Functional Leptin Receptor Research Articles

Molecular Hydrogen Improves Obesity and Diabetes by Inducing Hepatic FGF21 and Stimulating Energy Metabolism in db/db Mice

Recent extensive studies have revealed that molecular hydrogen (H(2)) has great potential for improving oxidative stress-related diseases by inhaling H(2) gas, injecting saline with dissolved H(2), or drinking water with dissolved H(2) (H(2)-water); however, little is known about the dynamic movement of H(2) in a body. First, we show that hepatic glycogen accumulates H(2) after oral administration of H(2)-water, explaining why consumption of even a small amount of H(2) over a short span time efficiently improves various disease models. This finding was supported by an in vitro experiment in which glycogen solution maintained H(2). Next, we examined the benefit of ad libitum drinking H(2)-water to type 2 diabetes using db/db obesity model mice lacking the functional leptin receptor. Drinking H(2)-water reduced hepatic oxidative stress, and significantly alleviated fatty liver in db/db mice as well as high fat-diet-induced fatty liver in wild-type mice. Long-term drinking H(2)-water significantly controlled fat and body weights, despite no increase in consumption of diet and water. Moreover, drinking H(2)-water decreased levels of plasma glucose, insulin, and triglyceride, the effect of which on hyperglycemia was similar to diet restriction. To examine how drinking H(2)-water improves obesity and metabolic parameters at the molecular level, we examined gene-expression profiles, and found enhanced expression of a hepatic hormone, fibroblast growth factor 21 (FGF21), which functions to enhance fatty acid and glucose expenditure. Indeed, H(2) stimulated energy metabolism as measured by oxygen consumption. The present results suggest the potential benefit of H(2) in improving obesity, diabetes, and metabolic syndrome.

Leptin and cancer: from cancer stem cells to metastasis

There is growing evidence that obesity is a risk factor of cancer incidence and mortality. Hence, the identification of the mechanistic links between obesity and cancer progression is emerging as a topic of widespread interest. Recently, several groups have addressed the functional roles of leptin, an adipocyte-derived adipokine, for mammary tumor progression. In this issue of Endocrine-Related Cancer, Zheng et al. study the role of leptin on tumor growth in a xenograft model of MMTV-Wnt1-derived cancer cells. They study growth of these cancer cells in the context of obese animals, such as ob/ob mice (lacking leptin) and db/db mice (lacking functional leptin receptors (LEPR)) and find that leptin triggers LEPR-positive cancer stem cell differentiation, thereby promoting tumor cell survival. These findings highlight the therapeutic potential for leptin and leptin signaling in the context of mammary tumor growth.

Intrauterine growth restriction (IUGR) is associated with increased leptin synthesis and binding capability in neonates

Animal studies suggest pathological foetal programming of hypothalamic circuits regulating food intake in the setting of leptin deficiency and intrauterine growth restriction (IUGR). We aimed to compare placental leptin synthesis and leptin-binding capability in venous cord blood between IUGR newborns and neonates born appropriate for gestational age (AGA). Prospective controlled multicentre study. Twenty-one ultrasound-proven IUGR and 33 AGA neonates. The concentration of leptin and soluble leptin receptor (sOB-R) in venous cord blood at birth was determined. Moreover, placental gene and protein expression of leptin and placental mRNA expression of functional and total leptin receptor isoforms were measured. Whereas log-leptin concentration in venous cord blood did not differ between IUGR and AGA newborns, the concentration of log-sOB-R was elevated in IUGR neonates (p(confounder adjusted)=0·009). Placental leptin protein synthesis as well as leptin mRNA was significantly higher in IUGR than in AGA infants (log-transformed, relative gene expression, p(confounder adjusted)=0·004). Analysis of gene expression of functional and total leptin receptor isoforms did not show any difference between both groups. Leptin-binding capability in venous cord blood is increased in IUGR newborns. Thus, via foetal programming, reduced biologically active leptin levels might contribute to a perturbed regulation of appetite.

