Onset Of Obesity Research Articles

Relationship between Prenatal or Postnatal Exposure to Pesticides and Obesity: A Systematic Review.

In recent years, the worldwide prevalence of overweight and obesity among adults and children has dramatically increased. The conventional model regarding the onset of obesity is based on an imbalance between energy intake and expenditure. However, other possible environmental factors involved, such as the exposure to chemicals like pesticides, cannot be discarded. These compounds could act as endocrine-disrupting chemicals (EDC) that may interfere with hormone activity related to several mechanisms involved in body weight control. The main objective of this study was to systematically review the data provided in the scientific literature for a possible association between prenatal and postnatal exposure to pesticides and obesity in offspring. A total of 25 human and 9 animal studies were analyzed. The prenatal, perinatal, and postnatal exposure to organophosphate, organochlorine, pyrethroid, neonicotinoid, and carbamate, as well as a combined pesticide exposure was reviewed. This systematic review reveals that the effects of pesticide exposure on body weight are mostly inconclusive, finding conflicting results in both humans and experimental animals. The outcomes reviewed are dependent on many factors, including dosage and route of administration, species, sex, and treatment duration. More research is needed to effectively evaluate the impact of the combined effects of different pesticides on human health.

New Pandemic: Obesity and Associated Nephropathy.

Incidence of obesity related renal disorders have increased 10-folds in recent years. One of the consequences of obesity is an increased glomerular filtration rate (GFR) that leads to the enlargement of the renal glomerulus, i.e., glomerulomegaly. This heightened hyper-filtration in the setting of type 2 diabetes irreparably damages the kidney and leads to progression of end stage renal disease (ESRD). The patients suffering from type 2 diabetes have progressive proteinuria, and eventually one third of them develop chronic kidney disease (CKD) and ESRD. For ameliorating the progression of CKD, inhibitors of renin angiotensin aldosterone system (RAAS) seemed to be effective, but on a short-term basis only. Long term and stable treatment strategies like weight loss via restricted or hypo-caloric diet or bariatric surgery have yielded better promising results in terms of amelioration of proteinuria and maintenance of normal GFR. Body mass index (BMI) is considered as a traditional marker for the onset of obesity, but apparently, it is not a reliable indicator, and thus there is a need for more precise evaluation of regional fat distribution and amount of muscle mass. With respect to the pathogenesis, recent investigations have suggested perturbation in fatty acid and cholesterol metabolism as the critical mediators in ectopic renal lipid accumulation associated with inflammation, increased generation of ROS, RAAS activation and consequential tubulo-interstitial injury. This review summarizes the renewed approaches for the obesity assessment and evaluation of the pathogenesis of CKD, altered renal hemodynamics and potential therapeutic targets.

High Fat Diet-Induced CD8+ T Cells in Adipose Tissue Mediate Macrophages to Sustain Low-Grade Chronic Inflammation.

Obesity in the United States and worldwide reached epidemic proportions within the last 20 years. Obesity is a very powerful health determinant or indicator that facilitates the development and progression of several metabolic diseases, insulin resistance, and low-grade chronic inflammation. Low-grade chronic inflammation in adipose tissue (AT) is marked by the accumulation of T cells, macrophages, and other immune cells and increased production of proinflammatory cytokines. During the onset of obesity but before the influx of macrophages, the AT is infiltrated by T cells that are strongly implicated in the initiation of obesity-associated inflammation. In comparing mice fed a high-fat diet (HFD) with those fed a normal diet (ND), we observed in HFD epididymal AT induction and infiltration of activated T cells, an accumulation and polarization of macrophages, and an increase in populations of activated CD4+ T cells and CD8+ T cells that express CXCR3 or killer cell lectin-like receptor subfamily G member 1 (KLRG1). Levels of inflammatory cytokines and leptin and the results of in vitro co-culture experiments revealed interactions among HFD- and ND-induced CD8+ T cells, macrophages, and adipocytes. Our findings suggest that obese tissues activate and induce both CD4+ and CD8+ CD69+ T cells and augment the expression of CXCR3 receptors, which promotes the recruitment and numbers of pro-inflammatory M1 macrophages to maintain low-grade chronic inflammation. The results support the hypothesis that CXCR3-expressing CD8+T cells play an essential role in the initiation and maintenance of adipose tissue inflammation.

