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A critical period for the trophic actions of leptin on AgRP neurons in the arcuate nucleus of the hypothalamus.
Kamitakahara A, Bouyer K, Wang CH, Simerly R
(2018) J Comp Neurol 526: 133-145
MeSH Terms: Age Factors, Agouti-Related Protein, Analysis of Variance, Animals, Animals, Newborn, Arcuate Nucleus of Hypothalamus, Axons, ELAV-Like Protein 3, Estrogen Receptor alpha, Female, Green Fluorescent Proteins, Integrases, Leptin, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Neurons, Neuropeptide Y, Receptors, Leptin, STAT3 Transcription Factor
Show Abstract · Added April 11, 2019
In the developing hypothalamus, the fat-derived hormone leptin stimulates the growth of axons from the arcuate nucleus of the hypothalamus (ARH) to other regions that control energy balance. These projections are significantly reduced in leptin deficient (Lep ) mice and this phenotype is largely rescued by neonatal leptin treatments. However, treatment of mature Lep mice is ineffective, suggesting that the trophic action of leptin is limited to a developmental critical period. To temporally delineate closure of this critical period for leptin-stimulated growth, we treated Lep mice with exogenous leptin during a variety of discrete time periods, and measured the density of Agouti-Related Peptide (AgRP) containing projections from the ARH to the ventral part of the dorsomedial nucleus of the hypothalamus (DMHv), and to the medial parvocellular part of the paraventricular nucleus (PVHmp). The results indicate that leptin loses its neurotrophic potential at or near postnatal day 28. The duration of leptin exposure appears to be important, with 9- or 11-day treatments found to be more effective than shorter (5-day) treatments. Furthermore, leptin treatment for 9 days or more was sufficient to restore AgRP innervation to both the PVHmp and DMHv in Lep females, but only to the DMHv in Lep males. Together, these findings reveal that the trophic actions of leptin are contingent upon timing and duration of leptin exposure, display both target and sex specificity, and that modulation of leptin-dependent circuit formation by each of these factors may carry enduring consequences for feeding behavior, metabolism, and obesity risk.
© 2017 Wiley Periodicals, Inc.
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MeSH Terms
What have we really learned about macrophage recruitment to adipose tissue?
Hasty AH, Gutierrez DA
(2014) Endocrinology 155: 12-4
MeSH Terms: Adipose Tissue, Animals, Bone Marrow, Gene Expression Regulation, Leptin, Male, Receptors, Leptin
Added May 20, 2014
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7 MeSH Terms
Molecular pathways: adiponectin and leptin signaling in cancer.
Vansaun MN
(2013) Clin Cancer Res 19: 1926-32
MeSH Terms: Adiponectin, Humans, Leptin, Models, Biological, Neoplasms, Receptors, Adiponectin, Receptors, Leptin, Signal Transduction
Show Abstract · Added May 9, 2014
The increasing percentage of obese individuals in the population and its independent association of increased risk for the development of cancer have heightened the necessity to understand the molecular mechanisms that underlie this connection. The deregulation of adipokines in the setting of obesity and their impact on cancer progression and metastasis is one such area of research. Adipokines are bioactive proteins that mediate metabolism, inflammation, angiogenesis, and proliferation. Altered levels of adipokines or their cognate receptors in cancers can ultimately lead to an imbalance in downstream molecular pathways. Discovery of adipokine receptors in various cancers has highlighted the potential for novel therapeutic targets. Leptin and adiponectin represent two adipokines that elicit generally opposing molecular effects. Epidemiologic studies have highlighted associations between increased serum leptin levels and increased tumor growth, whereas adiponectin exhibits an inverse correlation with cancer development. This review addresses the current level of understanding of molecular pathways activated by adiponectin and leptin to identify the areas of intervention and facilitate advancement in the field.
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8 MeSH Terms
Diabetes in Zucker diabetic fatty rat.
