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Aim: In our study, we aimed to investigate the value of fetal epicardial fat thickness (EFT) and modified myocardial performance index (mod-MPI) in fetal growth restriction (FGR) that develops after the 32nd week of gestation., Materials and Methods: Fifty-six pregnant women who met the inclusion and exclusion criteria were included in the study and were divided into two groups: pregnancies diagnosed with FGR after the 32nd week of gestation (FGR group) and those without (control group). Demographic and obstetric histories, ultrasonographic and clinical characteristics, fetal EFT and mod-MPI values, and neonatal outcomes of the groups were recorded, and comparisons were made between the groups. Additionally, the diagnostic performance of fetal EFT value in late FGR was investigated., Results: The FGR group had fetal EFT that was statistically significantly lower (1.11 ± 0.21 vs. 1.34 ± 0.23, p = 0.001). The FGR group had a significantly lower isovolumetric contraction time (ICT) (31.04 ± 6.88 vs. 35.14 ± 7.58, p = 0.048). The two groups' isovolumetric relaxation time (IRT), ejection time (ET), and mod-MPI values (p values 0.871, 0.55, and 0.750, respectively) were comparable. Receiver operating characteristic (ROC) analysis at a cutoff of 1.2 revealed 76.1% sensitivity and 74.2% specificity, respectively, for the diagnostic performance of the fetal EFT value in late-onset FGR. There was a positive predictive value (PPV) and negative predictive value (NPV) of 64.0% and 83.8%, respectively., Conclusion: We found that fetal EFT was significantly lower in FGR and may be useful in diagnosing FGR. However, we observed that mode-MPI did not change in FGR., (© 2024 Wiley Periodicals LLC.)

Objective: This study aimed to evaluate fetal epicardial fat thickness (EFT) together with fetal myocardial performance index (MPI) and its effects on neonatal outcomes in obese pregnant women., Materials and Methods: A total of 102 pregnant women, 51 obese and 51 of normal weight, were included in this prospective study. Fetal EFT, and MPI measurements were performed for all patients., Results: Fetal EFT and Mod-MPI showed a statistically significant difference between obese pregnant women and the control group (p=0.0001, p=0.001). The optimal fetal EFT predictive cut-off value for the 5th-minute APGAR score below 7 was 1.22 mm, with a sensitivity of 86.96% and a specificity of 54.43% (p=0.001)., Conclusion: Fetal EFT and mod-MPI were higher in obese pregnant women. It is encouraging that fetal EFT predicts low APGAR, but more important information can be obtained if postnatal follow-up of these cardiac changes caused by obesity can be performed., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

The distinct anatomic environment in which adipose tissues arise during organogenesis is a principle determinant of their adult expansion capacity. Metabolic disease results from a deficiency in hyperplastic adipose expansion within the dermal/subcutaneous depot; thus, understanding the embryonic origins of dermal adipose is imperative. Using single-cell transcriptomics throughout murine embryogenesis, we characterized cell populations, including Bcl11b + cells, that regulate the development of dermal white adipose tissue (dWAT). We discovered that BCL11b expression modulates the Wnt signaling microenvironment to enable adipogenic differentiation in the dermal compartment. Subcutaneous and visceral adipose arises from a distinct population of Nefl + cells during embryonic organogenesis, whereas Pi16 + /Dpp4 + fibroadipogenic progenitors support obesity-stimulated hypertrophic expansion in the adult. Together, these results highlight the unique regulatory pathways used by anatomically distinct adipose depots, with important implications for human metabolic disease., (© 2024 Traynor et al.; Published by Cold Spring Harbor Laboratory Press.)

Fetal hypoxemia decreases insulin and increases cortisol and norepinephrine concentrations and may restrict growth by decreasing glucose utilization and altering substrate oxidation. Specifically, we hypothesized that hypoxemia would decrease fetal glucose oxidation and increase lactate and pyruvate production. We tested this by measuring whole body glucose oxidation and lactate production, and molecular pathways in liver, muscle, adipose, and pancreas tissues of fetuses exposed to maternal hypoxemia for 9 days (HOX) compared with control fetal sheep (CON) in late gestation. Fetuses with more severe hypoxemia had lower whole body glucose oxidation rates, and HOX fetuses had increased lactate production from glucose. In muscle and adipose tissue, expression of the glucose transporter GLUT4 was decreased. In muscle, pyruvate kinase ( PKM ) and lactate dehydrogenase B ( LDHB ) expression was decreased. In adipose tissue, LDHA and lactate transporter ( MCT1 ) expression was increased. In liver, there was decreased gene expression of PKLR and MPC2 and phosphorylation of PDH, and increased LDHA gene and LDH protein abundance. LDH activity, however, was decreased only in HOX skeletal muscle. There were no differences in basal insulin signaling across tissues, nor differences in pancreatic tissue insulin content, β-cell area, or genes regulating β-cell function. Collectively, these results demonstrate coordinated metabolic responses across tissues in the hypoxemic fetus that limit glucose oxidation and increase lactate and pyruvate production. These responses may be mediated by hypoxemia-induced endocrine responses including increased norepinephrine and cortisol, which inhibit pancreatic insulin secretion resulting in lower insulin concentrations and decreased stimulation of glucose utilization. NEW & NOTEWORTHY Hypoxemia lowered fetal glucose oxidation rates, based on severity of hypoxemia, and increased lactate production. This was supported by tissue-specific metabolic responses that may result from increased norepinephrine and cortisol concentrations, which decrease pancreatic insulin secretion and insulin concentrations and decrease glucose utilization. This highlights the vulnerability of metabolic pathways in the fetus and demonstrates that constrained glucose oxidation may represent an early event in response to sustained hypoxemia and fetal growth restriction.

This study determined if a perturbation in in utero adipogenesis leading to later life adipose tissue (AT) dysfunction underlies programming of cardiometabolic risk in offspring born to dams with metabolic dysfunction. Female mice heterozygous for the leptin receptor deficiency (Het db ) had 2.4-fold higher prepregnancy fat mass and in late gestation had higher plasma insulin and triglycerides compared with wild-type (Wt) females ( P < 0.05). To isolate the role of the intrauterine milieu, wild-type (Wt) offspring from each pregnancy were studied. Differentiation potential in isolated progenitors and cell size distribution analysis revealed accelerated adipogenesis in Wt pups born to Het db dams, accompanied by a higher accumulation of neonatal fat mass. In adulthood, whole body fat mass by NMR was higher in male (69%) and female (20%) Wt offspring born to Het db versus Wt pregnancies, along with adipocyte hypertrophy and hyperlipidemia (all P < 0.05). Lipidomic analyses by gas chromatography revealed an increased lipogenic index (16:0/18:2n6) after high-fat/fructose diet (HFFD). Postprandial insulin, ADIPO-IR, and ex vivo AT lipolytic responses to isoproterenol were all higher in Wt offspring born to Het db dams ( P < 0.05). Intrauterine metabolic stimuli may direct a greater proportion of progenitors toward terminal differentiation, thereby predisposing to hypertrophy-induced adipocyte dysfunction. NEW & NOTEWORTHY This study reveals that accelerated adipogenesis during the perinatal window of adipose tissue development predisposes to later life hypertrophic adipocyte dysfunction, thereby compromising the buffering function of the subcutaneous depot.

Central obesity with cardiometabolic syndrome (CMS) is a major global contributor to human disease, and effective therapies are needed. Here, we show that cyclic GMP-selective phosphodiesterase 9A inhibition (PDE9-I) in both male and ovariectomized female mice suppresses preestablished severe diet-induced obesity/CMS with or without superimposed mild cardiac pressure load. PDE9-I reduces total body, inguinal, hepatic, and myocardial fat; stimulates mitochondrial activity in brown and white fat; and improves CMS, without significantly altering activity or food intake. PDE9 localized at mitochondria, and its inhibition in vitro stimulated lipolysis in a PPARα-dependent manner and increased mitochondrial respiration in both adipocytes and myocytes. PPARα upregulation was required to achieve the lipolytic, antiobesity, and metabolic effects of PDE9-I. All these PDE9-I-induced changes were not observed in obese/CMS nonovariectomized females, indicating a strong sexual dimorphism. We found that PPARα chromatin binding was reoriented away from fat metabolism-regulating genes when stimulated in the presence of coactivated estrogen receptor-α, and this may underlie the dimorphism. These findings have translational relevance given that PDE9-I is already being studied in humans for indications including heart failure, and efficacy against obesity/CMS would enhance its therapeutic utility.