Generation of Leptin Receptor Bone Marrow Chimeras: Recovery From Irradiation, Immune Cellularity, Cytokine Expression, and Metabolic Parameters

Leptin regulates appetite and metabolism but also immunity and inflammation. Although functional leptin receptors (LepR) are expressed on hematopoietic cells, the role of these receptors in regulating immune function in vivo remains controversial. To clarify this issue, we performed bone marrow (BM) transplantation between obese db/db mice, lacking LepR, and wild-type (WT) mice. Results indicate that expression of LepR on BM-derived cells directly, though partially, regulates spleen and thymus cellularity, although the environment of db mice contributes to maintaining reduced cellularity of these organs. Selective expression of LepR on BM-derived cells also modulates leptin and adiponectin levels, with induction of a more favorable adipokine environment in the WT→db/db group. However, LepR signaling in BM-derived cells is not involved in regulation of body weight (BW) and composition, glycemia, hepatosteatosis or adipose tissue inflammation, although it modulates expression of interleukin (IL)-1β in the brain. Finally, data indicate that db mice have an increased susceptibility to irradiation compared to WT mice in terms of BW loss and recovery of leukocyte counts in peripheral blood. Therefore, interpretation of results obtained using BM chimeras between WT and db mice should take into account the difference in radiation sensitivity between the two types of animals.

Leptin signaling in intestinal epithelium mediates resistance to enteric infection by Entamoeba histolytica.

Leptin is an adipocytokine that links nutrition to immunity. Previous observation that a genetic polymorphism in the leptin receptor affected susceptibility to Entamoeba histolytica infection led to the hypothesis that leptin signaling plays a protective role during intestinal amebic infection. Here we show that mice lacking the functional leptin receptor developed devastating mucosal destruction after E. histolytica infection. Bone marrow chimera experiments demonstrated that leptin receptor expressed on hematopoietic cells was not sufficient to confer resistance. Similarly peripheral knockout of the leptin receptor rendered animals susceptible, indicating that central expression of the leptin receptor was not sufficient to confer protection. The site of leptin action was localized to the gut via an intestinal epithelium-specific deletion of the leptin receptor, which rendered mice susceptible to infection and mucosal destruction by the parasite. Mutation of tyrosine 985 or 1138 in the intracellular domain of the leptin receptor, which mediates signaling through the SHP2/ERK and STAT3 pathways respectively, demonstrated that both were important for mucosal protection. We conclude that leptin-mediated resistance to amebiasis is via its actions on intestinal epithelium rather than hematopoietic cells or the brain, and requires leptin receptor signaling through both the STAT3 and SHP2/ERK pathways.

An intrinsic gut leptin-melanocortin pathway modulates intestinal microsomal triglyceride transfer protein and lipid absorption

Fat is delivered to tissues by apoB-containing lipoproteins synthesized in the liver and intestine with the help of an intracellular chaperone, microsomal triglyceride transfer protein (MTP). Leptin, a hormone secreted by adipose tissue, acts in the brain and on peripheral tissues to regulate fat storage and metabolism. Our aim was to identify the role of leptin signaling in MTP regulation and lipid absorption using several mouse models deficient in leptin receptor (LEPR) signaling and downstream effectors. Mice with spontaneous LEPR B mutations or targeted ablation of LEPR B in proopiomelanocortin (POMC) or agouti gene related peptide (AGRP) expressing cells had increased triglyceride in plasma, liver, and intestine. Furthermore, melanocortin 4 receptor (MC4R) knockout mice expressed a similar triglyceride phenotype, suggesting that leptin might regulate intestinal MTP expression through the melanocortin pathway. Mechanistic studies revealed that the accumulation of triglyceride in the intestine might be secondary to decreased expression of MTP and lipid absorption in these mice. Surgical and chemical blockade of vagal efferent outflow to the intestine in wild-type mice failed to alter the triglyceride phenotype, demonstrating that central neural control mechanisms were likely not involved in the observed regulation of intestinal MTP. Instead, we found that enterocytes express LEPR, POMC, AGRP, and MC4R. We propose that a peripheral, local gut signaling mechanism involving LEPR B and MC4R regulates intestinal MTP and controls intestinal lipid absorption.

