR) and beta-cell function (HOMA-β), circulating leptin and adiponectin concentrations at age 2 years. HOMA-IR, HOMA-β, leptin and adiponectin concentrations were similar in SGA versus OGA infants. Female sex and accelerated growth in length during mid-infancy (3–12 months) were associated with higher HOMA-IR. Caucasian ethnicity and decelerated growth in weight during late infancy (12–24 months) were associated with lower HOMA-IR. Current BMI was positively associated with circulating adiponectin in SGA infants only (+13.4% [4.0%–23.7%] per BMI z score increment). Insulin resistance and secretion, circulating leptin and adiponectin levels were normal in SGA subjects in infancy at age 2 years. The novel observation in SGA-specific positive association between current BMI and circulating adiponectin suggests dysfunctional adiposity-adiponectin negative feedback loop development during infancy in SGA subjects.

Abstract Background In the general population, a higher omega‐3 polyunsaturated fatty acids intake is associated with lower levels of several psychological symptoms, especially depression. However, the existing evidence in cancer is equivocal. Methods This phase IIB double‐blind, placebo‐controlled trial was aimed at comparing the effects of eicosapentaenoic acid monoacylglyceride (MAG‐EPA) supplementation and high oleic acid sunflower oil (HOSO; placebo) on depression levels (primary outcome) and other symptoms (anxiety, fear of cancer recurrence, fatigue, insomnia, perceived cognitive impairments; secondary outcomes). Participants, recruited in a prostate cancer clinic, were randomized to MAG‐EPA (3.75 g daily; n = 65) or HOSO (3.75 g daily; n = 65) for 1 year post‐radical prostatectomy (RP), starting 4–10 weeks before surgery. Patients completed self‐report scales at baseline (before RP) and 3, 6, 9, and 12 months after: Hospital Anxiety and Depression Scale (HADS), Fear of Cancer Recurrence Inventory (FCRI), Insomnia Severity Index (ISI), Fatigue Symptom Inventory (FSI), and Functional Assessment of Cancer Therapy—Cognitive Function (FACT‐Cog). Results Analyses showed significant reductions in HADS‐depression, HADS‐anxiety, FCRI, ISI, FSI‐number of days, and FACT‐Cog‐impact scores over time. A significant group‐by‐time interaction was obtained on FACT‐Cog‐Impact scores only; yet, the temporal change was significant in HOSO patients only. Conclusions Several symptoms significantly decreased over time, mainly within the first months of the study. However, MAG‐EPA did not produce greater reductions than HOSO. Omega‐3 supplementation does not seem to improve psychological symptoms of men treated with RP.

Psoriasis is a skin disease characterized by epidermal hyperplasia and an inappropriate activation of the adaptive immunity. A dysregulation of the skin's lipid mediators is reported in the disease with a predominance of the inflammatory cascade derived from n-6 polyunsaturated fatty acids (n-6 PUFAs). Bioactive lipid mediators derived from arachidonic acid (AA) are involved in the inflammatory functions of T cells in psoriasis, whereas n-3 PUFAs' derivatives are anti-inflammatory metabolites. Here, we sought to evaluate the influence of a supplementation of the culture media with eicosapentaenoic acid (EPA) on the lipid profile of a psoriatic skin model produced with polarized T cells. Healthy and psoriatic skin substitutes were produced following the auto-assembly technique. Psoriatic skin substitutes produced with or without T cells presented increased epidermal and dermal linolenic acid (LA) and AA levels. N-6 PUFA lipid mediators were strongly measured in psoriatic substitutes, namely, 13-hydroxyoctadecadienoic acid (13-HODE), prostaglandin E2 (PGE2) and 12-hydroxyeicosatetraenoic acid (12-HETE). The added EPA elevated the amounts of EPA, n-3 docosapentaenoic acid (DPA) and docosahexaenoic acid (DHA) in the epidermal and dermal phospholipids. The EPA supplementation balanced the production of epidermal lipid mediators, with an increase in prostaglandin E3 (PGE3), 12-hydroxyeicosapentaenoic acid (12-HEPE) and N-eicosapentaenoyl-ethanolamine (EPEA) levels. These findings show that EPA modulates the lipid composition of psoriatic skin substitutes by encouraging the return to a cutaneous homeostatic state.