Shiota M, Printz RL
(2012) Methods Mol Biol 933: 103-23
MeSH Terms: Animals, Diabetes Complications, Diabetes Mellitus, Type 2, Disease Models, Animal, Glucose, Hyperglycemia, Insulin Resistance, Insulin-Secreting Cells, Male, Obesity, Phenotype, Rats, Rats, Zucker, Receptors, Leptin
Show Abstract · Added February 19, 2015
Male Zucker diabetic fatty fa/fa (ZDF) rats develop obesity and insulin resistance at a young age, and then with aging, progressively develop hyperglycemia. This hyperglycemia is associated with impaired pancreatic β-cell function, loss of pancreatic β-cell mass, and decreased responsiveness of liver and extrahepatic tissues to the actions of insulin and glucose. Of particular interest are the insights provided by studies of these animals into the mechanism behind the progressive impairment of carbohydrate metabolism. This feature among others, including the development of obesity- and hyperglycemia-related complications, is common between male ZDF rats and humans with type 2 diabetes associated with obesity. We discuss the diabetic features and complications found in ZDF rats and why these animals are widely used as a genetic model for obese type 2 diabetes.
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14 MeSH Terms
Ablation of leptin receptor-mediated ERK activation impairs host defense against Gram-negative pneumonia.
Mancuso P, Myers MG, Goel D, Serezani CH, O'Brien E, Goldberg J, Aronoff DM, Peters-Golden M
(2012) J Immunol 189: 867-75
MeSH Terms: Amino Acid Substitution, Animals, Cells, Cultured, Extracellular Signal-Regulated MAP Kinases, Female, Immunity, Innate, Klebsiella Infections, Klebsiella pneumoniae, Leucine, MAP Kinase Signaling System, Macrophages, Alveolar, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Pneumonia, Bacterial, Receptors, Leptin, Tyrosine
Show Abstract · Added May 4, 2017
The adipocyte-derived hormone leptin plays an important role in regulation of energy homeostasis and the innate immune response against bacterial infections. Leptin's actions are mediated by signaling events initiated by phosphorylation of tyrosine residues on the long form of the leptin receptor. We recently reported that disruption of leptin receptor-mediated STAT3 activation augmented host defense against pneumococcal pneumonia. In this report, we assessed leptin receptor-mediated ERK activation, a pathway that was ablated in the l/l mouse through a mutation of the tyrosine 985 residue in the leptin receptor, to determine its role in host defense against bacterial pneumonia in vivo and in alveolar macrophage (AM) antibacterial functions in vitro. l/l mice exhibited increased mortality and impaired pulmonary bacterial clearance after intratracheal challenge with Klebsiella pneumoniae. The synthesis of cysteinyl-leukotrienes was reduced and that of PGE(2) enhanced in AMs in vitro and the lungs of l/l mice after infection with K. pneumoniae in vivo. We also observed reduced phagocytosis and killing of K. pneumoniae in AMs from l/l mice that was associated with reduced reactive oxygen intermediate production in vitro. cAMP, known to suppress phagocytosis, bactericidal capacity, and reactive oxygen intermediate production, was also increased 2-fold in AMs from l/l mice. Pharmacologic blockade of PGE(2) synthesis reduced cAMP levels and overcame the defective phagocytosis and killing of bacteria in AMs from l/l mice in vitro. These results demonstrate that leptin receptor-mediated ERK activation plays an essential role in host defense against bacterial pneumonia and in leukocyte antibacterial effector functions.
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18 MeSH Terms
The role of inflammatory pathway genetic variation on maternal metabolic phenotypes during pregnancy.
