The Impact of Maternal Obesity on Adipose Progenitor Cells.

The concept of Developmental Origin of Health and Disease (DOHaD) postulates that adult-onset metabolic disorders may originate from suboptimal conditions during critical embryonic and fetal programming windows. In particular, nutritional disturbance during key developmental stages may program the set point of adiposity and its associated metabolic diseases later in life. Numerous studies in mammals have reported that maternal obesity and the resulting accelerated growth in neonates may affect adipocyte development, resulting in persistent alterations in adipose tissue plasticity (i.e., adipocyte proliferation and storage) and adipocyte function (i.e., insulin resistance, impaired adipokine secretion, reduced thermogenesis, and higher inflammation) in a sex- and depot-specific manner. Over recent years, adipose progenitor cells (APCs) have been shown to play a crucial role in adipose tissue plasticity, essential for its development, maintenance, and expansion. In this review, we aim to provide insights into the developmental timeline of lineage commitment and differentiation of APCs and their role in predisposing individuals to obesity and metabolic diseases. We present data supporting the possible implication of dysregulated APCs and aberrant perinatal adipogenesis through epigenetic mechanisms as a primary mechanism responsible for long-lasting adipose tissue dysfunction in offspring born to obese mothers.

Knocking Down CDKN2A in 3D hiPSC-Derived Brown Adipose Progenitors Potentiates Differentiation, Oxidative Metabolism and Browning Process.

Human induced pluripotent stem cells (hiPSCs) have the potential to be differentiated into any cell type, making them a relevant tool for therapeutic purposes such as cell-based therapies. In particular, they show great promise for obesity treatment as they represent an unlimited source of brown/beige adipose progenitors (hiPSC-BAPs). However, the low brown/beige adipocyte differentiation potential in 2D cultures represents a strong limitation for clinical use. In adipose tissue, besides its cell cycle regulator functions, the cyclin-dependent kinase inhibitor 2A (CDKN2A) locus modulates the commitment of stem cells to the brown-like type fate, mature adipocyte energy metabolism and the browning of adipose tissue. Here, using a new method of hiPSC-BAPs 3D culture, via the formation of an organoid-like structure, we silenced CDKN2A expression during hiPSC-BAP adipogenic differentiation and observed that knocking down CDKN2A potentiates adipogenesis, oxidative metabolism and the browning process, resulting in brown-like adipocytes by promoting UCP1 expression and beiging markers. Our results suggest that modulating CDKN2A levels could be relevant for hiPSC-BAPs cell-based therapies.

Time impact on the antidiabetic effects of key bariatric surgeries: a network meta-analysis of randomized controlled trials with meta-regression.

BACKGROUND: Few studies compare the efficacy of the key bariatric procedures in type 2 diabetes management over the long term. None offer a reliable comparison of their respective efficacy loss over time. OBJECTIVES: To analyze and compare the time evolution of the antidiabetic effects of the key bariatric procedures. SETTING: Obesity surgery departments in America, Europe, and Asia. METHODS: All the randomized clinical trials assessing the efficacy of bariatric surgery in type 2 diabetes management with 1-5 years of follow-up were reviewed. A network meta-analysis with meta-regression was performed to compare the effectiveness of each technique and its respective efficacy loss temporal dynamics. RESULTS: Thirty-one trials involving 1906 patients were included. In comparison to Roux-en-Y gastric bypass, the 5-year complete or partial diabetes remission rates were inferior with medical treatment (odds ratio [OR] = .05; 95% credible interval [CrI]: .02-.13) and gastric banding (OR = .38; 95% CrI: .16-.87), equivalent with sleeve gastrectomy (OR = 1.08; 95% CrI: .59-1.97), and superior with 1 anastomosis gastric bypass (OR = 3.00; 95% CrI: 1.12-8.33) and biliopancreatic diversion and its affiliated techniques (OR = 3.71; 95% CrI: 1.16-12.55). However, remission rates and glycemic control progressively decreased whatever the treatment option evaluated. Moreover, this loss of efficacy followed a statistically comparable temporal dynamic to those of Roux-en-Y gastric bypass regardless of the therapeutic strategy implemented. CONCLUSIONS: No therapeutic modality offered stable antidiabetic effects. The gap observed between the techniques after a 5-year follow up concerning remission rates and glycemic control could depend essentially on the magnitude of the effects initially obtained. However, these results need to be confirmed over longer follow-up periods.