Fat stores are critical for reproductive success and may govern maturation initiation. Here, we report that signaling and sensing fat sufficiency for sexual maturation commitment requires the lipid carrier apolipophorin in fat cells and Sema1a in the neuroendocrine prothoracic gland (PG). Larvae lacking apolpp or Sema1a fail to initiate maturation despite accruing sufficient fat stores, and they continue gaining weight until death. Mechanistically, sensing peripheral body-fat levels via the apolipophorin/Sema1a axis regulates endocytosis, endoplasmic reticulum remodeling, and ribosomal maturation for the acquisition of the PG cells' high biosynthetic and secretory capacity. Downstream of apolipophorin/Sema1a, leptin-like upd2 triggers the cessation of feeding and initiates sexual maturation. Human Leptin in the insect PG substitutes for upd2, preventing obesity and triggering maturation downstream of Sema1a. These data show how peripheral fat levels regulate the control of the maturation decision-making process via remodeling of endomembranes and ribosomal biogenesis in gland cells., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

The concerning worldwide increase of obesity and chronic metabolic diseases, such as T2D, dyslipidemia, and cardiovascular disease, motivates further investigations into preventive and alternative therapeutic approaches. Over the past decade, there has been growing evidence that the formation and activation of thermogenic adipocytes (brown and beige) may serve as therapy to treat obesity and its associated diseases owing to its capacity to increase energy expenditure and to modulate circulating lipids and glucose levels. Thus, understanding the molecular mechanism of brown and beige adipocytes formation and activation will facilitate the development of strategies to combat metabolic disorders. Here, we provide a comprehensive overview of pathways and players involved in the development of brown and beige fat, as well as the role of thermogenic adipocytes in energy homeostasis and metabolism. Furthermore, we discuss the alterations in brown and beige adipose tissue function during obesity and explore the therapeutic potential of thermogenic activation to treat metabolic syndrome.

Adipose, or fat, tissue (AT) was once considered an inert tissue that primarily existed to store lipids, and was not historically recognized as an important organ in the regulation and maintenance of health. With the rise of obesity and more rigorous research, AT is now recognized as a highly complex metabolic organ involved in a host of important physiological functions, including glucose homeostasis and a multitude of endocrine capabilities. AT dysfunction has been implicated in several disease states, most notably obesity, metabolic syndrome and type 2 diabetes. The study of AT has provided useful insight in developing strategies to combat these highly prevalent metabolic diseases. This review highlights the major functions of adipose tissue and the consequences that can occur when disruption of these functions leads to systemic metabolic dysfunction.

Crosstalk between adipose and muscular tissues is hypothesized to regulate the number of muscular and adipose cells during fetal growth, with post-natal consequences on lean and fat masses. Such crosstalk largely remains, however, to be described. We hypothesized that a characterization of the proteomes of adipose and muscular tissues from bovine fetuses may enhance the understanding of the crosstalk between these tissues through the prediction of their secretomes and surfaceomes. Proteomic experiments have identified 751 and 514 proteins in fetal adipose tissue and muscle. These are mainly involved in the regulation of cell proliferation or differentiation, but also in pathways such as apoptosis, Wnt signalling, or cytokine-mediated signalling. Of the identified proteins, 51 adipokines, 11 myokines, and 37 adipomyokines were predicted, together with 26 adipose and 13 muscular cell surface proteins. Analysis of protein-protein interactions suggested 13 links between secreted and cell surface proteins that may contribute to the adipose-muscular crosstalk. Of these, an interaction between the adipokine plasminogen and the muscular cell surface alpha-enolase may regulate the fetal myogenesis. The in silico secretome and surfaceome analyzed herein exemplify a powerful strategy to enhance the elucidation of the crosstalk between cell types or tissues.

Adipogenesis in adulthood replaces fat cells that turn over and can contribute to the development of obesity. However, the proliferative potential of adipocyte progenitors in vivo is unknown (Faust et al., 1976; Faust et al., 1977; Hirsch and Han, 1969; Johnson and Hirsch, 1972). We addressed this by injecting labeled wild-type embryonic stem cells into blastocysts derived from lipodystrophic A-ZIP transgenic mice, which have a genetic block in adipogenesis. In the resulting chimeric animals, wild-type ES cells are the only source of mature adipocytes. We found that when chimeric animals were fed a high-fat-diet, animals with low levels of chimerism showed a significantly lower adipose tissue mass than animals with high levels of chimerism. The difference in adipose tissue mass was attributed to variability in the amount of subcutaneous adipose tissue as the amount of visceral fat was independent of the level of chimerism. Our findings thus suggest that proliferative potential of adipocyte precursors is limited and can restrain the development of obesity., Competing Interests: KH, YL, OD, ZL, GF, KB, CH, CY, JF No competing interests declared, (© 2020, Hedbacker et al.)

miR-760 is downregulated in various human tumors, and fat metabolism disorder correlates with tumor progression, especially anomalism of key fat metabolic enzymes that are positively modulated by c-Myc. The aim of our study is to elucidate the presumptive molecular mechanisms of miR-760-mediated esophageal squamous cell carcinoma (ESCC) cell function and to assess the therapeutic significance of miR-760 in ESCC patients. Quantitative real-time PCR (RT-qPCR) analysis indicated that miR-760 was significantly downexpressed in ESCC tissues and cell lines. Cell counting kit-8 (CCK-8) assay, colony formation assay, transwell assay, and flow cytometry denoted that induced ectopic overexpression of miR-760 dramatically inhibited ESCC cells proliferation, attenuated migration, and invasion facilitated apoptosis in vitro. Mechanistically, c-Myc predicted using bioinformatics was identified as a potential target gene of miR-760 by luciferase reporter assay. Furthermore, mRNA and protein expression levels of c-Myc and key fat metabolic enzymes were downregulated with miR-760 mimics. The above investigation results, responsible for the antineoplastic properties of miR-760 in ESCC, preliminarily highlighted that the hypothetical signal amongst miR-760, c-Myc, and key fat metabolic enzymes may develop a novel diagnostic marker, therapeutic target, and independent prognostic indicator., (© 2019 Wiley Periodicals, Inc.)

We previously demonstrated that periconception maternal administration (2 mg/kg body weight each) of cadmium chloride (CdCl2) plus methylmercury (II) chloride (CH3HgCl) impaired glucose homeostasis and increased body weights and abdominal adipose tissue weight of male offspring in the F1 generation. However, transgenerational effects of this exposure have not been studied. Therefore, the effects of periconception Cd+Hg administration on indices of chronic diseases at adulthood in F2-F4 generations were examined. Male and female progeny of Cd+Hg periconceptionally treated females, and offspring of vehicle control females were bred with naïve CD1 mice to obtain F2 offspring, with additional crosses as above to the F4 generation (F1-F4 animals were not administered Cd+Hg). Birth weights and litter size were similar in all generations. Indices of impaired glucose homeostasis were observed in matrilineally descended F2 male offspring, including reduced glucose tolerance, along with increased basal phosphorylation of insulin receptor substrate 1 (IRS1) at serine 307 suggesting altered insulin signaling. Reduced glucose tolerance was also seen in F4 males. Increased body weight and/or abdominal adiposity were observed through the F4 generation in males descended matrilineally from the treated female progenitors. Patrilineally derived F2 females displayed reduced glucose tolerance. Females (F2) patrilineally and matrilineally derived displayed significant kidney enlargement. Periconception administration of cadmium and mercury caused persistent transgenerational effects in offspring through the F4 generation in the absence of continued toxicant exposure, with persistent transgenerational effects inherited specifically through the matrilineal germline., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The pathological processes leading to heart failure are characterized by the formation of fibrosis and scar, yet the dynamics of scar production and removal are incompletely understood. Spontaneous disappearance of myocardial collagen is reported in infancy but doubted in adulthood where scar volume constitutes a better prognostic indicator than the conventional parameters of ventricular function. Whilst certain drugs are known to attenuate myocardial fibrosis evidence is emerging that stem cell therapy also has the potential to reduce scar size and improve myocardial viability. Both animal studies and clinical trials support the concept that, as in infancy, cellular processes can be triggered to remove collagen and regenerate injured myocardium. The molecular mechanisms likely involve anti-fibrotic cytokines growth factors and matrix-metalloproteinases. Autologous cardiac, bone-marrow and adipose tissue derived stem cells have each shown efficacy. Specific immune privileged mesenchymal stem cells and genetically modified immunomodulatory progenitor cells may in turn provide an allogenic source for the paracrine effects. Thus autologous and allogenic cells both have the potential through paracrine action to reduce scar volume, boost angiogenesis and improve ventricular morphology. The potential benefit of myocardial cell therapy for routine treatment of heart failure is an area that requires further study., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com.)