Urbanek M, Hayes MG, Lee H, Freathy RM, Lowe LP, Ackerman C, Jafari N, Dyer AR, Cox NJ, Dunger DB, Hattersley AT, Metzger BE, Lowe WL
(2012) PLoS One 7: e32958
MeSH Terms: Asian Continental Ancestry Group, Blood Glucose, C-Peptide, Cohort Studies, European Continental Ancestry Group, Fasting, Female, Genetic Predisposition to Disease, Glucose Tolerance Test, Glycated Hemoglobin A, Humans, Hyperglycemia, Inflammation, Interleukin-6, Interleukin-8, Polymorphism, Single Nucleotide, Pregnancy, Pregnancy Complications, Pregnancy Outcome, Receptors, Adiponectin, Receptors, Leptin, Resistin, Signal Transduction, Thailand, Tumor Necrosis Factor-alpha
Show Abstract · Added February 22, 2016
BACKGROUND - Since mediators of inflammation are associated with insulin resistance, and the risk of developing diabetes mellitus and gestational diabetes, we hypothesized that genetic variation in members of the inflammatory gene pathway impact glucose levels and related phenotypes in pregnancy. We evaluated this hypothesis by testing for association between genetic variants in 31 inflammatory pathway genes in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) cohort, a large multiethnic multicenter study designed to address the impact of glycemia less than overt diabetes on pregnancy outcome.
RESULTS - Fasting, 1-hour, and 2-hour glucose, fasting and 1-hour C-peptide, and HbA1c levels were measured in blood samples obtained from HAPO participants during an oral glucose tolerance test at 24-32 weeks gestation. We tested for association between 458 SNPs mapping to 31 genes in the inflammatory pathway and metabolic phenotypes in 3836 European ancestry and 1713 Thai pregnant women. The strongest evidence for association was observed with TNF alpha and HbA1c (rs1052248; 0.04% increase per allele C; p-value = 4.4×10(-5)), RETN and fasting plasma glucose (rs1423096; 0.7 mg/dl decrease per allele A; p-value = 1.1×10(-4)), IL8 and 1 hr plasma glucose (rs2886920; 2.6 mg/dl decrease per allele T; p-value = 1.3×10(-4)), ADIPOR2 and fasting C-peptide (rs2041139; 0.55 ug/L decrease per allele A; p-value = 1.4×10(-4)), LEPR and 1-hour C-peptide (rs1171278; 0.62 ug/L decrease per allele T; p-value = 2.4×10(-4)), and IL6 and 1-hour plasma glucose (rs6954897; -2.29 mg/dl decrease per allele G, p-value = 4.3×10(-4)).
CONCLUSIONS - Based on the genes surveyed in this study the inflammatory pathway is unlikely to have a strong impact on maternal metabolic phenotypes in pregnancy although variation in individual members of the pathway (e.g. RETN, IL8, ADIPOR2, LEPR, IL6, and TNF alpha,) may contribute to metabolic phenotypes in pregnant women.
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25 MeSH Terms
Haematopoietic leptin receptor deficiency does not affect macrophage accumulation in adipose tissue or systemic insulin sensitivity.
Gutierrez DA, Hasty AH
(2012) J Endocrinol 212: 343-51
MeSH Terms: Adipose Tissue, Animals, Bone Marrow Cells, Bone Marrow Transplantation, Dietary Fats, Inflammation, Insulin Resistance, Macrophages, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Obesity, Receptors, CCR2, Receptors, Leptin
Show Abstract · Added December 5, 2013
The adipokine leptin is primarily produced by white adipose tissue (AT) and is a potent monocyte/macrophage chemoattractant in vitro. The long form of the leptin receptor (LepR) is required for monocyte/macrophage chemotaxis towards leptin. In this study, we examined the effects of haematopoietic LepR as well as LepR with C-C chemokine receptor 2 (CCR2) deficiency (double knockout (DKO)) on macrophage recruitment to AT after two different periods of high fat diet (HFD) feeding. Briefly, 8-week-old C57BL/6 mice were transplanted with bone marrow (BM) from Lepr(+/+), Lepr(-/-) or DKO donors (groups named BM-Lepr(+/+), BM-Lepr(-/-) and BM-DKO respectively), and were placed on an HFD for 6 or 12 weeks. At the end of the study, macrophage infiltration and the inflammatory state of AT were evaluated by real-time RT-PCR, histology and flow cytometry. In addition, glucose and insulin tolerance were assessed at both time points. Our results showed no differences in macrophage accumulation or AT inflammatory state between the BM-Lepr(+/+) and BM-Lepr(-/-) mice after 6 or 12 weeks of HFD feeding; any effects observed in the BM-DKO were attributed to the haematopoietic deficiency of CCR2. In addition, no changes in glucose or insulin tolerance were observed between groups after either period of HFD feeding. Our findings suggest that although leptin is a potent chemoattractant in vitro, haematopoietic LepR deficiency does not affect macrophage accumulation in AT in early to moderate stages of diet-induced obesity.