The link between obesity and puberty: what is new?

The objective of this review is to assess the most recent literature on pubertal trends in boys and girls as well as evaluate genetic, epigenetic, and environmental factors implicated in the timing of pubertal progression. Recent studies confirm the previously described link between increased adiposity and earlier onset of puberty in girls, and more recent studies shed light onto the previously unclear situation in boys as a preponderance of recent longitudinal studies suggests that increased adiposity is linked with earlier pubertal timing also in boys. Discoveries of novel pathways highlights the complexity of pubertal development and suggest mechanistic links between nutrition, obesity, leptin, insulin resistance, and puberty. Furthermore, genetic and epigenetic variants can be linked to early puberty. Other factors, such as prenatal and postnatal environment, gut microbiota, and endocrine-disrupting chemicals have also been linked to both obesity and earlier puberty. Understanding how the interactions of these factors contribute the relationship between obesity and early pubertal onset is crucial as early puberty has been linked with long-term consequences, such as short stature, earlier type 2 diabetes, cardiovascular disease, and poor psychological and behavioral outcomes.

Implication of Heterozygous Variants in Genes of the Leptin-Melanocortin Pathway in Severe Obesity.

Unlike homozygous variants, the implication of heterozygous variants on the leptin-melanocortin pathway in severe obesity has not been established. To describe the frequency, the phenotype, and the genotype-phenotype relationship for heterozygous variants in LEP, LEPR, POMC, and PCSK1 in severe obesity. In this retrospective study, genotyping was performed on at least 1 of the LEP, LEPR, POMC, and PCSK1 genes in 1486 probands with severe obesity (600 children, 886 adults). The phenotype was collected in 60 subjects with heterozygous variants and 16 with homozygous variants. We analyzed variant frequency, body mass index (BMI), age of obesity onset, food impulsivity, and endocrine abnormalities. The frequency of subjects with homozygous variants was 1.7% (n = 26), and 6.7% (n = 100) with heterozygous variants. Adults with homozygous variants had a higher BMI (66 vs 53 kg/m2, P = .015), an earlier onset of obesity (0.4 vs 5.4 years, P < .001), more often food impulsivity (83% vs 42%, P = .04), and endocrine abnormalities (75% vs 26%, P < .01). The BMI was higher for subjects with high-impact heterozygous variants (61 vs 50 kg/m², P = .045) and those with a second heterozygous variant on the pathway (65 vs 49 kg/m², P < .01). In children, no significant differences were found for the age of obesity onset and BMI. Heterozygous variants in LEP, LEPR, POMC, and PCSK1 are frequent in severe obesity and sometimes associated with a phenotype close to that of homozygotes. These data suggest a systematic search for variants in severe early-onset obesity, to discuss therapy that targets this key pathway.

DDB1 binds histone reader BRWD3 to activate the transcriptional cascade in adipogenesis and promote onset of obesity.

Obesity has become a global pandemic. Identification of key factors in adipogenesis helps to tackle obesity and related metabolic diseases. Here, we show that DDB1 binds the histone reader BRWD3 to promote adipogenesis and diet-induced obesity. Although typically recognized as a component of the CUL4-RING E3 ubiquitin ligase complex, DDB1 stimulates adipogenesis independently of CUL4. A DDB1 mutant that does not bind CUL4A or CUL4B fully restores adipogenesis in DDB1-deficient cells. Ddb1+/- mice show delayed postnatal development of white adipose tissues and are protected from diet-induced obesity. Mechanistically, by interacting with BRWD3, DDB1 is recruited to acetylated histones in the proximal promoters of ELK1 downstream immediate early response genes and facilitates the release of paused RNA polymerase II, thereby activating the transcriptional cascade in adipogenesis. Our findings have uncovered a CUL4-independent function of DDB1 in promoting the transcriptional cascade of adipogenesis, development of adipose tissues, and onset of obesity.