Purpose: The aim of the study was to analyze the correlations between the expression of glucose transporters GLUT-1, GLUT-4, and GLUT-9 in human term placenta and selected maternal and fetal parameters in pregnancies complicated by diabetes mellitus (DM)., Materials and Methods: Placental samples were obtained from healthy control (n = 25) and diabetic pregnancies, including diet-controlled gestational diabetes mellitus (GDMG1) (n = 16), insulin-controlled gestational diabetes mellitus (GDMG2) (n = 6), and pregestational DM (PGDM) (n = 6). Computer-assisted quantitative morphometry of stained placental sections was performed to determine the expression of selected glucose transporter proteins. For the purposes of correlation analysis, the following parameters were selected: type of diabetes, gestational age, maternal prepregnancy body mass index (BMI), gestational weight gain, third trimester glycated hemoglobin concentration, placental weight, fetal birth weight (FBW) as well as ultrasonographic indicators of fetal adiposity, including subscapular (SSFM), abdominal (AFM), and midthigh (MTFM) fat mass measurements., Results: In the PGDM group, the analysis demonstrated positive correlations between the placental expression of GLUT-1, GLUT-4, and GLUT-9 and FBW, AFM, and SSFM measurements (p < .05). Similarly in the GDMG2 patients positive correlations between GLUT-4 expression, FBW and SSFM were observed (p < .05). In the multivariate regression analysis, only the type of diabetes and FBW were significantly associated with GLUTs expression (p < .001). In addition, maternal prepregnancy BMI significantly contributed to GLUT-1 expression (p < .001)., Conclusions: The study results revealed that placental expression of GLUT-1, GLUT-4, and GLUT-9 may be involved in the intensification of the fetal growth in pregnancies complicated by GDM/PGDM.

The aim of the study was to assess the standard foetal biometric measurements and foetal liver volume (FLV) in pregnancies complicated by gestational diabetes mellitus (GDM) at the time of GDM screening and to compare the results with foetuses in normal pregnancies. Ninety-seven pregnant women with normal singleton uncomplicated pregnancies between 24 and 28 weeks of gestation were allocated into GDM (+) (n: 33) and GDM (-) (n: 64) groups based on their 75 g oral glucose tolerance test results. Foetal biometric measurements and FLV measurements of the groups were compared. Although there were no significant differences in the standard biometric measurements between the two groups, FLV was significantly higher in the women with GDM (p < .01). The ROC analysis implied that with a cut-off value of FLV of 32.72 cm 3 for GDM prediction, the sensitivity was 78.8% and specificity was 56.3%. We suggest that FLV measurements during the second-trimester ultrasound scanning may be a tool for the prediction of GDM in the obstetric population. Impact statement What is already known on this subject? GDM is an important pregnancy disease, because of its possible foetal and maternal complications. Besides the standard biometric measurements, some other foetal body dimensions such as the anterior abdominal wall thickness, skinfold thickness, adipose tissue thickness, Wharton's jelly thickness, foetal liver length and foetal liver volume (FLV) have been evaluated as ultrasound parameters of glycaemic control. While the evaluation of foetal liver dimensions has a role in identifying foetal growth acceleration, previous studies addressed patients with insulin-dependent diabetes mellitus rather than gestational diabetes mellitus, utilised two-dimensional ultrasound and did not argue the diagnostic value of these findings. What do the results of this study add? In our study, besides the standard biometric measurements, the FLV measurements were evaluated by a three-dimensional ultrasound. Although there were no significant differences in the standard biometric measurements between the GDM (+) and GDM (-) groups, the FLV was significantly higher in women with GDM. The FLV was found to be a potential predictive factor for GDM. The ROC analysis implied that as a cut-off value of FLV of 32.72 cm 3 for GDM prediction, the sensitivity was 78.8% and the specificity was 56.3%. What are the implications of these findings for clinical practise and/or further research? Screening for GDM with oral glucose tolerance test within the limited weeks of gestation may not always be feasible. On the other hand, the mid-trimester ultrasound scanning is done almost in all pregnancies. Accordingly, FLV measurement might be an alternative method for the GDM diagnosis.

An adverse nutritional environment during the perinatal period increases the risk of adult-onset metabolic diseases, such as obesity, which may persist across generations. Adipose tissue (AT) from offspring of malnourished dams has been shown to display altered adipogenesis, lipogenesis, and adipokine expression, impaired thermogenesis, and low-grade inflammation. Although the exact mechanisms underlying these alterations remain unclear, epigenetic processes are believed to have an important role. In this review, we focus on epigenetic mechanisms in AT that may account for transgenerational dysregulation of adipocyte formation and adipose function. Understanding the complex interactions between maternal diet and epigenetic regulation of the AT in offspring may be valuable in improving preventive strategies against the obesity pandemic., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Purpose: To review the recent data about orbital development and sort out the controversies from the very early stages during embryonic life till final maturation of the orbit late in fetal life, and to appreciate the morphogenesis of all the definitive structures in the orbit in a methodical and timely fashion., Methods: The authors extensively review major studies detailing every aspect of human embryologic and fetal orbital morphogenesis including the development of extraocular muscles, orbital fat, vessels, nerves, and the supportive connective tissue framework as well as bone. These interdisciplinary studies span almost a century and a half, and include some significant controversial opposing points of view which the authors hopefully sort out. The authors also highlight a few of the most noteworthy molecular biologic studies regarding the multiple and interacting signaling pathways involved in regulating normal orbital morphogenesis., Results: Orbital morphogenesis involves a successive series of subtle yet tightly regulated morphogenetic events that could only be explained through the chronological narrative used by the authors. The processes that trigger and contribute to the formation of the orbits are complex and seem to be intricately regulated by multifaceted interactions and bidirectional cross-talk between a multitude of cellular building raw materials including the developing optic vesicles, neuroectoderm, cranial neural crest cells and mesoderm., Conclusions: Development of the orbit is a collective enterprise necessitating interactions between, as well as contributions from different cell populations both within and beyond the realm of the orbit. A basic understanding of the processes underlying orbital ontogenesis is a crucial first step toward establishing a genetic basis or an embryologic link with orbital disease.

The embryonic origin of distinct fat depots and the role for ontogeny in specifying the functional differences among adipocyte lineages between and within depots is unclear. Using a Cre/Lox-based strategy to track the fate of major mesodermal subcompartments in mice we present evidence that <50% of interscapular brown adipocytes are derived from progenitors of the central dermomyotome. Furthermore, we demonstrate that depot-specific adipocyte lineages spatially diverge as early as gastrulation, and that perigonadal adipocytes arise from separate mesodermal subcompartments in males and females. Last, we show adipocyte precursors (APs) of distinct lineages within the same depot exhibit indistinguishable responses to a high fat diet, indicating that ontogenetic differences between APs do not necessarily correspond to functional differences in this context. Altogether, these findings shed light on adipose tissue patterning and suggest that the behavior of adipocyte lineage cells is not strictly determined by developmental history., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2018. Published by The Company of Biologists Ltd.)