Leptin Functions Peripherally to Regulate Differentiation of Mesenchymal Progenitor Cells

Leptin functions through a well-documented central neuroendocrine pathway to regulate bone mass. However, the ability of leptin to modulate bone mass through a peripheral mechanism has been debated due to conflicting in vitro results and lack of sufficient in vivo models. We utilized mice with LoxP sites introduced into the long-form leptin receptor (ObRb) gene to determine how leptin regulates mesenchymal progenitor cell (MPC) differentiation and osteoblast function in vitro and in vivo. Rapid phosphorylation of Stat3 after leptin treatment of bone marrow stromal cells (BMSCs) from mice with conditional deletion of ObRb in macrophages (LysM(Cre+F/F)) confirmed expression of functional leptin receptors by BMSCs. Adenovirus-Cre mediated disruption of ObRb in primary stromal cells decreased mineralization and increased adipogenesis. In contrast, BMSCs harvested from leptin-signaling deficient Ob/Ob or Db/Db mice showed increased mineralization. To determine the physiologic relevance of these differences, mice with cell-specific deletion of ObRb in mesenchymal precursors (3.6(Cre+F/F)) or osteoblasts (2.3(Cre+F/F)) were generated. Although the 2.3(Cre+F/F) mice were grossly normal, the 3.6(Cre+F/F) mice displayed mild obesity that was not attributed to food intake. Femurs of 3.6(Cre+F/F) animals showed a 58%-61.9% increase in trabecular bone volume and a 65.5%-74% increase in bone mineral density. Cortical volume and mineral content were also increased 18%-22%. Primary 3.6(Cre+F/F) BMSCs recapitulated the high mineralization phenotype of Ob/Ob and Db/Db BMSCs. We conclude that leptin may have multiple peripheral roles depending on the differentiation state of MPC. Leptin (a) helps maintain MPCs in an undifferentiated state and (b) promotes mineralization of more differentiated osteoblasts.

ORIGINAL ARTICLE: Leptin on Peritoneal Macrophages of Patients with Endometriosis

Citation Wu M‐H, Huang M‐F, Chang F‐M, Tsai S‐J. Leptin on peritoneal macrophages of patients with endometriosis. Am J Reprod Immunol 2010; 63: 214–221Problem The expression of cyclooxygenase (COX)‐2 is considered as a marker of macrophage activation and has been implicated in the development of endometriosis. Leptin is an immunomodulator, which may also affect the development of endometriosis. However, how leptin contributes to these pathological processes has not been completely understood. The aim of this study was to investigate the effects of leptin on peritoneal macrophages and its relationship with endometriosis.Methods of study Peritoneal fluid from 60 women of reproductive age was obtained while they underwent laparoscopy. Forty patients had endometriosis and 20 patients did not have endometriosis. The concentration of leptin in the peritoneal fluid and prostaglandin F2α levels was measured by ELISA, and the other protein expression using Western blot when peritoneal macrophages were stimulated with leptin.Results Concentration of leptin in peritoneal fluid was increased in patients with endometriosis compared with disease‐free normal control. Functional leptin receptor was present in peritoneal macrophages. Treatment of peritoneal macrophages with leptin induced COX‐2 expression. Production of prostaglandin F2α by peritoneal macrophages was increased after leptin stimulation in women with endometriosis.Conclusion Elevated concentration of leptin in peritoneal fluid may contribute to the pathological process of endometriosis through activation of peritoneal macrophages.