Maternal obesity as a risk factor for developing diabetes in offspring: An epigenetic point of view.

According to the developmental origin of health and disease concept, the risk of many age-related diseases is not only determined by genetic and adult lifestyle factors but also by factors acting during early development. In particular, maternal obesity and neonatal accelerated growth predispose offspring to overweight and type 2 diabetes (T2D) in adulthood. This concept mainly relies on the developmental plasticity of adipose tissue and pancreatic ß-cell programming in response to suboptimal milieu during the perinatal period. These changes result in unhealthy hypertrophic adipocytes with decreased capacity to store fat, low-grade inflammation and loss of insulin-producing pancreatic ß-cells. Over the past years, many efforts have been made to understand how maternal obesity induces long-lasting adipose tissue and pancreatic ß-cell dysfunction in offspring and what are the molecular basis of the transgenerational inheritance of T2D. In particular, rodent studies have shed light on the role of epigenetic mechanisms in linking maternal nutritional manipulations to the risk for T2D in adulthood. In this review, we discuss epigenetic adipocyte and ß-cell remodeling during development in the progeny of obese mothers and the persistence of these marks as a basis of obesity and T2D predisposition.

Omega Loop Gastroileal Bypass (OLGIBP/SAGI) Versus One Anastomosis Gastric Bypass (OAGB): Medium-Term Results.

INTRODUCTION: In bariatric surgery, new surgical techniques are continually being developed. The one anastomosis gastric bypass (OAGB) has become increasingly common since 2001. However, some patients experience bile reflux or excessive weight loss. This study aimed to assess a new bariatric procedure designed to avoid some of the drawbacks of conventional OAGB. MATERIAL AND METHODS: To lower the complication rate and pathophysiological impact after OAGB, we performed an omega loop gastroileal bypass (OLGIBP/SAGI) with a 300-cm common limb. We compared this technique with OAGB. RESULTS: Seventeen patients underwent OLGIBP and 23 underwent OAGB. Mean operative time was 108 min for OLGIBP vs 103 min for OAGB. The mean hospital length of stay was 3 days (1 to 7). No complications related to the gastroenterostomy occurred. At 3 years, among OAGB patients, there were 5 (21.7%) cases of bile reflux including 2 (8.7%) requiring a revision to Roux-en-Y gastric bypass. Among OLGIBP patients, there were 3 (17.6%) cases of bile reflux 1 (5.9%) requiring a revision to Roux-en-Y gastric bypass. There was no albumin deficiency. At 3 years, % of total weight loss (TWL) was 43.6 + - 6.2 in the OAGB group vs 48.2 + - 7.4 in the OLGIBP group. CONCLUSIONS: The bariatric and metabolic outcomes of OLGIBP are expected to be similar to those of OAGB. The OLGIBP technique should reduce the risks of malnutrition and bile reflux. The two techniques can be safely performed and offer alternatives in bariatric surgery.

Emerging Roles for the INK4a/ARF (CDKN2A) Locus in Adipose Tissue: Implications for Obesity and Type 2 Diabetes.

Besides its role as a cell cycle and proliferation regulator, the INK4a/ARF (CDKN2A) locus and its associated pathways are thought to play additional functions in the control of energy homeostasis. Genome-wide association studies in humans and rodents have revealed that single nucleotide polymorphisms in this locus are risk factors for obesity and related metabolic diseases including cardiovascular complications and type-2 diabetes (T2D). Recent studies showed that both p16INK4a-CDK4-E2F1/pRB and p19ARF-P53 (p14ARF in humans) related pathways regulate adipose tissue (AT) physiology and adipocyte functions such as lipid storage, inflammation, oxidative activity, and cellular plasticity (browning). Targeting these metabolic pathways in AT emerged as a new putative therapy to alleviate the effects of obesity and prevent T2D. This review aims to provide an overview of the literature linking the INK4a/ARF locus with AT functions, focusing on its mechanisms of action in the regulation of energy homeostasis.