Objective: To evaluate whether fetal epicardial fat thickness (EFT) differs in diabetic and nondiabetic pregnant women., Methods: Retrospective case-control study of pregnancies between 24 and 36 weeks complicated by preexisting (PDM) or gestational (GDM) diabetes mellitus, matched one to one with controls for body mass index and gestational age (GA). Epicardial fat was identified as the hypoechogenic area between myocardium and visceral pericardium over the right ventricle and its thickness was measured by a single observer blinded to clinical condition and outcomes. A linear regression analysis was performed to assess the relationship between GA and EFT, and regression lines were compared between diabetics and controls., Results: 53 PDM and 53 GDM pregnant women were matched with controls. With the exception of maternal age, the demographics were similar among groups. EFT increased significantly with advancing gestation in both diabetics and controls (P < 0.0001) and was significantly greater in diabetics than in controls (P < 0.0001). The best fit lines were different between diabetics (EFT = 0.05 × GA + 0.07 mm; R 2  = 0.70) and controls (EFT = 0.07 × GA + 0.04 mm; R 2  = 0.93) (P < 0.0001)., Conclusion: Fetal EFT was greater in diabetics than in nondiabetics, and even greater in pregestational diabetics. EFT maybe an additional and/or earlier marker to identify early changes in fetal metabolism before accelerated fetal growth and polyhydramnios is apparent., (© 2018 Wiley Periodicals, Inc.)

Background: Fetal fat is indicative of the energy balance within the fetus, which may be disrupted in pregnancy complications such as fetal growth restriction, macrosomia, and gestational diabetes. Water-fat separated MRI is a technique sensitive to tissue lipid content, measured as fat fraction (FF), and can be used to accurately measure fat volumes. Modified two-point Dixon and chemical shift encoded MRI (CSE-MRI) are water-fat separated MRI techniques that could be applied to imaging of fetal fat. Modified two-point Dixon has biases present that are corrected in CSE-MRI which may contribute to differences in the fat measurements., Purpose: To compare the measurement of fetal fat volume and FF by modified two-point Dixon and CSE-MRI., Study Type: Cross-sectional study for comparison of two MRI pulse sequences., Population: Twenty-one pregnant women with singleton pregnancies., Field Strength/sequence: 1.5T, modified two-point Dixon and CSE-MRI., Assessment: Manual segmentation of total fetal fat volume and mean FF from modified 2-point Dixon and CSE-MRI FF images., Statistical Tests: Reliability was assessed by calculating the intraclass correlation coefficient (ICC). Agreement was assessed using a one-sample t-test on the fat measurements difference values (modified two-point Dixon - CSE-MRI). The difference scores were tested against a value of 0, which would indicate that the measurements were identical., Results: The fat volume and FF measured by modified two-point Dixon and CSE-MRI had excellent reliability, demonstrated by ICCs of 0.93 (P < 0.001) and 0.90 (P < 0.001), respectively. They were not in agreement, with CSE-MRI giving mean fat volumes 180 mL greater and mean FF 3.0% smaller than modified two-point Dixon., Data Conclusion: The reliability between modified two-point Dixon and CSE-MRI indicates that either technique can be used to compare fetal fat measurements in different participants, but they are not in agreement possibly due to uncorrected biases in modified two-point Dixon., Level of Evidence: 4 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018., (© 2018 International Society for Magnetic Resonance in Medicine.)

Hypoxia is one of the most common and severe challenges to the maintenance of homeostasis. Oxygen sensing is a property of all tissues, and the response to hypoxia is multidimensional involving complicated intracellular networks concerned with the transduction of hypoxia-induced responses. Of all the stresses to which the fetus and newborn infant are subjected, perhaps the most important and clinically relevant is that of hypoxia. Hypoxia during gestation impacts both the mother and fetal development through interactions with an individual's genetic traits acquired over multiple generations by natural selection and changes in gene expression patterns by altering the epigenetic code. Changes in the epigenome determine "genomic plasticity," i.e., the ability of genes to be differentially expressed according to environmental cues. The genomic plasticity defined by epigenomic mechanisms including DNA methylation, histone modifications, and noncoding RNAs during development is the mechanistic substrate for phenotypic programming that determines physiological response and risk for healthy or deleterious outcomes. This review explores the impact of gestational hypoxia on maternal health and fetal development, and epigenetic mechanisms of developmental plasticity with emphasis on the uteroplacental circulation, heart development, cerebral circulation, pulmonary development, and the hypothalamic-pituitary-adrenal axis and adipose tissue. The complex molecular and epigenetic interactions that may impact an individual's physiology and developmental programming of health and disease later in life are discussed.

Purpose: To examine the feasibility of using MRI to identify differences in liver size and fat deposition in fetal guinea pigs exposed to an in utero environment influenced by maternal consumption of a Western diet., Materials and Methods: Female guinea pigs fed either an energy-dense Western Diet (WD), comprised of increased saturated fats and simple sugars, or a Control Diet (CD) from weaning through pregnancy, underwent MR scanning near term (~ 60 days; term ~ 69 days). Maternal weights were collected at mating and at MR scanning. T1-weighted, T2-weighted, and IDEAL water-fat images were acquired at 3 Tesla. The images were used to segment maternal adipose tissue, fetal liver, fetal brain, fetal adipose tissue, and total fetal volumes and to measure maternal and fetal hepatic fat fractions., Results: Weights of WD sows were lower prior to pregnancy (P = .04), however their weight gain over pregnancy did not differ from the CD group (P = .98). The WD sows had less total adipose tissue (TAT) at MR scanning (P = .04), while hepatic fat content was significantly elevated (P = .04). When controlling for litter size, WD fetuses had larger livers (P = .02), smaller brains (P = .01), and increased total adipose tissue volume (P = .01) when normalized by fetal volume. The WD fetuses also had increased hepatic fat fractions compared to CD fetal livers (P < .001)., Conclusion: Maternal Western Diet consumption prior to and during pregnancy induces differences in maternal liver fat content, fetal liver volume and liver fat storage, as well as changes in fetal adipose tissue deposition that can be measured in utero using MRI.

Adipose tissue is distributed in depots throughout the body with specialized roles in energy storage and thermogenesis. PDGFRα is a marker of adipocyte precursors, and increased PDGFRα activity causes adipose tissue fibrosis in adult mice. However, the function of PDGFRα during adipose tissue organogenesis is unknown. Here, by analyzing mice with juxtamembrane or kinase domain point mutations that increase PDGFRα activity (V561D or D842V), we found that PDGFRα activation inhibits embryonic white adipose tissue organogenesis in a tissue-autonomous manner. By lineage tracing analysis, we also found that collagen-expressing precursor fibroblasts differentiate into white adipocytes in the embryo. PDGFRα inhibited the formation of adipocytes from these precursors while favoring the formation of stromal fibroblasts. This imbalance between adipocytes and stromal cells was accompanied by overexpression of the cell fate regulator Zfp521. PDGFRα activation also inhibited the formation of juvenile beige adipocytes in the inguinal fat pad. Our data highlight the importance of balancing stromal versus adipogenic cell expansion during white adipose tissue development, with PDGFRα activity coordinating this crucial process in the embryo., Competing Interests: The authors declare no competing or financial interests., (© 2017. Published by The Company of Biologists Ltd.)

Objectives: Neonatal adiposity is associated with chronic metabolic sequelae such as diabetes and obesity. Identifying fetuses at risk for excess neonatal body fat may lead to research aimed at limiting nutritional excess in the prenatal period. We sought to determine whether fetal arm and leg soft tissue measurements at 28 weeks' gestation were predictive of neonatal percent body fat METHODS : In this prospective observational cohort study of singleton term pregnancies, we performed sonography at 28 and 36 weeks' gestation, including soft tissue measurements of the fetal arm and thigh (fractional limb volume and cross-sectional area). We estimated the neonatal body composition (percent body fat) using anthropometric measurements and air displacement plethysmography. We estimated Spearman correlations between sonographic findings and percent body fat and performed modeling to predict neonatal percent body fat using maternal characteristics and sonographic findings., Results: Our analysis of 44 women yielded a mean maternal age of 30 years, body mass index of 26 kg/m(2), and birth weight of 3382 g. Mean neonatal percent body fat was 8.1% by skin folds at birth and 12.2% by air displacement plethysmography 2 weeks after birth. Fractional thigh volume measurements at 28 weeks yielded the most accurate model for predicting neonatal percent body fat (R(2) = 0.697; P = .001), outperforming models that used abdominal circumference (R(2)= 0.516) and estimated fetal weight (R(2)= 0.489)., Conclusions: Soft tissue measurements of the fetal thigh at 28 weeks correlated better with neonatal percent body fat than currently used sonographic measurements. After validation in a larger cohort, our models may be useful for prenatal intervention strategies aimed at the prevention of excess fetal fat accretion and, potentially, optimization of long-term metabolic health.