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15 MeSH Terms
Genetic polymorphisms in obesity-related genes and endometrial cancer risk.
Chen X, Xiang YB, Long JR, Cai H, Cai Q, Cheng J, Wen W, Gao YT, Zheng W, Shu XO
(2012) Cancer 118: 3356-64
MeSH Terms: Adiponectin, Endometrial Neoplasms, Female, Genetic Predisposition to Disease, Humans, Leptin, Middle Aged, Obesity, Polymorphism, Single Nucleotide, Receptors, Adiponectin, Receptors, Leptin, Risk Factors
Show Abstract · Added December 10, 2013
BACKGROUND - Obesity is associated with circulating levels of adiponectin and leptin and endometrial cancer risk. Little is known about whether single nucleotide polymorphisms (SNPs) in the genes that encode adiponectin (ADIPOQ), leptin (LEP), adiponectin receptor 1 (ADIPOR1), adiponectin receptor 2 (ADIPOR2), and leptin receptor (LEPR) are associated with endometrial cancer.
METHODS - The authors selected 87 tagging SNPs to capture common genetic variants in these 5 genes. These SNPs were evaluated in 1028 endometrial cancer cases and 1932 community controls recruited from Chinese women. Logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs).
RESULTS - Three of the 10 SNPs evaluated in the ADIPOQ gene were significantly associated with reduced cancer risk. The OR for women homozygous for the minor allele (A/A) for rs3774262 was 0.68 (95% CI, 0.48-0.97) compared with women homozygous for the major allele (G/G). Similar results were found for SNPs rs1063539 and rs12629945 in ADIPOQ, which were in linkage disequilibrium with rs3774262. These associations became nonsignificant after Bonferroni correction was applied. Controls with the minor allele A at rs3774262 had lower weight, smaller waist and hip circumferences, and lower body mass index than controls with the major allele G (all P < .05). Women homozygous for the minor allele (T/T) of rs2071045 in the LEP gene also had significantly lower risk (OR, 0.70; 95% CI, 0.54-0.90) than women homozygous for the major allele (C/C). No other SNPs in the LEP, ADIPOR1, ADIPOR2, or LEPR genes were found to be associated with cancer risk.
CONCLUSIONS - Although a chance finding cannot be ruled out, the consistency of findings for gene-endometrial cancer risk and gene-obesity measurements suggests that genetic polymorphisms in the ADIPOQ gene may play a role in endometrial cancer development.
Copyright © 2011 American Cancer Society.
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12 MeSH Terms
Exercise training does not correct abnormal cardiac glycogen accumulation in the db/db mouse model of type 2 diabetes.