Bariatric Surgery After Previous Antireflux Surgery Without Takedown of the Previous Fundoplication: a Prospective Study.

BACKGROUND: The increased prevalence of reflux disease in obese patients, combined with widespread availability of laparoscopic antireflux surgery, has increased the likelihood that more patients will seek bariatric surgery having previously undergone fundoplication. OBJECTIVES: This study examined our series of laparoscopic bariatric surgery after previous antireflux surgery without takedown of the previous fundoplication. We discuss our results, our technique and the tips and tricks to avoid complication after this procedure. SETTING: Private practice. METHODS: We operated on patients suffering from obesity who had already undergone laparoscopic Nissen. The patients were eligible for bariatric surgery according to the French National Institute of Health's criteria for bariatric surgery. The pre-operative assessment involved gastroscopy with biopsies looking for Helicobacter pylori, oesophago-gastroduodenoscopy, investigation for sleep apnoea syndrome and a full laboratory assessment. The patients took part in their choice of surgery. RESULTS: The patients' post-operative course was uncomplicated. No patients had symptoms of gastro-esophageal reflux late after surgery and good gastrointestinal comfort was achieved (no pain, no reflux). All of the patients were satisfied. Length of stay was 3 to 5 days. All patients exhibited significant weight loss. CONCLUSION: Bariatric surgery is possible after fundoplication without taking down the fundoplication. It appears to be a viable alternative in patients seeking weight loss surgery after fundoplication, which is currently assumed contraindicated.

Transcription profiling in the liver of undernourished male rat offspring reveals altered lipid metabolism pathways and predisposition to hepatic steatosis.

Clinical and animal studies have reported an association between low birth weight and the development of nonalcoholic fatty liver disease (NAFLD) in offspring. Using a model of prenatal maternal 70% food restriction diet (FR30) in the rat, we previously showed that maternal undernutrition predisposes offspring to altered lipid metabolism in adipose tissue, especially on a high-fat (HF) diet. Here, using microarray-based expression profiling combined with metabolic, endocrine, biochemical, histological, and lipidomic approaches, we assessed whether FR30 procedure sensitizes adult male offspring to impaired lipid metabolism in the liver. No obvious differences were noted in the concentrations of triglycerides, cholesterol, and bile acids in the liver of 4-mo-old FR30 rats whichever postweaning diet was used. However, several clues suggest that offspring's lipid metabolism and steatosis are modified by maternal undernutrition. First, lipid composition was changed (i.e., higher total saturated fatty acids and lower elaidic acid) in the liver, whereas larger triglyceride droplets were observed in hepatocytes of undernourished rats. Second, FR30 offspring exhibited long-term impact on hepatic gene expression and lipid metabolism pathways on a chow diet. Although the transcriptome profile was globally modified by maternal undernutrition, cholesterol and bile acid biosynthesis pathways appear to be key targets, indicating that FR30 animals were predisposed to impaired hepatic cholesterol metabolism. Third, the FR30 protocol markedly modifies hepatic gene transcription profiles in undernourished offspring in response to postweaning HF. Overall, FR30 offspring may exhibit impaired metabolic flexibility, which does not enable them to properly cope with postweaning nutritional challenges influencing the development of nonalcoholic fatty liver.

Effect of Maternal Obesity and Preconceptional Weight Loss on Male and Female Offspring Metabolism and Olfactory Performance in Mice.

According to the "developmental origins of health and disease" (DOHaD) concept, maternal obesity predisposes the offspring to non-communicable diseases in adulthood. While a preconceptional weight loss (WL) is recommended for obese women, its benefits on the offspring have been poorly addressed. We evaluated whether preconceptional WL was able to reverse the adverse effects of maternal obesity in a mouse model, exhibiting a modification of foetal growth and of the expression of genes encoding epigenetic modifiers in liver and placenta. We tracked metabolic and olfactory behavioural trajectories of offspring born to control, obese or WL mothers. After weaning, the offspring were either put on a control diet (CD) or a high-fat (HFD). After only few weeks of HFD, the offspring developed obesity, metabolic alterations and olfactory impairments, independently of maternal context. However, male offspring born to obese mother gained even more weight under HFD than their counterparts born to lean mothers. Preconceptional WL normalized the offspring metabolic phenotypes but had unexpected effects on olfactory performance: a reduction in olfactory sensitivity, along with a lack of fasting-induced, olfactory-based motivation. Our results confirm the benefits of maternal preconceptional WL for male offspring metabolic health but highlight some possible adverse outcomes on olfactory-based behaviours.