The hypothesis of fetal origins of adult disease states that early life events program the occurrence of significant adult diseases, including diabetes and obesity. Maternal diabetes is associated with general stress environment for developing fetus, and gestational diabetes is an independent risk factor for type 2 diabetes and metabolic syndrome in offspring. Intra-uterine fetal programming of fetal tissues exposes the offspring to increased risk of impaired glucose tolerance, type 2 diabetes, and cardiovascular disease. Here, we examined the transmission of maternal diabetes-induced fetal programming in second generation and compared maternal and paternal routes of intergenerational effects. We organized 40 Wistar rats into three groups, male offspring of diabetic mothers, female offspring of diabetic mothers, and offspring of control mothers. These groups were mated with normal healthy rats to assess the effect of grand-maternal diabetes on pregnancy outcome in F2 rats, as well as glucose-sensing parameters, insulin resistance, and glucose tolerance prenatally and postnatally. We found that F2 offspring of diabetic mothers had impaired glucose sensing, increased oxidative stress, insulin resistance, and impaired glucose tolerance, and these effects were more prominent in the F2 offspring of F1 female rats (F2-DF1F). We deduce that fetal programming of maternal diabetes is mostly transmitted through maternal line across two generations.

The nutritional imprinting, whose mechanisms remain still dark and which seem to continue through the following generations, highlight the key-role of the inadequacy between the pre-and postnatal nutritional environment and the programming of the obesity., (© 2016 médecine/sciences – Inserm.)

Insulin is the primary acute anabolic coordinator of nutrient partitioning. Hyperglycemia is the main stimulant of insulin secretion, but other nutrients such as specific amino acids, fatty acids, and ketoacids can potentiate pancreatic insulin release. Incretins are intestinal hormones with insulinotropic activity and are secreted in response to food ingestion, thus integrating diet chemical composition with the regulation of insulin release. In addition, prolactin is required for proper islet development, and it stimulates β-cell proliferation. Counterintuitively, bacterial components appear to signal insulin secretion. In vivo lipopolysaccharide infusion acutely increases circulating insulin, which is paradoxical as endotoxemia is a potent catabolic condition. Insulin is a potent anabolic orchestrator of nutrient partitioning, and this is particularly true in adipocytes. Insulin dictates lipid accretion in a dose-dependent manner during preadipocyte development in adipose tissue-derived stromal vascular cell culture. However, in vivo studies focused on insulin's role in regulating adipose tissue metabolism from growing, and market weight pigs are sometimes inconsistent, and this variability appears to be animal, age and depot dependent. Additionally, porcine adipose tissue synthesizes and secretes a number of adipokines (leptin, adiponectin, and so forth) that directly or indirectly influence insulin action. Therefore, because insulin has an enormous impact on agriculturally important phenotypes, it is critical to have a better understanding of how insulin homeostasis is governed., (Copyright © 2016 Elsevier Inc. All rights reserved.)

High-Mobility-Group-A1 (HMGA1) proteins are non-histone proteins that regulate chromatin structure and gene expression during embryogenesis, tumourigenesis and immune responses. In vitro studies suggest that HMGA1 proteins may be required to regulate adipogenesis. To examine the role of HMGA1 in vivo, we generated transgenic mice overexpressing HMGA1 in adipose tissues. HMGA1 transgenic mice showed a marked reduction in white and brown adipose tissue mass that was associated with downregulation of genes involved in adipogenesis and concomitant upregulation of preadipocyte markers. Reduced adipogenesis and decreased fat mass were not associated with altered glucose homeostasis since HMGA1 transgenic mice fed a regular-chow diet exhibited normal glucose tolerance and insulin sensitivity. However, when fed a high-fat diet, overexpression of HMGA1 resulted in decreased body-weight gain, reduced fat mass, but improved insulin sensitivity and glucose tolerance. Although HMGA1 transgenic mice exhibited impaired glucose uptake in adipose tissue due to impaired adipogenesis, the increased glucose uptake observed in skeletal muscle may account for the improved glucose homeostasis. Our results indicate that HMGA1 plays an important function in the regulation of white and brown adipogenesis in vivo and suggests that impaired adipocyte differentiation and decreased fat mass is not always associated with impaired whole-body glucose homeostasis.

Purpose: To characterize the connective tissue found between the subcutaneous adipose tissue and the underlying muscle tissue in different regions and at different stages of human fetal development. We aim to identify its structural similarities to adult deep fascia, and to establish its role in myofascial development., Methods: Samples from the arm, forearm, low back and thigh regions (from sites topographically homologous to the adult deep fascia) of five fetus body donors were obtained to perform gross anatomy dissection and histologic sections. Sections were stained with hematoxylin-eosin and Masson trichrome stain to observe their overall structure. Antiserum to protein S100 was used to analyze the presence and distribution of nerve fibers, and immunohistochemistry processing with Tcf4 marker was used to ensure fibroblast activity., Results: Gross anatomy and histological sections of fetal samples showed the presence of connective tissue topographically and morphologically equivalent to adult deep fasciae. Developing blood vessels and nerves were found evenly distributed within the connective tissue during early development and in the portion adjacent to the muscle at later stages. The presence of Tcf4+ fibroblasts was confirmed in all analyzed mesenchymal connective tissue., Conclusions: Deep fascia is present from week 21 of human development in the lower back and upper and lower limbs. Blood vessels and nerves develop parallel to it and occasionally cross it from the deep to superficial plane. The presence of Tcf4+ fibroblasts in the deep fascia suggests a crucial role for this structure in muscle morphogenesis.

Despite the growing interest in adipose tissue as a therapeutic target of metabolic diseases, the identity of adipocyte precursor cells (preadipocytes) and the formation of adipose tissue during embryonic development are still poorly understood. Here, we clarified the identity and dynamic processes of preadipocytes in mouse white adipose tissue during embryogenesis through direct examination, lineage tracing and culture systems. Surprisingly, we found that lipid-lacking but perilipin(+) or adiponectin(+) proliferating preadipocytes started to emerge at embryonic day 16.5, and these cells underwent active proliferation until birth. Moreover, these preadipocytes resided as clusters and were distributed along growing adipose vasculatures. Importantly, the embryonic preadipocytes exhibited considerable coexpression of stem cell markers, such as CD24, CD29 and PDGFRα, and a small portion of preadipocytes were derived from PDGFRβ(+) mural cells, in contrast to the adult preadipocytes present in the stromal vascular fraction. Further analyses with in vitro and ex vivo culture systems revealed a stepwise but dynamic regulation of preadipocyte formation and differentiation during prenatal adipogenesis. To conclude, we unraveled the identity and characteristics of embryonic preadipocytes, which are crucial for the formation and expansion of adipose tissue during embryogenesis., (© 2015. Published by The Company of Biologists Ltd.)

Mitochondrial DNA (mtDNA) content is dependent on the energy requirements of tissues. To date, no comprehensive study has been conducted to examine mtDNA copy number variations in pigs. In the current study, quantitative polymerase chain reaction was performed to quantify the mtDNA copy number in 15 pig tissue types at 5 growth stages from embryo to adult. Observable differences in mtDNA content were detected in the tissues, including a 6-fold greater mtDNA content in the heart compared with the lung of 180-day-old samples. mtDNA content in the heart, longissimus dorsi muscle, psoas major muscle, kidney, brain, ovary, and subcutaneous adipose increased with growth. Expression of the replicative mitochondrial helicase (TWINKLE), which regulates mtDNA turnover, was significantly associated with changes in mtDNA copy numbers across tissues during growth (r = 0.33, P = 0.01). We demonstrated that the expression levels of mitochondrial genes were positively correlated with mtDNA copy number.