119-OR: Ankyrin-B Modulates Lipid Metabolism in Brown Adipocytes

Human variants in the membrane adaptor ankyrin-B (AnkB) present at frequencies from 0.05 to 7% across different ethnicities have been linked to obesity and type 2 diabetes (T2D). We reported that knock-in mice bearing T2D-linked human AnkB variants develop age- or diet-dependent obesity and insulin resistance (IR). We also found that conditional loss of AnkB in both white (WAT) and brown (BAT) adipose tissue (AT) in mice (AT-AnkB KO) results in age-dependent obesity with WAT hypertrophy, lipotoxicity, systemic inflammation, and IR. We delineated that defects in the internalization of the glucose transporter GLUT4 in WAT, which resulted from deficits in AnkB, caused cell-autonomous WAT hyperplasia and ectopic lipid deposition in peripheral tissues. AT-AnkB KO mice also exhibit lower energy expenditure (EE) before the onset of obesity, which is concomitant with reduced BAT mitochondrial content and brown adipocyte whitening. However, whether primary BAT dysfunction caused by AnkB deficits contribute to metabolic syndrome in these mice and the roles of AnkB in BAT is unknown. Here, we present evidence of a cell-autonomous role of AnkB in lipid metabolism in brown adipocytes. Histological and electron microscopy analyses suggest that conditional AnkB loss in BAT of non-obese mice (BAT-AnkB KO) causes lipid accumulation in BAT characterized by an increase in surface area covered by lipid droplets, a shift towards larger lipid droplets, and a corresponding decrease in mitochondrial content. Differentiated brown adipocytes from mice with total AnkB deficiency (AnkB KO) or from BAT-AnkB KO mice phenocopy the in vivo changes in lipid and mitochondria content, which corresponds with changes in associated gene expression. We will discuss our latest results combining physiology, transcriptomic, proteomic, and cellular analysis that shed light into the pathways modulated by AnkB in BAT and their contribution to systemic metabolic regulation. Disclosure A. Aguillard: None. J. Tzeng: None. D. Lorenzo: None. Funding National Institutes of Health (3P30DK072476-13S1)

202-OR: Cell-Autonomous Impairment of BCAA Catabolism in White Adipocytes Leads to Systemic Metabolic Dysregulation

Increased levels of serum branched-chain amino acids (BCAA) is associated with obesity, insulin resistance (IR), and type 2 diabetes (T2D). However, the mechanisms that trigger perturbations in BCAA homeostasis, and whether elevated BCAA causes obesity and other metabolic impairments or is a consequence of them is not clear. Young knock-in mice bearing the human T2D-linked R1788W variant in the cytoskeletal protein ankyrin-B (AnkB) show normal body weight and composition. These mice display increased glucose uptake by white adipose tissue (WAT) due to deficient internalization of the glucose transporter GLUT4. We reported that sustained elevation in glucose disposal in WAT leads to the onset of increased adiposity, lipotoxicity, systemic inflammation, and IR in AnkB mutant mice with age or in young animals fed Western diets. Non-obese R1788W AnkB mice also exhibit transcriptional changes consistent with lower BCAA catabolism in WAT. Here, we show that AnkB deficits impair BCAA catabolism in WAT prior to the onset of obesity. Lean R1788W AnkB mice show reduction in surface levels of the BCAA transporter Asct2 and BCAA uptake together with downregulation of BCAA catabolic enzymes in WAT. These deficits are concomitant with elevations in serum levels of BCAA and related acylcarnitines. Reduced expression of BCAA catabolic enzymes was also observed in WAT of lean WAT-specific AnkB KO mice. In contrast, AnkB deficiency did not alter BCAA oxidation in skeletal muscle (SKM), brown adipose tissue, or liver. Studies in control and R1788W AnkB mice fed isocaloric low and high fat (HFD) diets enriched in BCAA suggest that BCAA elevation triggers mitochondrial dysfunction, impairments in insulin secretion by the pancreas and in insulin signaling in SKM. Our data indicates that elevated circulating BCAA impair glucose tolerance and insulin sensitivity independently of obesity, and that these deleterious effects are potentiated by HFD. Disclosure J. Tzeng: None. A. Aguillard: None. D. Lorenzo: None. Funding American Diabetes Association (1-19-JDF-081 to D.L.)

Is resistin the master link between inflammation and inflammation-related chronic diseases?