Elabela and Apelin actions in healthy and pathological pregnancies.

Pregnancy is a dynamic and precisely organized process during which one or more baby develops. Embryonic development relies on the formation of the placenta, allowing nutrient and oxygen exchange between the mother and the fetus. Dysfunction of placental formation lead to pregnancy disorders such as preeclampsia (PE) with serious deleterious consequences for fetal and maternal health. Identifying factors involved in fetoplacental homeostasis could inform better diagnostic and therapeutic strategies for these pathological pregnancies. Here, we summarize actions of elabela, apelin and their common receptor APJ in the fetoplacental unit. Studies indicate that elabela is crucial for embryo cardiovascular system formation and early placental development, while apelin acts in mid/late gestation to modulate fetal angiogenesis and energy homeostasis. Most of these findings, drawn from animal models, indicate a key role of elabela/apelin-APJ system in the fetoplacental unit. This review also provides an overview of clinical studies investigating elabela/apelin-APJ system in pathological complicated pregnancies such as PE and gestational diabetes mellitus (GDM). While elabela-deficient mice display all the features of PE, current clinical studies show no difference in circulating elabela levels between PE and control patients which does not support a role in PE development. Conversely, apelin levels are increased during PE, but the use of apelin as an early PE marker remains to be fully investigated.

Maternal high-fat diet during suckling programs visceral adiposity and epigenetic regulation of adipose tissue stearoyl-CoA desaturase-1 in offspring.

OBJECTIVE: The lactation-suckling period is critical for white adipose tissue (WAT) development. Early postnatal nutrition influences later obesity risk but underlying mechanisms remain elusive. Here, we tested whether altered postnatal nutrition specifically during suckling impacts epigenetic regulation of key metabolic genes in WAT and alter long-term adiposity set point. METHODS: We analyzed the effects of maternal high-fat (HF) feeding in rats exclusively during lactation-suckling on breast milk composition and its impact on male offspring visceral epidydimal (eWAT) and subcutaneous inguinal (iWAT) depots during suckling and in adulthood. RESULTS: Maternal HF feeding during lactation had no effect on mothers' body weight (BW) or global breast milk composition, but induced qualitative changes in breast milk fatty acid (FA) composition (high n-6/n-3 polyunsaturated FA ratio and low medium-chain FA content). During suckling, HF neonates showed increased BW and mass of both eWAT and iWAT depot but only eWAT displayed an enhanced adipogenic transcriptional signature. In adulthood, HF offspring were predisposed to weight gain and showed increased hyperplastic growth only in eWAT. This specific eWAT expansion was associated with increased expression and activity of stearoyl-CoA desaturase-1 (SCD1), a key enzyme of FA metabolism. SCD1 converts saturated FAs, e.g. palmitate and stearate, to monounsaturated FAs, palmitoleate and oleate, which are the predominant substrates for triglyceride synthesis. Scd1 upregulation in eWAT was associated with reduced DNA methylation in Scd1 promoter surrounding a PPARγ-binding region. Conversely, changes in SCD1 levels and methylation were not observed in iWAT, coherent with a depot-specific programming. CONCLUSIONS: Our data reveal that maternal HF feeding during suckling programs long-term eWAT expansion in part by SCD1 epigenetic reprogramming. This programming events occurred with drastic changes in breast milk FA composition, suggesting that dietary FAs are key metabolic programming factors in the early postnatal period.

Epigenetic Programming of Adipose Tissue in the Progeny of Obese Dams.