Polyunsaturated fatty acids (PUFAs) play an important role in the establishment and the maintenance of the skin barrier function. However, the impact of their derived lipid mediators remains unclear. Skin substitutes were engineered according to the self-assembly method with a culture medium supplemented with 10 mu M of both alpha-linolenic acid (ALA) and linoleic acid (LA). The supplementation with ALA and LA decreased testosterone absorption through a tissue-engineered reconstructed skin model, thus indicating an improved skin barrier function following supplementation. The exogenously provided fatty acids were incorporated into the phospholipid and triglyceride fractions of the skin substitutes. Indeed, the dual supplementation increased the levels of eicosapentaenoic acid (EPA) (15-fold), docosapentaenoic acid (DPA) (3-fold), and LA (1.5-fold) in the epidermal phospholipids while it increased the levels of ALA ( > 20-fold), DPA (3-fold) and LA (1.5-fold) in the epidermal triglycerides. The bioactive lipid mediator profile of the skin substitutes, including prostaglandins, hydroxy-fatty acids, N-acylethanolamines and monoacylglycerols, was next analyzed using liquid chromatography-tandem mass spectrometry. The lipid supplementation further modulated bioactive lipid mediator levels of the reconstructed skin substitutes, leading to a lipid mediator profile more representative of the one found in normal human skin. These findings show that an optimized supply of PUFAs via culture media is essential for the establishment of improved barrier function in vitro. Statement of significance Supplementation of the culture medium with 10 mu M of both alpha-linolenic acid (ALA) and linoleic acid (LA) improved the skin barrier function of a tissue-engineered skin model. The exogenously provided fatty acids were incorporated into the phospholipid and triglyceride fractions of the skin substitutes and further modulated bioactive lipid mediator levels, including prostaglandins, hydroxy-fatty acids, N-acylethanolamines and monoacylglycerols. These findings highlight the important role of ALA and LA in skin homeostasis and show that an optimized supply of polyunsaturated fatty acids via culture media is essential for the establishment of improved barrier function in vitro. (C) 2021 The Authors. Published by Elsevier Ltd on behalf of Acta Materialia Inc.

Psoriasis is an autoimmune skin disease with an increased number of leukocytes infiltrating the dermal and epidermal compartments compared with normal skin. N-3 polyunsaturated fatty acids (n-3 PUFAs) are frequently used in the clinic in order to attenuate the symptoms of psoriasis. For psoriatic patients, a supplementation of the diet with alpha-linolenic acid (ALA) reduces the activation of T cell signaling pathways, leading to a significant reduction in inflammatory cytokine secretion. However, the precise mechanism of action of n-3 PUFAs in psoriasis is still not understood. In the present study, we elucidated the bioaction of ALA on the adaptive immune component of psoriasis by using a psoriatic skin model produced with the addition of activated T cells. Healthy and psoriatic skin substitutes were produced according to the self-assembly method, using culture media supplemented with 10 μM of ALA. T cells were isolated from blood samples using a negative selection isolation method. ALA supplementation regulated the hyperproliferation and abnormal cell differentiation of psoriatic keratinocytes stimulated by T cells. Additionally, the exogenous ALA was correctly incorporated into the phospholipids of keratinocytes, which resulted in increased levels of ALA, eicosapentaenoic acid (EPA) and n-3 docosapentaenoic acid (n-3 DPA). The infiltration of T cells into the epidermis was reduced when ALA was added to the culture medium, and significant decreases in the levels of inflammatory cytokines and chemokines such as CXCL1, interleukin-6 (IL-6) and interleukin-8 (IL-8) were consequently measured in psoriatic substitutes supplemented with this n-3 PUFA. Altogether, our results showed that in this psoriatic skin model enriched with T cells, ALA exerted its beneficial effect by decreasing the quantities of inflammatory mediators released by T cells.