There are three different types of adipose tissue (AT)-brown, white, and beige-that differ with stage of development, species, and anatomical location. Of these, brown AT (BAT) is the least abundant but has the greatest potential impact on energy balance. BAT is capable of rapidly producing large amounts of heat through activation of the unique uncoupling protein 1 (UCP1) located within the inner mitochondrial membrane. White AT is an endocrine organ and site of lipid storage, whereas beige AT is primarily white but contains some cells that possess UCP1. BAT first appears in the fetus around mid-gestation and is then gradually lost through childhood, adolescence, and adulthood. We focus on the interrelationships between adipocyte classification, anatomical location, and impact of diet in early life together with the extent to which fat development differs between the major species examined. Ultimately, novel dietary interventions designed to reactivate BAT could be possible.

Brown adipocytes and muscle and dorsal dermis descend from precursor cells in the dermomyotome, but the factors that regulate commitment to the brown adipose lineage are unknown. Here, we prospectively isolated and determined the molecular profile of embryonic brown preadipose cells. Brown adipogenic precursor activity in embryos was confined to platelet-derived growth factor α(+), myogenic factor 5(Cre)-lineage-marked cells. RNA-sequence analysis identified early B-cell factor 2 (Ebf2) as one of the most selectively expressed genes in this cell fraction. Importantly, Ebf2-expressing cells purified from Ebf2(GFP) embryos or brown fat tissue did not express myoblast or dermal cell markers and uniformly differentiated into brown adipocytes. Interestingly, Ebf2-expressing cells from white fat tissue in adult animals differentiated into brown-like (or beige) adipocytes. Loss of Ebf2 in brown preadipose cells reduced the expression levels of brown preadipose-signature genes, whereas ectopic Ebf2 expression in myoblasts activated brown preadipose-specific genes. Altogether, these results indicate that Ebf2 specifically marks and regulates the molecular profile of brown preadipose cells.

Obesity is an escalating threat of pandemic proportions and has risen to such unrivaled prominence in such a short period of time that it has come to define a whole generation in many countries around the globe. The burden of obesity, however, is not equally shared among the population, with certain ethnicities being more prone to obesity than others, while some appear to be resistant to obesity altogether. The reasons behind this ethnic basis for obesity resistance and susceptibility, however, have remained largely elusive. In recent years, much evidence has shown that the level of brown adipose tissue thermogenesis, which augments energy expenditure and is negatively associated with obesity in both rodents and humans, varies greatly between ethnicities. Interestingly, the incidence of low birth weight, which is associated with an increased propensity for obesity and cardiovascular disease in later life, has also been shown to vary by ethnic background. This review serves to reconcile ethnic variations in BAT development and function with ethnic differences in birth weight outcomes to argue that the variation in obesity susceptibility between ethnic groups may have its origins in the in utero programming of BAT development and function as a result of evolutionary adaptation to cold environments.

Selenium (Se) has been utilized in the differentiation of primary pig and rat preadipocytes, indicating that it may have proadipogenic potential; however, some studies have also demonstrated that Se has antiadipogenic activity. In this study, chicken embryonic fibroblasts (CEFs) were used to investigate the role of Se in adipogenesis in vitro and in ovo. Se supplementation increased lipid droplet accumulation and inhibited proliferation of cultured CEFs isolated from 6-day-old embryos dose-dependently. This suggests that Se may play a role in cell cycle inhibition, thereby promoting the differentiation of fibroblasts to adipocytes. Se did not stimulate adipogenic differentiation of CEFs isolated from 9- to 12-day-old embryos, implying a permissive stage of adipogenic determination by Se at earlier embryonic ages. Microarray analysis comparing control and Se treatments on CEFs from 6-day-old embryos and confirmatory analysis by quantitative real-time polymerase chain reaction revealed that genes involved in adipocyte determination and differentiation, fatty acid uptake and triacylglycerol synthesis were up-regulated. In addition, up-regulation of an anti-lipolytic G0/G1 switch gene 2 and down-regulation of a prolipolytic monoglyceride lipase may lead to inhibition of lipolysis by Se. Both osteogenic and myogenic genes were down-regulated, and several genes related to oxidative stress response during adipogenesis were up-regulated. In ovo injection of Se at embryonic day 8 increased adipose tissue mass by 30% and caused adipocyte hypertrophy in 17-day-old chicken embryos, further supporting the proadipogenic role of Se during the embryonic development of chickens. These results suggest that Se plays a significant role in several mechanisms related to adipogenesis., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The United States is a world leader in poultry production, which is the reason why achieving better performance and muscle growth each year is a necessity. Reducing accretion of adipose tissue is another important factor for poultry producers because this allows more nutrients to be directed toward muscle growth, but the effect of embryonic adipose growth on posthatch development has not been fully understood. The purpose of this study was to investigate the total DNA mass, morphological characteristics, differentiation markers, and triglyceride breakdown factors of embryonic adipose tissue, and their relation to hyperplastic and hypertrophic growth within layers (Leghorn) and meat-type chickens (broilers). After embryonic day (E) 12, broiler weight was significantly higher than Leghorn, and this trend continued throughout the rest of incubation and posthatch (P < 0.05). Neck and leg fat pad weights between the 2 breeds did not differ at most of the time points. A remarkable increase in total DNA mass was observed between E12 and E14 in both Leghorn and broilers (P < 0.05), indicating a high potential for hyperplastic growth during this time. Histological analysis revealed clusters of preadipocytes at E12; however, the majority of these cells differentiated by E14 and continued to grow until the time of hatch. The adipocyte sizes between both breeds did not generally differ, even though broilers are known to have larger adipocytes posthatch. Fatty acid-binding protein 4 expression levels in Leghorn and broilers continued to rise with each time point, which paralleled the expansion of mature adipocytes. Adipose triglyceride lipase was highly expressed at E20 and d 1 posthatch to mobilize triglyceride degradation for energy during hatching. Thus, embryonic chicken adipose tissue was found to develop by hyperplastic mechanisms followed by hypertrophy. At embryonic stages and early posthatch, layer- and meat-type chicken adipose growth does not differ, which suggests breed differences occur posthatch., (© 2014 Poultry Science Association Inc.)

The Developmental Origins of Health and Disease hypothesis holds that alterations to homeostasis during critical periods of development can predispose individuals to adult-onset chronic diseases such as diabetes and metabolic syndrome. It remains controversial whether preimplantation embryo manipulation, clinically used to treat patients with infertility, disturbs homeostasis and affects long-term growth and metabolism. To address this controversy, we have assessed the effects of in vitro fertilization (IVF) on postnatal physiology in mice. We demonstrate that IVF and embryo culture, even under conditions considered optimal for mouse embryo culture, alter postnatal growth trajectory, fat accumulation, and glucose metabolism in adult mice. Unbiased metabolic profiling in serum and microarray analysis of pancreatic islets and insulin sensitive tissues (liver, skeletal muscle, and adipose tissue) revealed broad changes in metabolic homeostasis, characterized by systemic oxidative stress and mitochondrial dysfunction. Adopting a candidate approach, we identify thioredoxin-interacting protein (TXNIP), a key molecule involved in integrating cellular nutritional and oxidative states with metabolic response, as a marker for preimplantation stress and demonstrate tissue-specific epigenetic and transcriptional TXNIP misregulation in selected adult tissues. Importantly, dysregulation of TXNIP expression is associated with enrichment for H4 acetylation at the Txnip promoter that persists from the blastocyst stage through adulthood in adipose tissue. Our data support the vulnerability of preimplantation embryos to environmental disturbance and demonstrate that conception by IVF can reprogram metabolic homeostasis through metabolic, transcriptional, and epigenetic mechanisms with lasting effects for adult growth and fitness. This study has wide clinical relevance and underscores the importance of continued follow-up of IVF-conceived offspring.