Lack of Association Between the Leptin Receptor Gene (LEPR) Gln223Arg Polymorphism and Late-onset Alzheimer Disease

The principal hypothesis for pathogenesis of Alzheimer disease (AD) is the amyloid cascade hypothesis, which emphasizes an imbalance between production and clearance of beta-amyloid (Abeta) in the brain. Insulin has important effects on the regulation of the Abeta level in the brain, modulating both Abeta production and clearance. An optimal brain insulin level promotes Abeta clearance, which may play protective roles against AD. A functional human leptin receptor gene (LEPR) polymorphism, a glutamine to an arginine substitution at codon 223 (Gln223Arg), has been associated with insulin resistance capacity and an altered leptin-binding activity. The LEPR Gln223Arg polymorphism may thus play an important role in the pathogenesis of AD. In this study, we examined the association between the LEPR Gln223Arg polymorphism and late-onset Alzheimer disease (LOAD) in a Japanese population. Our sample includes 49 patients with LOAD and 134 normal controls. Our preliminary data showed no significant association between the LEPR Gln223Arg polymorphism and LOAD (genotype distribution: chi=0.11, df=2, P=0.945; allele frequency: chi=0.058, df=1, P=0.81, odds ratio=1.08, 95% confidence interval=0.59 to 2.03). Our results suggest that the LEPR polymorphism may not play a major role in the development of LOAD.

S7.2 Altered autonomic control of cardiovascular function in obesity: Insights from obese Zucker rats

Human obesity is associated with the development of hypertension and exaggerated cardiovascular responses to stress. Underlying these attributes are elevated sympathetic nerve activity (SNA) and impaired baroreflexes. To begin to determine mechanisms underlying obesity-associated deficits in autonomic control we studied obese Zucker rats (OZR), which are hyperphagic due to a mutated leptin receptor. Compared to lean Zucker rats (LZR), which have functional leptin receptors, the OZR become obese shortly after weaning and develop autonomic deficits as they approach adulthood. Adult OZR have elevated arterial pressure (AP) and SNA compared to LZR. In addition, OZR have exaggerated sympatho-excitatory responses (somatic and diving reflexes) but blunted sympathetic baroreflexes compared to LZR. The following studies were performed in adult OZR and LZR (14–16 wks old) that were anesthetized with urethane (1.7 g/kg LZR weight, iv), ventilated, and paralyzed. Direct recordings of baroreceptor afferent nerve activity (aortic depressor nerve, ADN) showed that ADN responses to evoked changes in AP were comparable in OZR and LZR. In contrast, electrical stimulation of the ADN evoked blunted inhibitions of SNA and AP in OZR compared to LZR. This deficit appears to extend to other sympatho-inhibitory reflexes initiated by the vagus nerve, because stimulation of the vagal afferents (electrical or by iv injection of phenybiguanide, 1–16 µg) elicited smaller decreases in SNA in OZR compared to LZR. These data suggest that impaired baroreflexes in OZR are not due to the ability to sense changes in AP, but altered central mechanisms that regulate SNA.

Leptin mRNA expresses in the bull reproductive organ

Leptin, a 167-amino acid hormone, is secreted mainly by fat tissue. It has some powerful effects on the regulation of metabolism and reproductive function through endocrine and probably paracrine mechanisms. The contribution rate of leptin function on the male reproductive system is not still clear. Characterization of leptin expression in reproductive organs will suggest that in addition to its endocrine action, leptin has also paracrine/autocrine effects on reproduction. The expression of functional leptin receptor mRNA has been already recognized in testis of rodents, human and cattle. Thus, the aim of the present study was to investigate the presence of leptin mRNA in the bovine testis, because it will be the first step for understanding of its paracrine/autocrine effects on the male reproductive organs in cattle. The present study was the first to showed leptin mRNA expression in the testis of Holstein cattle using reverse transcription and polymerase chain reaction (RT-PCR) analysis. RT-PCR products were amplified with nested PCR using inner leptin primer pairs to emphasis the first results. Besides, bovine beta actin gene was acted as an internal positive control as well as RNA purification marker. Our findings suggest that in addition to its endocrine actions at the hypothalamic-pituitary axis, leptin can has an autocrine and/or paracrine role in bull testicular function.