( Int J Gynecol Obstet . 2021;154:444–450) Preeclampsia (PE) is a serious and complex pregnancy-related disorder with negative effects on both the mother and fetus. Prevention is vital to reduce 18% of maternal mortality that results from PE in the United States each year. After years of study, its causes and mechanisms have not yet been fully unraveled. A recent review and analysis have shown an association between maternal vitamin D levels during pregnancy and an increased risk of PE.

Le cancer de la prostate est associé à de nombreux symptômes affectant la qualité de vie des patients. Des études ont démontré une relation entre l'alimentation et certains de ces symptômes, mais aucune relation n'a été décrite chez les hommes atteints de cancer de la prostate. L'objectif de la présente étude était donc d'évaluer le lien entre une supplémentation quotidienne en oméga-3 longues chaines et la qualité de vie générale et spécifique au cancer de la prostate dans cette population. Une étude clinique randomisée contrôlée a été conduite auprès de 130 hommes traités par prostatectomie radicale pour un cancer de la prostate (score de Gleason ≥7). Les participants ont été randomisés à une dose quotidienne de 3g d'oméga-3 longues chaines ou de placebo 4-10 semaines avant leur chirurgie, et jusqu'à un an post-chirurgie. La qualité de vie a été évaluée à l'aide de questionnaires validés: SF-36 pour le bien-être général et EPIC-26 pour les fonctions urinaire, sexuelle, hormonale et intestinale. Ces questionnaires ont été complétés lors de la randomisation et tous les trois mois post-chirurgie pendant un an. Les associations entre l'intervention et les différents domaines de qualité de vie ont été évaluées par des modèles linéaires mixtes. La pondération par probabilité inverse de censure a été utilisée pour traiter les attritions. Les analyses en intention-de-traiter n'ont montré aucune différence entre les deux groupes. À 12 mois de suivi, les analyses per-protocole ont montré une augmentation significative du score de fonction urinaire irritative (DM=5,09; p=0,04) et du fonctionnement physique (DM=5,20; p=0,04) pour le groupe oméga-3, comparativement au placebo. Nos résultats suggèrent qu'une supplémentation quotidienne en oméga-3 longues chaines améliore la qualité de vie des hommes atteints de cancer de la prostate traités par prostatectomie radicale, au niveau de la fonction urinaire irritative et du fonctionnement physique. Les auteurs déclarent ne pas avoir de liens d'intérêts.

Context: Fetal overgrowth "programs" an elevated risk of obesity and type 2 diabetes in adulthood. Plausibly, adipokines may be involved in programming metabolic health. Objective: This work aimed to evaluate whether large-for-gestational-age (LGA), an indicator of fetal overgrowth, is associated with altered circulating leptin and adiponectin levels in infancy, and assess the determinants. Methods: In the Canadian 3D birth cohort, we studied 70 LGA (birth weight > 90th percentile) and 140 optimal-for-gestational-age (OGA, 25th-75th percentiles) infants matched by maternal ethnicity, smoking, and gestational age at delivery. The primary outcomes were fasting leptin, and total and high-molecular-weight (HMW) adiponectin concentrations at age 2 years. Results: LGA infants had higher body mass index (BMI) than OGA infants. However, there were no significant differences in leptin, and total and HMW adiponectin concentrations. Leptin concentrations were positively associated with female sex, weight (z score) gain 0 to 24 months, current BMI, and the sum of triceps and subscapular skinfold thickness, and negatively associated with maternal age and White ethnicity. Female sex was associated with lower total and HMW adiponectin concentrations. Weight (z score) gain 0 to 24 months and current BMI were positively correlated with total and HMW adiponectin concentrations in LGA infants only. Conclusion: This study is the first to demonstrate that LGA does not matter for circulating leptin and adiponectin concentrations in infancy, and there may be LGA-specific positive associations between weight gain or current BMI and adiponectin concentrations in infancy, suggesting dysfunction in establishing the adiposity-adiponectin negative feedback loop in LGA individuals.