The stroma is a key component of the lymph node structure and function. However, little is known about its origin, exact cellular composition and the mechanisms governing its formation. Lymph nodes are always encapsulated in adipose tissue and we recently demonstrated the importance of this relation for the formation of lymph node stroma. Adipocyte precursor cells migrate into the lymph node during its development and upon engagement of the Lymphotoxin-b receptor switch off adipogenesis and differentiate into lymphoid stromal cells (Bénézech et al.). Based on the lymphoid stroma potential of adipose tissue, we present a method using a lymph node/fat pad chimera that allows the lineage tracing of lymph node stromal cell precursors. We show how to isolate newborn lymph nodes and EYFP(+) embryonic adipose tissue and make a LN/ EYFP(+) fat pad chimera. After transfer under the kidney capsule of a host mouse, the lymph node incorporates local adipose tissue precursor cells and finishes its formation. Progeny analysis of EYFP(+) fat pad cells in the resulting lymph nodes can be performed by flow-cytometric analysis of enzymatically digested lymph nodes or by immunofluorescence analysis of lymph nodes cryosections. By using fat pads from different knockout mouse models, this method will provide an efficient way of analyzing the origin of the different lymph node stromal cell populations.

Epidemiological studies demonstrated initially that maternal undernutrition results in low birth weight with increased risk for long-lasting energy balance disorders. Maternal obesity and diabetes associated with high birth weight, excessive nutrition in neonates, and rapid catchup growth also increase the risk of adult-onset obesity. As stated by the Developmental Origin of Health and Disease concept, nutrient supply perturbations in the fetus or neonate result in long-term programming of individual body weight set point. Adipose tissue is a key fuel storage unit involved mainly in the maintenance of energy homeostasis. Studies in numerous animal models have demonstrated that the adipose tissue is the focus of developmental programming events in a sex- and depot-specific manner. In rodents, adipose tissue development is particularly active during the perinatal period, especially during the last week of gestation and during early postnatal life. In contrast to rodents, this process essentially takes place before birth in bigger mammals. Despite these different developmental time windows, altricial and precocial species share several mechanisms of adipose tissue programming. Offspring from malnourished dams present adipose tissue with a series of alterations: impaired glucose uptake, insulin and leptin resistance, low-grade inflammation, modified sympathetic activity with reduced noradrenergic innervations, and thermogenesis. These modifications reprogram adipose tissue metabolism by changing fat distribution and composition and by enhancing adipogenesis, predisposing the offspring to fat accumulation. Subtle adipose tissue circadian rhythm changes are also observed. Inappropriate hormone levels, modified tissue sensitivity (especially glucocorticoid system), and epigenetic mechanisms are key factors for adipose tissue programming during the perinatal period.

In mammals, the male and female hormones androgen and estrogen act as endocrine regulators of energy metabolism. However, adipose tissue is also a site of androgen and estrogen synthesis; androgens convert to estrogens in these tissues, and adipose tissue is also a reservoir of steroids that act locally in a paracrine and intracrine manner. Thus, in adipose tissue, the local output of sex hormones is more complex than would be suggested by routine measurement of serum hormone concentrations. This review integrates studies on the effects of androgens and estrogens in the developmental programming of adipose tissue function in early life and addresses the contributions of local androgen and estrogen metabolism on adipose tissue function in adults.

Maternal nutrient reduction (MNR) during fetal development may predispose offspring to chronic disease later in life. Increased regeneration of active glucocorticoids by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in metabolic tissues is fundamental to the developmental programming of metabolic syndrome, but underlying mechanisms are unknown. Hexose-6-phosphate dehydrogenase (H6PD) generates NADPH, the cofactor for 11β-HSD1 reductase activity. CCAAT/enhancer binding proteins (C/EBPs) and the glucocorticoid receptor (GR) regulate 11β-HSD1 expression. We hypothesize that MNR increases expression of fetal C/EBPs, GR, and H6PD, thereby increasing expression of 11β-HSD1 and reductase activity in fetal liver and adipose tissues. Pregnant MNR baboons ate 70% of what controls ate from 0.16 to 0.9 gestation (term, 184 days). Cortisol levels in maternal and fetal circulations increased in MNR pregnancies at 0.9 gestation. MNR increased expression of 11β-HSD1; H6PD; C/EBPα, -β, -γ; and GR in female but not male perirenal adipose tissue and in male but not female liver at 0.9 gestation. Local cortisol level and its targets PEPCK1 and PPARγ increased correspondingly in adipose and liver tissues. C/EBPα and GR were found to be bound to the 11β-HSD1 promoter. In conclusion, sex- and tissue-specific increases of 11β-HSD1, H6PD, GR, and C/EBPs may contribute to sexual dimorphism in the programming of exaggerated cortisol regeneration in liver and adipose tissues and offsprings' susceptibility to metabolic syndrome.

The midfacial deep fatty tissue has been divided into the buccal and parapharyngeal fat pads although the former carries several extensions in adults. Using histological sections of 15 large human fetuses, we demonstrated that the parapharyngeal fat pad corresponds to the major content of the prestyloid compartment of the parapharyngeal space or, simply, the prestyloid fat. The buccal and prestyloid fatty tissues were separated by the medial and lateral pterygoid muscles. In these tissues, superficial parts, corresponding to the lower body and the masseteric extension of the adult buccal fat pad, were well encapsulated and showed the most advanced stage of histogenesis. As the sphenoid bone was not fully developed even in the largest specimens, the temporal, infratemporal, and pterygopalatine fossae joined to provide a large space for a single, large upper extension of the buccal fat pad. In the intermediate part of the extension course, the larger specimens carried a narrower part between the maxilla and the temporalis muscle. The single, upper extension appeared to divide into several extensions, as seen in adults. The periocular fat was clearly separated from the upper extension of the buccal fat pad by the sheet-like orbitalis muscle. A communication between the prestyloid fat and the buccal fat pad likely occurred through a potential space along the lingual nerve immediately superior to the deep part of the submandibular gland. At this site, therefore, the prestyloid fat may be injured or infected when the buccal fat pad is treated surgically., (Copyright © 2012 Wiley Periodicals, Inc.)

The combination of obesity and type 2 diabetes is a serious health problem, which is projected to afflict 300 million people worldwide by 2020. Both clinical and translational laboratory studies have demonstrated that chronic inflammation is associated with obesity and obesity-related conditions such as insulin resistance. However, the precise etiopathogenetic mechanisms linking obesity to diabetes remain to be elucidated, and the pathways that mediate this phenomenon are not fully characterized. One of the most recently identified signaling pathways, whose activation seems to affect many metabolic disorders, is the "inflammasome," a multiprotein complex composed of NLRP3 (nucleotide-binding domain and leucine-rich repeat protein 3), ASC (apoptosis-associated speck-like protein containing a CARD), and procaspase-1. NLRP3 inflammasome activation leads to the processing and secretion of the proinflammatory cytokines interleukin- (IL-) 1 β and IL-18. The goal of this paper is to review new insights on the effects of the NLRP3 inflammasome activation in the complex mechanisms of crosstalk between different organs, for a better understanding of the role of chronic inflammation in metabolic disease pathogenesis. We will provide here a perspective on the current research on NLRP3 inflammasome, which may represent an innovative therapeutic target to reverse the detrimental metabolic consequences of the metabolic inflammation.

Purpose: Excessive fetal fat as the hallmark of GDM pregnancy complications is one consequence of fetal hyperinsulinism. Noninvasive methods for fetal surveillance and measurement of fetal fat are needed. The purpose of this study was to test the hypothesis that measurements of the fetal anterior abdominal wall thickness (AAWT) in women with GDM will allow early detection of fetal hyperinsulinism., Materials and Methods: Amniocentesis was performed between 28 and 32 weeks of gestation (wks) in 220 women with GDM (diagnosed by 75 g oGTT at 24 to 28 wks). Amniotic fluid insulin levels (AFIL) were determined by a commercially available radioimmunoassay. Transabdominal ultrasound provided fetal biometric measurements following standard procedures and the AAWT including fetal skin and subcutaneous tissue at the time of amniocentesis. Maternal parameters (weight, BMI, oGTT blood glucose levels and mean daily blood glucose levels) were correlated with fetal biometric data and with AFIL., Results: There was no difference in AAWT in women with GDM and no correlation with mean AFIL. AFIL also did not correlate with any other fetal measurement or with mean oGTT blood glucose levels. AFIL only showed a correlation with maternal weight (p = 0.02) and maternal BMI (p = 0.01). The correlation was present for values both before pregnancy and at the time of amniocentesis., Conclusion: In the early third trimester, AAWT measurements do not correlate with fetal insulin levels., (© Georg Thieme Verlag KG Stuttgart · New York.)