Resistin has been firstly discovered in mice and was identified as an adipose tissue-secreted hormone or adipokine linking obesity and insulin resistance. In humans, resistin has been characterized as a hormone expressed and secreted by Immune cells especially by macrophages, and was linked to many inflammatory responses including inflammation of adipose tissue due to macrophages’ infiltration. Human and mouse resistin display sequence and structural similarities and also dissimilarities that could explain their different expression pattern. In mice, strong pieces of evidence clearly associated high resistin plasma levels to obesity and insulin resistance suggesting that resistin could play an important role in the onset and progression of obesity and insulin resistance via resistin-induced inflammation. In humans, the link between resistin and obesity/insulin resistance is still a matter of debate and needs more epidemiological studies. Also, resistin has been linked to other chronic diseases such as cardiovascular diseases and cancers where resistin has been proposed in many studies as a biological marker.

High-fat diet and dyslipidemia synergistically contribute to T cell senescence in gut associated lymphoid tissue.

Obesity can compromise immune response and immune surveillance. Recent studies have linked obesity with systemic T cell senescence and thymus involution. However, these studies failed to distinguish the influence of obesity from the influence of diet composition on premature T cell senescence. High-fat diet (HFD) can influence the immunity of gut-associated lymphoid tissue (GALT) preceding the onset of obesity. Despite GALT is sensitive to the changes in the dietary composition and metabolic status, it still remains elusive how HFD and obesity contribute to T cell senescence in the GALT. In this study, we illustrated the interplay of the HFD, obesity and intestinal immunity by comparing the immune features of diet-induced obese (DIO) to those of diet-resistant (DR) mice. As expected, DIO mice exhibited increased serum lipid levels and liver steatosis whereas dyslipidemia was absent in DR mice. DIO mice demonstrated a shift from naïve to effector-memory (EM) phenotype in the T cells derived from the spleens and PPs. Moreover, DIO mice showed up-regulation of PD1 and KLRG1 on the T cells. Similar but mild trends were observed in the naïve and EM T cells from DR mice. Furthermore, we proved that the senescent-like changes in splenic and PPs-derived T cells positively correlated with the serum lipid concentrations. Taken together, our results indicate that HFD components function synergistically with dyslipidemia to induce T cell senescence in the GALT.

BACE2 suppression in mice aggravates the adverse metabolic consequences of an obesogenic diet

ObjectivePancreatic β-cell dysfunction is a central feature in the pathogenesis of type 2 diabetes (T2D). Accumulating evidence indicates that β-site APP-cleaving enzyme 2 (BACE2) inhibition exerts a beneficial effect on β-cells in different models of T2D. Thus, targeting BACE2 may represent a potential therapeutic strategy for the treatment of this disease. Here, we aimed to investigate the effects of BACE2 suppression on glucose homeostasis in a model of diet-induced obesity. MethodsBACE2 knock-out (BKO) and wild-type (WT) mice were fed with a high-fat diet (HFD) for 2 or 16 weeks. Body weight, food intake, respiratory exchange ratio, locomotor activity, and energy expenditure were determined. Glucose homeostasis was evaluated by glucose and insulin tolerance tests. β-cell proliferation was assessed by Ki67-positive nuclei, and β-cell function was determined by measuring glucose-stimulated insulin secretion. Leptin sensitivity was evaluated by quantifying food intake and body weight after an intraperitoneal leptin injection. Neuropeptide gene expression and insulin signaling in the mediobasal hypothalamus were determined by qPCR and Akt phosphorylation, respectively. ResultsAfter 16 weeks of HFD feeding, BKO mice exhibited an exacerbated body weight gain and hyperphagia, in comparison to WT littermates. Glucose tolerance was similar in both groups, whereas HFD-induced hyperinsulinemia, insulin resistance, and β-cell expansion were more pronounced in BKO mice. In turn, leptin-induced food intake inhibition and hypothalamic insulin signaling were impaired in BKO mice, regardless of the diet, in accordance with deregulation of the expression of hypothalamic neuropeptide genes. Importantly, BKO mice already showed increased β-cell proliferation and glucose-stimulated insulin secretion with respect to WT littermates after two weeks of HFD feeding, before the onset of obesity. ConclusionsCollectively, these results reveal that BACE2 suppression in an obesogenic setting leads to exacerbated body weight gain, hyperinsulinemia, and insulin resistance. Thus, we conclude that inhibition of BACE2 may aggravate the adverse metabolic effects associated with obesity.