Shearer J, Ross KD, Hughey CC, Johnsen VL, Hittel DS, Severson DL
(2011) Am J Physiol Endocrinol Metab 301: E31-9
MeSH Terms: Animals, Body Weight, Diabetes Mellitus, Experimental, Diabetes Mellitus, Type 2, Diabetic Cardiomyopathies, Exercise Therapy, Glycogen, Glycogen Storage Disease Type IIb, Mice, Mice, Inbred C57BL, Mice, Transgenic, Myocardium, Physical Conditioning, Animal, Receptors, Leptin
Show Abstract · Added April 24, 2014
Substrate imbalance is a well-recognized feature of diabetic cardiomyopathy. Insulin resistance effectively limits carbohydrate oxidation, resulting in abnormal cardiac glycogen accumulation. Aims of the present study were to 1) characterize the role of glycogen-associated proteins involved in excessive glycogen accumulation in type 2 diabetic hearts and 2) determine if exercise training can attenuate abnormal cardiac glycogen accumulation. Control (db(+)) and genetically diabetic (db/db) C57BL/KsJ-lepr(db)/lepr(db) mice were subjected to sedentary or treadmill exercise regimens. Exercise training consisted of high-intensity/short-duration (10 days) and low-intensity/long-duration (6 wk) protocols. Glycogen levels were elevated by 35-50% in db/db hearts. Exercise training further increased (2- to 3-fold) glycogen levels in db/db hearts. Analysis of soluble and insoluble glycogen pools revealed no differential accumulation of one glycogen subspecies. Phosphorylation (Ser(640)) of glycogen synthase, an indicator of enzymatic fractional activity, was greater in db/db mice subjected to sedentary and exercise regimens. Elevated glycogen levels were accompanied by decreased phosphorylation (Thr(172)) of 5'-AMP-activated kinase and phosphorylation (Ser(79)) of its downstream substrate acetyl-CoA carboxylase. Glycogen concentration was not associated with increases in other glycogen-associated proteins, including malin and laforin. Novel observations show that exercise training does not correct diabetes-induced elevations in cardiac glycogen but, rather, precipitates further accumulation.
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14 MeSH Terms
Circulating ghrelin, leptin, and soluble leptin receptor concentrations and cardiometabolic risk factors in a community-based sample.
Ingelsson E, Larson MG, Yin X, Wang TJ, Meigs JB, Lipinska I, Benjamin EJ, Keaney JF, Vasan RS
(2008) J Clin Endocrinol Metab 93: 3149-57
MeSH Terms: Adult, Body Mass Index, Cardiovascular Diseases, Energy Metabolism, Female, Ghrelin, Humans, Leptin, Male, Metabolic Syndrome, Middle Aged, Multivariate Analysis, Receptors, Leptin, Risk Factors, Sex Characteristics
Show Abstract · Added April 15, 2014
CONTEXT - The conjoint effects and relative importance of ghrelin, leptin, and soluble leptin receptor (sOB-R), adipokines involved in appetite control and energy expenditure in mediating cardiometabolic risk, is unknown.
OBJECTIVE - The objective of the study was to study the cross-sectional relations of these adipokines to cardiometabolic risk factors in a community-based sample.
DESIGN, SETTING, AND PARTICIPANTS - We measured circulating ghrelin, leptin, and sOB-R in 362 participants (mean age 45 yr; 54% women) of the Framingham Third Generation Cohort.
MAIN OUTCOME MEASURES - Body mass index, waist circumference (WC), blood pressure, lipid measures, fasting glucose, smoking, and metabolic syndrome (MetS) were measured.
RESULTS - Ghrelin and leptin concentrations were significantly higher in women (P < 0.0001). In multivariable models, ghrelin was inversely associated with age and systolic blood pressure, and leptin was positively related to body mass index and WC. sOB-R was positively associated with age, total cholesterol, and fasting glucose and inversely with WC and high-density lipoprotein cholesterol. Ghrelin and sOB-R concentrations were significantly lower with number of MetS components (P for trend = 0.022 and < 0.0001, respectively), whereas leptin concentrations were higher (P for trend = 0.0001). Relating all adipokines to MetS conjointly, higher ghrelin and leptin concentrations were associated with decreased and increased odds of MetS (odds ratio 0.55, P < 0.0001; odds ratio 4.44, P = 0.0002, per 1 sd increase of respective log adipokine).
CONCLUSIONS - In our community-based sample, we observed a sexual dimorphism in circulating ghrelin and leptin concentrations. Ghrelin, leptin, and sOB-R were associated with number of MetS components cross-sectionally, consistent with the hypothesis that these adipokines may have a central role in cardiometabolic risk.
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15 MeSH Terms