Genetic Studies of Leptin Concentrations Implicate Leptin in the Regulation of Early Adiposity.
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ABSTRACT:
SUBMITTER: Yaghootkar H
PROVIDER: S-EPMC7679778 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:ContextThere is evidence that leptin is involved in the etiology of obesity-related cardiovascular disease in adults. This raises the question of whether leptin levels in adolescence are indicative of adiposity-related cardiovascular risk.ObjectiveThis study investigated gender-specific patterns of plasma leptin during adolescence, assessed which adiposity measurements are most strongly associated with plasma leptin, and estimated to what degree leptin-adiposity associations are influenced by genetic factors.MethodsPlasma leptin concentrations were determined using a sandwich immunoassay. Associations between plasma leptin and several adiposity measurements were examined using generalized estimating equations. Genetic contribution to leptin-adiposity association was estimated by Cholesky decomposition models using twin design.ResultsPlasma leptin levels were higher in females than males at all Tanner stages. In females, body mass index, waist circumference, fat mass index (FMI), and percentage body fat (%BF) had similar associations with leptin levels. In males, %BF and FMI were more strongly associated with leptin levels than body mass index and waist circumference. In both males and females, percentage trunk fat had the weakest association with leptin among the five adiposity measures. Shared genetic factors account for more than 80% of the phenotypic correlation between %BF and leptin.ConclusionsWe found gender differences in leptin levels and leptin-adiposity associations. In both genders, leptin levels were strongly associated with %BF and FMI, particularly in males. Shared genetic factors contributed largely to the phenotypic correlation between leptin and %BF. Our findings underscored the importance of further investigation of leptin as a biomarker of adiposity in adolescents.
| S-EPMC2741718 | biostudies-literature
Project description:Mice lacking the RIIβ regulatory subunit of cyclic AMP-dependent protein kinase A (PKA) display reduced adiposity and resistance to diet-induced obesity. Here we show that RIIβ knockout (KO) mice have enhanced sensitivity to leptin's effects on both feeding and energy metabolism. After administration of a low dose of leptin, the duration of hypothalamic JAK/STAT3 signalling is increased, resulting in enhanced POMC mRNA induction. Consistent with the extended JAK/STAT3 activation, we find that the negative feedback regulator of leptin receptor signalling, Socs3, is inhibited in the hypothalamus of RIIβ KO mice. During fasting, RIIβ-PKA is activated and this correlates with an increase in CREB phosphorylation. The increase in CREB phosphorylation is absent in the fasted RIIβ KO hypothalamus. Selective inhibition of PKA activity in AgRP neurons partially recapitulates the leanness and resistance to diet-induced obesity of RIIβ KO mice. Our findings suggest that RIIβ-PKA modulates the duration of leptin receptor signalling and therefore the magnitude of the catabolic response to leptin.
| S-EPMC4576457 | biostudies-literature
Project description:BACKGROUND: Although leptin, an adipocyte derived hormone which regulates food intake and energy balance, is released after injections of tumour necrosis factor (TNF) and interleukin 1, plasma concentrations have not been characterised in chronic inflammation. Leptin may contribute to the anorexia and body weight loss associated particularly with the acute stages of inflammatory bowel disease. AIMS: To investigate plasma leptin concentrations during the time course of intestinal inflammation in different animal models. METHODS: Plasma leptin was measured at different time points in rats with trinitrobenzene sulphonic acid (TNBS) induced colitis, indomethacin induced ileitis, or endotoxic shock caused by lipopolysaccharide (LPS). Systemic TNF-alpha was also measured during acute inflammation. RESULTS: Plasma leptin concentrations increased fourfold eight hours after induction of TNBS colitis (p<0.0001) and twofold after administration of ethanol alone (p<0.02). Plasma leptin responses throughout the first post-treatment day were correlated with myeloperoxidase activity and gross damage scores. Similar leptin overexpression was observed in indomethacin induced ileitis and in rats with endotoxic shock. Plasma concentrations were lower in TNBS treated rats than in controls on day 5 before reaching a similar concentration on day 14. Anorexia and body weight loss were observed during the first four days post-TNBS. A significant increase in systemic TNF-alpha was only detected in LPS treated rats. CONCLUSION: Elevated plasma leptin concentrations, correlated with the degree of inflammation and associated with anorexia, were induced in rats during the early stages of experimental intestinal inflammation but proved transient; this might account for discrepancies in recent results concerning concentrations in patients with inflammatory bowel diseases.