Pairing Binge Drinking and a High-Fat Diet in Adolescence Modulates the Inflammatory Effects of Subsequent Alcohol Consumption in Mice.

Alcohol binge drinking (BD) and poor nutritional habits are two frequent behaviors among many adolescents that alter gut microbiota in a pro-inflammatory direction. Dysbiotic changes in the gut microbiome are observed after alcohol and high-fat diet (HFD) consumption, even before obesity onset. In this study, we investigate the neuroinflammatory response of adolescent BD when combined with a continuous or intermittent HFD and its effects on adult ethanol consumption by using a self-administration (SA) paradigm in mice. The inflammatory biomarkers IL-6 and CX3CL1 were measured in the striatum 24 h after BD, 3 weeks later and after the ethanol (EtOH) SA. Adolescent BD increased alcohol consumption in the oral SA and caused a greater motivation to seek the substance. Likewise, mice with intermittent access to HFD exhibited higher EtOH consumption, while the opposite effect was found in mice with continuous HFD access. Biochemical analyses showed that after BD and three weeks later, striatal levels of IL-6 and CX3CL1 were increased. In addition, in saline-treated mice, CX3CL1 was increased after continuous access to HFD. After oral SA procedure, striatal IL-6 was increased only in animals exposed to BD and HFD. In addition, striatal CX3CL1 levels were increased in all BD- and HFD-exposed groups. Overall, our findings show that adolescent BD and intermittent HFD increase adult alcohol intake and point to neuroinflammation as an important mechanism modulating this interaction.

Eating Speed, Eating Frequency, and Their Relationships with Diet Quality, Adiposity, and Metabolic Syndrome, or Its Components.

Excess body weight is a major global health concern, particularly due to its associated increased health risks. Several strategies have been proposed to prevent overweight and obesity onset. In the past decade, it has been suggested that eating speed/rate and eating frequency might be related to obesity. The main aim of this narrative review was to summarize existing evidence regarding the impact of eating speed/rate and eating frequency on adiposity, metabolic syndrome (MetS), or diet quality (DQ). For this purpose, a literature search of observational and interventional trials was conducted between June and September 2020 in PubMed and Web of Sciences databases, without any data filters and no limitations for publication date. Results suggest that children and adults with a faster eating speed/rate may be associated with a higher risk of developing adiposity, MetS or its components. Furthermore, a higher eating frequency could be associated with diet quality improvement, lower adiposity, and lower risk of developing MetS or its components. Further interventional trials are warranted to clarify the mechanism by which these eating behaviors might have a potential impact on health.

The Absence of Cortisol Awakening Response Is Associated With Personality Traits in Bariatric Women

Abstract Background: There is a large body of evidence linking obesity to the HPA axis and cortisol secretion or metabolism. Early work hypothesized that obesity onset may be associated with over-activation of the HPA axis, causing an extenuation of the system. The cortisol awakening response (CAR) has been suggested to be a reliable marker of HPA axis activity and has already been examined in samples of individuals with obesity. Our objective was to compare individuals showing a morning cortisol peak (CAR responders) from those who did not (non-responders) and identify possible metabolic or psychological differences among these two groups. Our hypothesis was that the two groups differed in the level of anxiety and aspects of their personality rather than in their metabolic profile. Methods: CAR response was determined using a baseline to peak cut-off of 2.5 nM. Nine CAR non-responder women awaiting bariatric surgery (BMI: 50.8 ± 4.6 kg/m2) were compared to 9 sex- and age-matched CAR responders (BMI: 48.1 ± 5.9 kg/m2). Participants collected salivary cortisol upon awakening as well as 15, 30 minutes after and responded to psychological questionnaires that measured anxiety (State and trait anxiety inventory questionnaire) and personality traits (Temperament and character inventory). Results: Non-responders were all non-diabetic women aged 37 ± 8 years. There was no significant difference between CAR responders and non-responders in terms of BMI or waist circumference. No difference was found in metabolic variables such as glycaemia or the lipid profile. As expected, non-responders had a significantly lower CAR AUCi when compared to responders (p&amp;lt;0.001). However there was no difference in awakening cortisol concentration. Despite our hypothesis, no significant difference was found in general level of anxiety between the two groups. Finally, we analyzed aspects of human personality. We found that CAR responders scored significantly higher in character traits such as self-directedness (p=0.02), cooperativeness (p=0.03) and self-transcendence (p&amp;lt;0.01). Conclusion: The CAR differences in women with severe obesity are not associated with adiposity. Our data show that non-responders exhibit traits related to reduced self-determination and responsibility but also lower level of self-consciousness and helpfulness, which could be associated with a reduction in patient compliance and possibly less weight loss after surgery.