Prolonged AICAR-induced AMP-kinase activation promotes energy dissipation in white adipocytes: novel mechanisms integrating HSL and ATGL

This study was designed to investigate the effects of prolonged activation of AMP-activated protein kinase (AMPK) on lipid partitioning and the potential molecular mechanisms involved in these processes in white adipose tissue (WAT). Rat epididymal adipocytes were incubated with 5'-aminoimidasole-4-carboxamide-1-beta-d-ribofuranoside (AICAR;0.5 mM) for 15 h. Also, epididymal adipocytes were isolated 15 h after AICAR was injected (i.p. 0.7 g/kg body weight) in rats. Adipocytes were utilized for various metabolic assays and for determination of gene expression and protein content. Time-dependent in vivo plasma NEFA concentrations were determined. AICAR treatment significantly increased AMPK activation, inhibited lipogenesis, and increased FA oxidation. This was accompanied by upregulation of peroxisome proliferator-activated receptor (PPAR)alpha, PPARdelta, and PPARgamma-coactivator-1alpha (PGC-1alpha) mRNA levels. Lipolysis was first suppressed, but then increased, both in vitro and in vivo, with prolonged AICAR treatment. Exposure to AICAR increased adipose triglyceride lipase (ATGL) content and FA release, despite inhibition of basal and epinephrine-stimulated hormone-sensitive lipase (HSL) activity. Here, we provide evidence that prolonged AICAR-induced AMPK activation can remodel adipocyte metabolism by upregulating pathways that favor energy dissipation versus lipid storage in WAT. Additionally, we show novel time-dependent effects of AICAR-induced AMPK activation on lipolysis, which involves antagonistic modulation of HSL and ATGL.

Leptin Signaling in the Nucleus Tractus Solitarii Increases Sympathetic Nerve Activity to the Kidney

The hypothalamic arcuate nucleus was initially regarded as the principal site of leptin action, but there is increasing evidence for functional leptin receptors in extrahypothalamic sites, including the nucleus tractus solitarii (NTS). We demonstrated previously that arcuate injection of leptin increases sympathetic nerve activity (SNA) to brown adipose tissue and kidney. In this study, we tested the hypothesis that leptin signaling in the NTS affects sympathetic neural outflow. Using a stereotaxic device in anesthetized rats, we microinjected leptin (0.25 to 1.00 microg) or saline into the NTS while recording SNA to kidney and brown adipose tissue. Microinjection of leptin into the commissural and medial subnuclei of the caudal NTS at the level of the area postrema in Sprague-Dawley rats produced a dose-related increase in renal SNA (+112+/-15% with leptin 1 microg; n=7; P<0.001) but did not increase SNA to brown adipose tissue (-15+/-12%; P value not significant). This effect depended on intact functional leptin receptors, because it was not observed in Zucker obese rats that have a missense mutation in the leptin receptor. Rostral NTS injection of leptin failed to increase SNA, indicating that leptin signaling in the NTS is probably confined to the caudal NTS at the level of the area postrema. In summary, this study demonstrates that leptin signaling in the caudal NTS increases SNA to the kidney but not to the brown adipose tissue. The study strengthens the concept of a distributed brain network of leptin action and demonstrates that these distributed brain sites can mediate contrasting sympathetic responses to leptin.

Functional ENTPD1 polymorphisms in African Americans with diabetes and end-stage renal disease.

OBJECTIVEThe vascular ectonucleotidase ENTPD1 protects against renal injury and modulates glucose homeostasis in mouse models. We sought to determine whether human variation in ENTPD1 influences predisposition to diabetes or diabetic nephropathy.RESEARCH DESIGN AND METHODSWe analyzed ENTPD1 single nucleotide polymorphisms (SNPs) in 363 African American control subjects, 380 subjects with type 2 diabetes and end-stage renal disease (DM-ESRD), and 326 subjects with ESRD unrelated to diabetes (non–DM-ESRD). Using human cell lines, we correlated disease-associated ENTPD1 haplotypes with ENTPD1 gene expression. Finally, we studied consequences of ENTPD1 deletion in a mouse model of type 2 diabetes (db/db).RESULTSA common ENTPD1 two-SNP haplotype was associated with increased risk for DM-ESRD (P = 0.0027), and an uncommon four-SNP haplotype was associated with protection against DM-ESRD (P = 0.004). These haplotypes correlated with ENTPD1 gene expression levels in human cell lines in vitro. Subjects with high ENTPD1-expressing haplotypes were enriched in the DM-ESRD group. By crossing ENTPD1-null mice with db mice, we show that ENTPD1 deletion has prominent effects on metabolic syndrome traits. Specifically, deletion of ENTPD1 lowered glucose levels in control (db/−) mice with one functional leptin receptor and dramatically lowered weights in db/db mice with no functional leptin receptors. Similar effects were seen in aged ENTPD1-null mice with normal leptin receptors.CONCLUSIONSENTPD1 polymorphisms appear to influence susceptibility to type 2 diabetes and/or diabetic nephropathy in African Americans. Studies in human cell lines and in vivo mouse data support a potential role for ENTPD1 genetic variation in susceptibility to type 2 diabetes.