| S-EPMC1727345 | biostudies-other
Project description:Kidney cancers often delete chromosome 3p, spanning the VHL tumor suppressor gene, and chromosome 14q, which presumably harbors ? 1 tumor suppressor genes. pVHL inhibits the hypoxia-inducible transcription factor (HIF), and HIF2? is a kidney cancer oncoprotein. In this article, we identify focal, homozygous deletions of the HIF1? locus on 14q in clear cell renal carcinoma cell lines. Wild-type HIF1? suppresses renal carcinoma growth, but the products of these altered loci do not. Conversely, downregulation of HIF1? in HIF1?-proficient lines promotes tumor growth. HIF1? activity is diminished in 14q-deleted kidney cancers, and all somatic HIF1? mutations identified in kidney cancers tested to date are loss of function. Therefore, HIF1? has the credentials of a kidney cancer suppressor gene.Deletion of 14q is a frequent event in clear cell renal carcinoma and portends a poor prognosis. In this study, we provide genetic and functional evidence that HIF1? is a target of 14q loss in kidney cancer.
| S-EPMC3202343 | biostudies-literature
Project description:OBJECTIVE: Pigment epithelium-derived factor (PEDF) belongs to the serpin family of peptidase inhibitors (serpin F1) and is among the most abundant glycoproteins secreted by adipocytes. In vitro and mouse in vivo data revealed PEDF as a candidate mediator of obesity-induced insulin resistance. Therefore, we assessed whether common genetic variation within the SERPINF1 locus contributes to adipose tissue-related prediabetic phenotypes in humans. SUBJECTS/METHODS: A population of 1,974 White European individuals at increased risk for type 2 diabetes was characterized by an oral glucose tolerance test with glucose and insulin measurements (1,409 leptin measurements) and genotyped for five tagging SNPs covering 100% of common genetic variation (minor allele frequency ? 0.05) in the SERPINF1 locus. In addition, a subgroup of 486 subjects underwent a hyperinsulinaemic-euglycaemic clamp and a subgroup of 340 magnetic resonance imaging (MRI) and spectroscopy (MRS). RESULTS: After adjustment for gender and age and Bonferroni correction for the number of SNPs tested, SNP rs12603825 revealed significant association with MRI-derived total adipose tissue mass (p?=?0.0094) and fasting leptin concentrations (p?=?0.0035) as well as nominal associations with bioelectrical impedance-derived percentage of body fat (p?=?0.0182) and clamp-derived insulin sensitivity (p?=?0.0251). The association with insulin sensitivity was completely abolished by additional adjustment for body fat (p?=?0.8). Moreover, the fat mass-increasing allele of SNP rs12603825 was significantly associated with elevated fasting PEDF concentrations (p?=?0.0436), and the PEDF levels were robustly and positively associated with all body fat parameters measured and with fasting leptin concentrations (p<0.0001, all). CONCLUSION: In humans at increased risk for type 2 diabetes, a functional common genetic variant in the gene locus encoding PEDF contributes to overall body adiposity, obesity-related insulin resistance, and circulating leptin levels.
| S-EPMC3311576 | biostudies-literature
Project description:BackgroundOrofacial clefts are the most common malformations of the head and neck, with a worldwide prevalence of 1 in 700 births. They are commonly divided into CL(P) and CP based on anatomic, genetic, and embryologic findings. A Nigerian craniofacial anomalies study (NigeriaCRAN) was set up in 2006 to investigate the role of gene-environment interaction in the origin of orofacial clefts in Nigeria.Subjects and methodsDNA isolated from saliva from Nigerian probands was used for genotype association studies and direct sequencing of cleft candidate genes: MSX1 , IRF6 , FOXE1, FGFR1 , FGFR2 , BMP4 , MAFB, ABCA4 , PAX7, and VAX1 , and the chromosome 8q region.ResultsA missense mutation A34G in MSX1 was observed in nine cases and four HapMap controls. No other apparent causative variations were identified. Deviation from Hardy Weinberg equilibrium (HWE) was observed in these cases (p = .00002). A significant difference was noted between the affected side for unilateral CL (p = .03) and bilateral clefts and between clefts on either side (p = .02). A significant gender difference was also observed for CP (p = .008).ConclusionsReplication of a mutation previously implicated in other populations suggests a role for the MSX1 A34G variant in the development of CL(P).