Serotonin as a Regulator of Leptin-Mediated Food Intake Control Within a Novel Neuronal Circuit Between the Hypothalamus and Raphe Nuclei

The onset and exacerbation of obesity involves the overproduction of the adipocyte-derived hormone leptin, a key mediator of homeostatic appetite regulation and a signal for satiety. Although leptin’s hypothalamic regulation of food intake has been extensively investigated, its role in tandem with the anorectic neurotransmitter serotonin (5-HT) has been less characterized. 5-HT is synthesized in the dorsal raphe nucleus (DRN) where anatomical projections to many hypothalamic nuclei have previously been identified. Preliminary studies in our lab have: (1) identified serotonergic neurons responsive to leptin in the DRN that project to the arcuate nucleus (ARC) of the hypothalamus and (2) demonstrated leptin injected into the DRN significantly decreases food intake. The objective of the current study was to identify the role of 5-HT in leptin’s regulation of food intake first within the DRN, then between the DRN and the ARC. Adult male Sprague Dawley rats underwent stereotaxic surgery for guide cannula implantation in the DRN. After recovery, animals were administered 100 µg of p-chlorophenylalanine (PCPA), an inhibitor of 5-HT synthesis, in the DRN each day for four days. On the fourth day, leptin was also administered in the DRN (5 µg/rat) and food intake was measured over a 24-hour time course. ANOVA analysis revealed a significant difference in 24-hour food intake [F (3, 18) = 3.972; P = 0.0246] and post-hoc analysis showed that animals treated with leptin significantly decreased food intake (17.2 ± 2.0 g) compared to control rats (25.4 ± 0.9 g), whereas PCPA-treated rats did not differ from the control rats, suggesting that depletion of 5-HT attenuated leptin’s ability to regulate food intake within the DRN. To examine the role of 5-HT on leptin’s hypothalamic action, a subsequent experiment was conducted by implanting an additional cannula into the ARC for the administration of leptin or vehicle on the fourth day of treatment. ANOVA analysis revealed a significant difference in 24-hour food intake [F (3, 16) = 5.998; P = 0.0061] and post-hoc analysis showed that only rats treated with leptin in the ARC significantly decreased food intake (14.0 ± 1.5 g) compared to controls (21.8 ± 0.5 g). 5-HT depletion was assessed post-mortem using immunohistochemistry and was later quantified. Collectively, these results demonstrate that leptin’s ability to regulate food intake is dependent on 5-HT, regardless of the area of regulation (i.e. DRN or the hypothalamus).

Identification of Key Genes and Pathways for Childhood Obesity Using System Biology Approach Based on Comprehensive Gene Information

Introduction: Childhood obesity is one of the most important public health issues of the 21st century. Epidemiological studies have suggested that obesity during childhood increases the risk of developing comorbidities, such as type 2 diabetes, later in life. Childhood obesity is a complex disease whose molecular mechanisms are not completely elucidated. In this context, a system biology approach could contribute to the scientific knowledge regarding genetic factors related to childhood obesity onset. Aim: To identify molecular mechanisms involved in childhood obesity by implementing a system biology approach. Methods: Experimentally validated and computationally predicted genes related to Pediatric Obesity (C2362324) were downloaded from the DisGeNET v7.0 database. The protein-protein interaction (PPI) network was constructed using the STRING v11.0 database and analyzed using NetworkAnalyst v3.0 and Cytoscape v3.8.1. The relevance of each node for the network structure and functionality was assessed using the degree method to define hub genes. Functional and pathway enrichment analyses were performed based on Gene Ontology (GO) terms and KEGG Pathways. Results: The search on the DisGeNET database retrieved 191 childhood obesity-related genes. The PPI network of these genes showed 19 hub genes (STAT3, SIRT1, BCL2, IRS1, PPARG, SOCS3, TGFB1, HDAC4, DNMT1, ADCY3, PPARA, NEDD4L, ACACB, NR0B2, VEGFA, APOA1, GHR, CALR, and MKKS). These hub genes were involved in biological processes of lipid storage / kinase activity, regulation of fatty-acid metabolic processes, regulation of pri-miRNA transcription by RNA polymerase II, and negative regulation of small molecules and carbohydrate metabolic processes. In terms of molecular functions, repressing of transcription factors biding was found enriched. Regarding KEGG Pathways, the hub genes are involved with adipocytokine signaling, insulin resistance, longevity regulation, and cytokine signaling pathways. Conclusion: Our approach identified 19 hub genes, which are highly connected and probably have a key role in childhood obesity. Moreover, functional enrichment analyses demonstrated they are enriched in several biological processes and pathways related to the underlying molecular mechanisms of obesity. These findings provide a more comprehensive information regarding genetic and molecular factors behind childhood obesity pathogenesis. Further experimental investigation of our findings may shed light on the pathophysiology of this disease and contribute to the identification of new therapeutic targets.