Expression of Leptin and Its Functional Receptor on Disc Cells

Human herniated disc tissues and rat nucleus pulposus (NP) cells were used following approval by the authors' institutional Human Ethics Review Committee and Animal Care and Use Committee. To determine the expression of leptin and its functional receptor in herniated disc tissues, and to elucidate whether leptin can stimulate rat NP cells to proliferate in vitro. There is evidence showing that chondrocytes express leptin and functional leptin receptor, and leptin stimulates chondrocyte proliferation in vitro and may play a role in the pathogenesis of osteoarthritis by contributing to osteophyte formation. Intervertebral disc degeneration, similar to osteoarthritis, is also a complicated process in which increased cell proliferation is involved. However, little attention has been paid to the causes of the increased cell proliferation during disc degeneration. Forty-five herniated discs were harvested and immunostained to determine the distribution and type of leptin/functional leptin receptor-expressing cells. The proliferating activity of rat NP cells stimulated with leptin was also evaluated by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and by immunostaining for proliferation cell nuclear antigen (PCNA). Immunohistochemical results from 45 herniated discs showed that leptin/functional leptin receptor-positive cells are commonly seen in cell clusters and proliferating fibrocartilaginous areas, and that the percentage of leptin/functional leptin receptor-positive cells correlates with the age of the patients. Leptin administration led to increased proliferation of rat NP cells in a dose-dependent manner, as shown by MTT assay and by counting the percentage of PCNA-positive cells. Our results suggested that disc cells can express leptin and its functional receptor, that leptin can stimulate proliferation of disc cells in vitro, and therefore that leptin may play a role in the process of intervertebral disc degeneration by contributing to the formation of cell cluster and proliferating fibrocartilaginous tissue.

Leptin-stimulated inhibition of mitochondrial permeability transition is dependent on presence of functional OB-RB leptin receptor

Myocardial protection against ischaemia/reperfusion (I/R) injury is associated with activation of the PI3K-AKT and p44/42 MAPK signalling pathways, collectively known as the RISK pathway. Leptin, first identified as an obesity associated hormone, has been demonstrated to diminish I/R injury in the heart via activation of RISK pathway components. There are several different isoforms of the leptin receptor with most data suggesting that the OB-RB leptin receptor is the most physiologically important.

Differential Secretion of Satiety Hormones With Progression of Obesity in JCR:LA‐corpulent Rats

To characterize the gastrointestinal tract at the onset and in well-established obesity. Lean (+/?) and obese (cp/cp) male JCR:LA-cp rats lacking a functional leptin receptor were killed at 3.5 weeks and 9 months of age and plasma concentrations of satiety hormones determined. The small intestine, colon, and stomach were measured, weighed, and mRNA levels of satiety genes quantified. At the onset of obesity, obese rats had greater intestine, colon, and liver mass when adjusted for body weight compared to lean rats. Conversely, adult rats with established obesity had lower intestine and colon mass and length after adjustment for body weight. Early changes in gene expression included decreased ghrelin mRNA levels in stomach and increased peptide YY (PYY) mRNA levels in duodenum of young obese rats. After massive accumulation of adipose tissue had occurred, adult obese rats had increased proglucagon and ghrelin mRNA expression in the proximal intestine. In the distal small intestine, obese rats had lower proglucagon, ghrelin, and PYY mRNA levels. Finally, at the onset and in well-established obesity, obese rats had higher plasma insulin, amylin, glucagon like peptide-1 (GLP-1), and PYY, a finding, with the exception of insulin, unique to this model. Plasma total ghrelin levels were significantly lower at the onset of obesity and established obesity compared to the lean rats. Several defects are manifested in the obese gut early on in the disease before the accumulation of large excesses of body fat and represent potential targets for early intervention in obesity.