| S-EPMC3206991 | biostudies-literature
Project description:BackgroundPrevious longitudinal studies have shown inconsistent results regarding the influence of adipokines on changes in weight and body fat. We aimed to determine the predictive value of serum leptin, adiponectin, and their ratio on subsequent changes in obesity measures in children.MethodsTwo hundred forty-six obese and 532 nonobese children aged 6-11 years were remeasured for BMI and waist circumference after 6.4 ± 0.2 years. Z-score of BMI was used to standardize for age and sex. Obesity was defined using the international BMI cutoffs. Waist-to-height ratio (WHtR) was calculated to define central obesity using a boundary value of 0.5. Fasting serum leptin and adiponectin levels were measured at baseline.ResultsNewly identified obese children had significantly higher levels of leptin and leptin-to-adiponectin ratio than nonobese children. There were lower adiponectin levels in boys with persistent obesity versus those with transient obesity. After adjusting for age, Tanner stage, and corresponding adiposity measures at baseline, leptin levels and leptin-to-adiponectin ratio were positively associated with BMI Z-score gain in girls and WHtR gain in boys. An inverse association between leptin and BMI Z-score gain was detected in boys. Stratified analyses revealed significant associations only in the nonobese and prepubertal group. There were no significant associations between adiponectin and changes in obesity measures.ConclusionsHigh leptin levels and leptin-to-adiponectin ratio are sex-specific predictors of obesity measures gain in nonobese and prepubertal children. Body composition measurement is necessary to assess fat mass growth and distribution during childhood and adolescence.
| S-EPMC5444411 | biostudies-literature
Project description:Low birth weight and rapid postnatal weight gain are independent and additive risk factors for the subsequent development of metabolic disease. Despite an abundance of evidence for these associations, mechanistic data are lacking. The hormone leptin has received significant interest as a potential programming factor, because differences in the profile of leptin in early life have been associated with altered susceptibility to obesity. Whether leptin alone is a critical factor for programming obesity has, until now, remained unclear. Using the leptin-deficient ob/ob mouse, we show that low birth weight followed by rapid catch-up growth during lactation (recuperated offspring) leads to a persistent increase in body weight in adult life, both in wild-type and ob/ob animals. Furthermore, recuperated offspring are hyperphagic and epididymal fat pad weights are significantly increased, reflecting greater adiposity. These results show definitively that factors other than leptin are crucial in the programming of energy homeostasis in this model and are powerful enough to alter adiposity in a genetically obese strain.
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Project description:Obesity remains an unmet global health burden. Detrimental anatomical distribution of body fat is a major driver of obesity-mediated mortality risk and is demonstrably heritable. However, our understanding of the full genetic contribution to human adiposity is incomplete, as few studies measure adiposity directly. To address this, we impute whole-body imaging adiposity phenotypes in UK Biobank from the 4,366 directly measured participants onto the rest of the cohort, greatly increasing our discovery power. Using these imputed phenotypes in 392,535 participants yielded hundreds of genome-wide significant associations, six of which replicate in independent cohorts. The leading causal gene candidate, ADAMTS14, is further investigated in a mouse knockout model. Concordant with the human association data, the Adamts14-/- mice exhibit reduced adiposity and weight-gain under obesogenic conditions, alongside an improved metabolic rate and health. Thus, we show that phenotypic imputation at scale offers deeper biological insights into the genetics of human adiposity that could lead to therapeutic targets.
| S-EPMC9852585 | biostudies-literature
Project description:Leptin is an adipokine that is thought to be important in many inflammatory diseases, and is known to influence the function of several leukocyte types. However, no clear consensus is present regarding the responsiveness of neutrophils for this adipokine. In this study a 2D DIGE proteomics approach was used as an unbiased approach to identify leptin-induced effects on neutrophils. Additionally chemotaxis and survival experiments were performed to reproduce results from literature showing putative effects of leptin on these neutrophil responses. Leptin did not induce any significant changes in the proteome provided leptin was added at physiologically relevant concentrations (250 ng). Our leptin batches were biologically active as they induced proliferation in LeptinR expressing Ba/F3 cells. At high concentrations (25000 ng) leptin induced a change in neutrophil proteome. Seventeen differently regulated spots were identified of which twelve could be characterized by mass spectrometry. Two of these identified proteins, SerpinB1 and p40 phox, were chosen for further analysis but leptin-induced expression analyzed by western blot were highly variable. Additionally leptin also induced neutrophil survival at these high concentrations. No leptin-induced chemotaxis of human neutrophils was detected at any concentration. In conclusion, physiological concentrations of leptin do not affect neutrophils. High leptin concentrations induced survival and changes in the neutrophils proteome, but this was most likely mediated by an indirect effect. However, it cannot be ruled out that the effects were mediated by a yet not-identified leptin receptor on human neutrophils.
| S-EPMC3774682 | biostudies-literature