Lrg1 is a Driver of Brown Adipose Tissue Dysfunction in Obesity

Background Energy is stored as lipid within white adipose tissue (WAT) however, over-nutrition can lead to excess WAT, obesity and metabolic disease. Brown adipose tissue (BAT) has a primary role in energy expenditure through futile cycling of the electron transport chain (ETC) to generate heat. BATs heat producing capacity may be a novel approach to treating obesity. Adult humans possess metabolically active BAT, but the onset of obesity can reduce BAT thermogenic activity and mass. Obesity can bring about morphological changes to BAT, causing BAT to resemble WAT in a process termed “whitening”. WAT is a well-known endocrine organ. Specific endocrine signals from WAT could be responsible for reduced BAT activity in obesity. Leucine-rich-α2-glycoprotein 1 (LRG1) is an adipose-associated secretory protein and potential adipokine, with plasma levels positively correlated to body mass index in humans. Hypothesis It is hypothesized that LRG1 is an adipokine which negatively regulates thermogenesis in BAT and contributes to obesity related loss of BAT. Methods Male Lrg1 global knockout (KO) mice or wild type (WT) controls were fed standard chow (STD) or high fat diet (HFD) for 10 weeks. At 18 weeks of age systemic and BAT metabolic characteristics were determined by whole body indirect calorimetry, high-resolution tissue respirometry, quantitative PCR and immunoblots. Results After 10 weeks of HFD feeding Lrg1 KO mice fed STD and HFD had significantly higher percentage of body mass comprised of BAT than WT controls (Figure 1A). Lrg1 KO mice fed HFD had a lower respiratory exchange ratio (RER), indicating a greater use of fat oxidation compared to WT controls (Figure 1B). Mitochondrial respiration was used to measure changes in cellular energy. In response to HFD WT mice exhibit a decrease in mitochondrial respiration through complex 1 of the electron transport chain (ETC) (Figure 2A). The mitochondrial function of Lrg1 KO mice BAT is protected from HFD-induced dysfunction at Complex 1 of the ETC (Figure 2A). Uncoupling protein 1 (UCP1), a key protein involved in thermogenesis, Ucp1 mRNA is significantly increased in the BAT of Lrg1 KO STD and HFD fed mice compared to WT (Figure 2B). Ucp1 mRNA expression increase in Lrg1 KO mice was confirmed by measuring UCP1 protein with an immunoblot (Figure 2C). Conclusion Loss of Lrg1 protects BAT from dysfunction in diet-induced obesity.

High‐fat diet alters body composition and serum cytokines before the overt onset of obesity