According to the Developmental Origin of Health and Disease (DOHaD) concept, maternal obesity and the resulting accelerated growth in neonates predispose offspring to obesity and associated metabolic diseases that may persist across generations. In this context, the adipose tissue has emerged as an important player due to its involvement in metabolic health, and its high potential for plasticity and adaptation to environmental cues. Recent years have seen a growing interest in how maternal obesity induces long-lasting adipose tissue remodeling in offspring and how these modifications could be transmitted to subsequent generations in an inter- or transgenerational manner. In particular, epigenetic mechanisms are thought to be key players in the developmental programming of adipose tissue, which may partially mediate parts of the transgenerational inheritance of obesity. This review presents data supporting the role of maternal obesity in the developmental programming of adipose tissue through epigenetic mechanisms. Inter- and transgenerational effects on adipose tissue expansion are also discussed in this review.

Effect of diet in females (F1) from prenatally undernourished mothers on metabolism and liver function in the F2 progeny is sex-specific.

PURPOSE: Poor maternal nutrition sensitises to the development of metabolic diseases and obesity in adulthood over several generations. The prevalence increases when offspring is fed with a high-fat (HF) diet after weaning. This study aims to determine whether such metabolic profiles can be transmitted to the second generation and even aggravated when the mothers were exposed to overnutrition, with attention to potential sex differences. METHODS: Pregnant Wistar rats were subjected to ad libitum (control) or 70% food-restricted diet (FR) during gestation (F0). At weaning, F1 females were allocated to three food protocols: (1) standard diet prior to and throughout gestation and lactation, (2) HF diet prior to and standard diet throughout gestation and lactation, and (3) HF diet prior to and throughout gestation and lactation. F2 offspring was studied between 16 and 32 weeks of age. RESULTS: FR-F2 offspring on standard diet showed normal adiposity and had no significant metabolic alterations in adulthood. Maternal HF diet resulted in sex-specific effects with metabolic disturbances more apparent in control offspring exposed to HF diet during gestation and lactation. Control offspring displayed glucose intolerance associated with insulin resistance in females. Female livers overexpressed lipogenesis genes and those of males the genes involved in lipid oxidation. Gene expression was significantly attenuated in the FR livers. Increased physical activity associated with elevated corticosterone levels was observed in FR females on standard diet and in all females from overnourished mothers. CONCLUSIONS: Maternal undernutrition during gestation (F0) improves the metabolic health of second-generation offspring with more beneficial effects in females.

Transgenerational Epigenetic Mechanisms in Adipose Tissue Development.

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.

Reduced PPARγ2 expression in adipose tissue of male rat offspring from obese dams is associated with epigenetic modifications.

According to the Developmental Origin of Health and Disease (DOHaD) concept, maternal obesity and accelerated growth in neonates program obesity later in life. White adipose tissue (WAT) has been the focus of developmental programming events, although underlying mechanisms remain elusive. In rodents, WAT development primarily occurs during lactation. We previously reported that adult rat offspring from dams fed a high-fat (HF) diet exhibited fat accumulation and decreased peroxisome proliferator-activated receptor γ (PPARγ) mRNA levels in WAT. We hypothesized that PPARγ down-regulation occurs via epigenetic malprogramming which takes place during adipogenesis. We therefore examined epigenetic modifications in the PPARγ1 and PPARγ2 promoters in perirenal (pWAT) and inguinal fat pads of HF offspring at weaning (postnatal d 21) and in adulthood. Postnatal d 21 is a period characterized by active epigenomic remodeling in the PPARγ2 promoter (DNA hypermethylation and depletion in active histone modification H3ac and H3K4me3) in pWAT, consistent with increased DNA methyltransferase and DNA methylation activities. Adult HF offspring exhibited sustained hypermethylation and histone modification H3ac of the PPARγ2 promoter in both deposits, correlated with persistent decreased PPARγ2 mRNA levels. Consistent with the DOHaD hypothesis, retained epigenetic marks provide a mechanistic basis for the cellular memory linking maternal obesity to a predisposition for later adiposity.-Lecoutre, S., Pourpe, C., Butruille, L., Marousez, L., Laborie, C., Guinez, C., Lesage, J., Vieau, D., Eeckhoute, J., Gabory, A., Oger, F., Eberlé, D., Breton, C. Reduced PPARγ2 expression in adipose tissue of male rat offspring from obese dams is associated with epigenetic modifications.

Maternal obesity programs increased leptin gene expression in rat male offspring via epigenetic modifications in a depot-specific manner.