This study measured organochlorine pesticides (OCPs) including hexachlorocyclohexanes (HCHs), hexachlorobenzene (HCB), heptachlor and dichlorodiphenyltrichloroethanes (DDTs), polychlorinated biphenyls (PCBs), polychlorinated naphthalenes (PCNs) and polybrominated diphenyl ethers (PBDEs) in tissues of six mother-fetus pairs of harbor seals that were hunted for subsistence in Alaska waters of the Northern Pacific Ocean. These data suggest that significant amounts of these contaminants were transferred from mother harbor seals to fetuses during pregnancy and distributed among fetal organs. The tissue distribution depended on the chemical groups, the specific compounds in the groups and the target organs. Concentration profiles of ∑OCPs, ∑PCBs, ∑PCNs and ∑PBDEs were remarkably similar among maternal blubber, liver, and placenta, fetal blubber, and liver (except for HCHs), possibly indicating that the placenta did not serve as a barrier for all of the compounds analyzed. DDTs, HCB, HCHs, PCBs and PBDEs could penetrate the placenta and accumulate in the blubber of the fetus in utero, while HCHs, PCBs and PBDEs penetrated the placenta and accumulated more preferentially in the fetal liver than in the fetal brain in comparison with DDTs and HCB. Heptachlor and PCNs penetrated the placenta and accumulated in the fetal liver and brain instead of fetal blubber. Similar maternal transfer trends for OCPs, PCBs, PCNs and PBDEs were shown by fetal to maternal (FM) blubber ratios and FM liver ratios. Prenatal transfer of these toxic contaminants from mothers to fetus presumably through the placenta may pose health risks to the fetus during early development., (Copyright © 2012 Elsevier B.V. All rights reserved.)

This study reports the metabolic and morphological characteristics of bovine intermuscular adipose tissue (AT) throughout foetal growth. Our hypothesis was that the histological and molecular features of intermuscular AT would be different from those previously reported for foetal perirenal AT, based on its anatomical location near the muscle and the recent identification of two distinct adipocyte precursors in mouse AT depending on their locations. To address this question, intermuscular AT was sampled from Charolais and Blond d'Aquitaine foetuses at 180, 210 and 260 days post conception (dpc). The two bovine breeds were chosen because of the higher adiposity of Charolais than Blond d'Aquitaine cattle during the postnatal life. Regardless of the breed, adipocyte volume increased slightly (+38%, P < 0.01) with increasing foetal age. This was concomitant with a decrease (P < 0.05) in the activity of enzymes involved in de novo fatty acid (FA) synthesis (FA synthase and glucose-6-phosphate dehydrogenase) and FA esterification (glycerol-3-phosphate dehydrogenase) when expressed per million adipocytes, and with an increase (P ⩽ 0.01) in mRNA abundances for uncoupling protein 1, adiponectin and leptin (LEP) between 180 and 260 dpc. No difference was observed in the adipocyte volume between breeds, which was consistent with the lack of major between-breed differences in mRNA abundances or activities of enzymes involved in lipid metabolism. The mRNA abundance of lipoprotein lipase was maintained across ages, suggesting a storage of circulating FA rather than of FA synthesized de novo. Plasma LEP increased with foetal age, but only in the Charolais breed (+71%, P ⩽ 0.01), and was two- to threefold higher in Charolais than Blond d'Aquitaine foetuses. Regardless of the breed, bovine intermuscular AT contained predominantly unilocular adipocytes believed to be white adipocytes that were larger at 260 dpc than at 180 dpc. These data thus challenge current concepts of the largely brown nature of bovine foetal AT (based on histological and metabolic features of perirenal AT as previously reported a few days before or after birth).

Background: We investigated the associations between second trimester amniotic fluid (AF) levels of human adiponectin and placental growth factor (PLGF) in small for gestational age (SGA), large for gestational age (LGA) and appropriate for gestational age (AGA) fetuses., Materials and Methods: Adiponectin and PLGF levels were determined by enzyme immunoassay in AF of 21 SGA, 13 LGA and 44 AGA fetuses between 15-22 weeks of gestation, derived from pregnant women who underwent amniocentesis., Results: Adiponectin and PLGF levels were detectable in AF. Median (25th-75th percentile) adiponectin levels were 16.1 (10.9-32.3) ng/ml in SGA, 19.5 (15.1-30.9) ng/ml in AGA, and 18.2 (14.7-30.8) ng/ml in LGA fetuses. Median (25th-75th percentile) PLGF levels were 24.2 (19.9-34.9) pg/nl in SGA, 26.4 (20.9-33.8) pg/ml in AGA and 33.5 (21.8-40.4) pg/ml in LGA fetuses. The differences were not statistically significant. Nevertheless, indication of differentiation of levels existed when SGA and LGA fetuses in the extremes of distribution were considered. Specifically, very severely SGA fetuses (≤2.5th percentile) tended to have high levels of adiponectin and reduced levels of PLGF in AF., Conclusion: This is the first study presenting adiponectin and PLGF concentrations in early second trimester amniotic fluid in AGA, SGA and LGA fetuses. The altered concentrations of adiponectin and PLGF in very severely SGA fetuses possibly result from the growth-promoting effect of these factors through the metabolic route and the vascular integrity of the placenta, respectively.

Purpose: We hypothesized that the remnant of the primitive pulmonary venous plexus in the embryo provides a pathway for direct communication from each lobe of the lung to the mediastinum. We assessed the presence and location of these connections by using 64-row multidetector computed tomography (CT)., Materials and Methods: This study was approved by the institutional ethics committee. First, we analyzed the multidetector row CT images of 120 normal lungs for the presence of septal structures between the pulmonary veins and the mediastinum and the extension of mediastinal fat into these septal structures. Second, we analyzed 62 patients with pneumothorax for the presence of cross-bridging structures in the pleural cavities., Results: We frequently observed septal structures (36% to 77%) and the extension of mediastinal fat (8% to 56%) in the right apical segment, left apical posterior segment, both right and left anterior segments, right medial segment, and left inferior lingular segment. Cross-bridging structures were observed in 44% of right and 38% of left pneumothoraces and were noted in the right apical and posterior segments, left apical posterior segment, both anterior segments, right middle lobe, and left lingular segments. Septal and cross-bridging structures both showed a similar distribution pattern., Conclusions: Venous septal structures in normal lungs and cross-bridging structures in pneumothoraces visualized on CT images suggest the presence of direct pathways from each lobe of the lung to the mediastinum.

The current epidemic of obesity and overweight has caused a surge of interest in the study of adipose tissue formation. Much progress has been made in defining the transcriptional networks controlling the terminal differentiation of adipocyte progenitors into mature adipocytes. However, the early steps of adipocyte development and the embryonic origin of this lineage have been largely disregarded until recently. In mammals, two functionally different types of adipose tissues coexist, which are both involved in energy balance but assume opposite functions. White adipose tissue (WAT) stores energy, while brown adipose tissue (BAT) is specialized in energy expenditure. WAT and BAT can be found as several depots located in various sites of the body. Individual fat depots exhibit different timing of appearance during development, as well as distinct functional properties, suggesting possible differences in their developmental origin. This hypothesis has recently been revisited through large-scale genomics studies and in vivo lineage tracing approaches, which are reviewed in this report. These studies have provided novel fundamental insights into adipocyte biology, pointing out distinct developmental origins for WAT and BAT, as well as for individual WAT depots. They suggest that the adipose tissue is composed of distinct mini-organs, exhibiting developmental and functional differences, as well as variable contribution to obesity-related metabolic diseases.