Rising trends in childhood obesity are related, in part, to increased dietary fat intake. Accelerated bone growth, a hallmark of juvenile obesity but one of its most overlooked complications, can lead to irreversible skeletal damage and chronic adult disability. Paradoxically, obese children typically have low to normal levels of the growth promoting hormone insulin-like growth factor-1 (IGF-1), despite their accelerated growth rate. Obesity is characterized by chronic inflammation driven by cytokines such as interleukin-6 (IL-6) which can suppress bone elongation by inhibiting IGF-1. We previously found that a high-fat diet increases bone growth and alters serum cytokines in young male and female mice before significant changes in body mass were evident. Our goal here was to determine whether excess body fat could explain the increase in bone elongation rate when overall body mass remains similar. We tested the hypothesis that mice on a high-fat diet exhibit changes in body composition along with higher levels of inflammatory cytokines before they develop overt obesity. Methods Male 3-week-old C57BL/6 mice (N=6/diet) were put on high-fat (60% kCal fat) or control (10% kCal fat) diet for 2 weeks after weaning. Serum cytokines (Leptin, TNF-α, IGF-1, IL-6, VEGF, IL-1α, IL-1β, MCP-1) were measured by ELISA. Skinfold thickness in the rump region was measured in a separate group of mice using a dial micrometer to estimate body fat. Statistical significance (p<0.05) was determined in SPSS using Mann-Whitney and t-tests. Results After only 2 weeks, tibial elongation rate was over 10% higher in mice on a high-fat diet (t=2.1, p<0.05), but had no difference in body mass (t=0.5, p=0.62). Among the cytokines measured, TNF-α (z=2.9, p<0.01) and IL-6 (z=2.7, p<0.01) were both decreased in the high-fat diet group, while VEGF (z=2.7, p<0.01) was increased. Rump skinfold was nearly 7% greater (t=2.6, p<0.05) in the high-fat diet group, indicating a higher proportion of body fat. Discussion Our results support the hypothesis that a high-fat diet alters body composition and inflammatory cytokines before overt signs of obesity. Unexpectedly, the most robust change was a 1.5-fold decrease in IL-6, rather than the increase that we had predicted. Since elevated levels of IL-6 suppress growth, our findings of decreased IL-6 are consistent with accelerated bone lengthening. IL-6 also has a role in energy metabolism, and so the changes in body composition that we observed (increased subcutaneous fat) might play a role in altering serum cytokines. Significance These results are relevant for understanding the development of obesity-related skeletal complications. Reduced inflammatory cytokines such as IL-6 could serve as a useful biomarker of potential adverse effects, providing the opportunity to implement interventions to mitigate long-term skeletal damage before it might otherwise be recognized.

Brown Adipose Tissue: New Challenges for Prevention of Childhood Obesity. A Narrative Review.

Pediatric obesity remains a challenge in modern society. Recently, research has focused on the role of the brown adipose tissue (BAT) as a potential target of intervention. In this review, we revised preclinical and clinical works on factors that may promote BAT or browning of white adipose tissue (WAT) from fetal age to adolescence. Maternal lifestyle, type of breastfeeding and healthy microbiota can affect the thermogenic activity of BAT. Environmental factors such as exposure to cold or physical activity also play a role in promoting and activating BAT. Most of the evidence is preclinical, although in clinic there is some evidence on the role of omega-3 PUFAs (EPA and DHA) supplementation on BAT activation. Clinical studies are needed to dissect the early factors and their modulation to allow proper BAT development and functions and to prevent onset of childhood obesity.

Precision nutrition based on phenotypical traits and the (epi)genotype: nutrigenetic and nutrigenomic approaches for obesity care.

The purpose of this article is to rationally review and critically appraise the current knowledge in the most relevant nongenetic and genetic factors influencing obesity predisposition. This information may be translated into the implementation of personalized nutrition approaches involving precision nutrigenetic and nutrigenomic strategies for obesity monitoring and weight management. The importance and influence of several nongenetic contributors to obesity onset and individual responses to weight-loss interventions have been highlighted including the role of age, sex or perinatal feeding and others related to an individual's lifestyle and modifiable. Nutrigenetic studies have analysed potential interactions between polymorphisms influencing energy homeostasis/body composition and dietary factors in relation to adiposity phenotypes and therapy responsiveness. A second approach comprises the Nutrigenomic analysis of gene expression modifications in response to the consumption of specific nutrients or dietary bioactive compounds, which may involve epigenetic mechanisms including deoxyribonucleic acid methylation and micro-ribonucleic acid expression profiles. Taken together, these findings encompass the importance of taking into account up-to-date advances in Nutrigenetic and Nutrigenomic hallmarks, globally analysing the risk of weight gain and related outcomes after following nutrition counselling, this contributing to improve obesity care considering phenotypical traits and the genetic make-up for precision obesity care.