OBJECTIVE: According to the Developmental Origin of Health and Disease (DOHaD) concept, maternal obesity and accelerated growth in neonates predispose offspring to white adipose tissue (WAT) accumulation. In rodents, adipogenesis mainly develops during lactation. The mechanisms underlying the phenomenon known as developmental programming remain elusive. We previously reported that adult rat offspring from high-fat diet-fed dams (called HF) exhibited hypertrophic adipocyte, hyperleptinemia and increased leptin mRNA levels in a depot-specific manner. We hypothesized that leptin upregulation occurs via epigenetic malprogramming, which takes place early during development of WAT. METHODS: As a first step, we identified in silico two potential enhancers located upstream and downstream of the leptin transcription start site that exhibit strong dynamic epigenomic remodeling during adipocyte differentiation. We then focused on epigenetic modifications (methylation, hydroxymethylation, and histone modifications) of the promoter and the two potential enhancers regulating leptin gene expression in perirenal (pWAT) and inguinal (iWAT) fat pads of HF offspring during lactation (postnatal days 12 (PND12) and 21 (PND21)) and in adulthood. RESULTS: PND12 is an active period for epigenomic remodeling in both deposits especially in the upstream enhancer, consistent with leptin gene induction during adipogenesis. Unlike iWAT, some of these epigenetic marks were still observable in pWAT of weaned HF offspring. Retained marks were only visible in pWAT of 9-month-old HF rats that showed a persistent "expandable" phenotype. CONCLUSIONS: Consistent with the DOHaD hypothesis, persistent epigenetic remodeling occurs at regulatory regions especially within intergenic sequences, linked to higher leptin gene expression in adult HF offspring in a depot-specific manner.

Depot- and sex-specific effects of maternal obesity in offspring's adipose tissue.

According to the Developmental Origin of Health and Disease (DOHaD) concept, alterations of nutrient supply in the fetus or neonate result in long-term programming of individual body weight (BW) setpoint. In particular, maternal obesity, excessive nutrition, and accelerated growth in neonates have been shown to sensitize offspring to obesity. The white adipose tissue may represent a prime target of metabolic programming induced by maternal obesity. In order to unravel the underlying mechanisms, we have developed a rat model of maternal obesity using a high-fat (HF) diet (containing 60% lipids) before and during gestation and lactation. At birth, newborns from obese dams (called HF) were normotrophs. However, HF neonates exhibited a rapid weight gain during lactation, a key period of adipose tissue development in rodents. In males, increased BW at weaning (+30%) persists until 3months of age. Nine-month-old HF male offspring was normoglycemic but showed mild glucose intolerance, hyperinsulinemia, and hypercorticosteronemia. Despite no difference in BW and energy intake, HF adult male offspring was predisposed to fat accumulation showing increased visceral (gonadal and perirenal) depots weights and hyperleptinemia. However, only perirenal adipose tissue depot exhibited marked adipocyte hypertrophy and hyperplasia with elevated lipogenic (i.e. sterol-regulated element binding protein 1 (Srebp1), fatty acid synthase (Fas), and leptin) and diminished adipogenic (i.e. peroxisome proliferator-activated receptor gamma (Pparγ), 11ß-hydroxysteroid dehydrogenase type 1 (11ß-Hds1)) mRNA levels. By contrast, very few metabolic variations were observed in HF female offspring. Thus, maternal obesity and accelerated growth during lactation program offspring for higher adiposity via transcriptional alterations of visceral adipose tissue in a depot- and sex-specific manner.

Maternal obesity alters the apelinergic system at the feto-maternal interface.

Apelin and its receptor APJ have been implicated in pathologies including cardiovascular disease, diabetes and obesity. Little is known about the function of the apelinergic system during gestation. We evaluated in mice this system at the feto-maternal interface in insulin-resistant obese female (HF) mice. Maternal apelinemia was decreased at term and fetal apelinemia was sixfold higher than maternal level. Ex-vivo, the placenta releases apelin at E12.5 and E18.5. In HF pregnant mice at term, apelinemia as well as placental apelin and APJ mRNA levels were increased whereas placental release of apelin was drastically reduced compared to controls.