Leptin Receptor Signaling is Required for Vaccine‐Induced Protection Against Helicobacter pylori

A vaccine against Helicobacter pylori would be a desirable alternative to antibiotic therapy. Vaccination has been shown to be effective in animal models but the mechanism of protection is poorly understood. Previous studies investigating the gene expression in stomachs of vaccinated mice showed changes in adipokine expression correlated to a protective response. In this study, we investigate a well-characterized adipokine-leptin, and reveal an important role for leptin receptor signaling in vaccine-induced protection. Leptin receptor signaling-deficient (C57BL/Ks Lepr(db)), wild-type C57BL/Ks m littermates and C57BL/6 mice were vaccinated, and then challenged with H. pylori. Levels of bacterial colonization, antibody levels, and gastric infiltrates were compared. The local gene expression pattern in the stomach of leptin receptor signaling-deficient and wild-type mice was also compared using microarrays. Interestingly, while vaccinated wild-type lean C57BL/6 and C57BL/Ks m mice were able to significantly reduce colonization compared to controls, vaccinated obese C57BL/Ks Lepr(db) were not. All mice responded to vaccination, i.e. developed infiltrates predominantly of T lymphocytes in the gastric mucosa, and made H. pylori-specific antibodies. A comparison of expression profiles in protected C57BL/6 and nonprotected C57BL/Ks Lepr(db) mice revealed a subset of inflammation-related genes that were more strongly expressed in nonprotected mice. Our data suggest that functional leptin receptor signaling is required for mediating an effective protective response against H. pylori.

Regulation of vascular insulin signaling by protein tyrosine phosphatase 1B (PTP1B) in mouse models of obesity

Insulin resistance is a major risk factor in obese individuals, and PTP1B is a crucial negative regulator of insulin signaling in metabolic tissues but the role of PTP1B in the development of vascular insulin resistance is unknown. Previously, we have found that PTP1B impairs the insulin‐induced activation of anti‐mitogenic pathways (Akt) while enhancing insulin‐induced activation of mitogenic pathways (p42/44 MAPK) in cultured vascular smooth muscle cells. In this study we tested the hypothesis that deletion of PTP1B improves insulin‐induced activation of Akt while decreasing activation of p42/44 MAPK in the aorta of mouse models of obesity. On a high fat (35.5%) diet, PTP1B knockout (KO) mice were protected from weight gain and had improved insulin‐induced activation of Akt compared to those observed in aortae from wild type (WT) mice on the same diet. Activation of p42/44 MAPK was not statistically different between WT and PTP‐1B KO mice. In contrast, deletion of PTP1B did not correct weight gain in leptin receptor mutant (db/db) mice and did not improve the insulin‐induced activation of Akt in aortae of db/db mice. Moreover, insulin‐induced activation of p42/44 MAPK in aortae was not different in all groups. These data suggest that, in the absence of a functional leptin receptor, PTP1B does not contribute to vascular insulin resistance as assessed by activation of Akt. (NIH Grants HL58139 and DK616874)

Leptin as an immunological adjuvant: enhanced migratory and CD8+T cell stimulatory capacity of human dendritic cells exposed to leptin

Leptin is an adipocyte-derived hormone/cytokine that links nutrition, metabolism, and immune homeostasis and is endowed to modulate several immune responses. We previously demonstrated that both immature and mature human dendritic cells (DCs) express a functional leptin receptor, and we found that leptin activates DCs, licenses them for Th1 priming, and promotes DC survival. Moreover, we found that leptin induces rearrangement of actin microfilaments, leading to uropod and ruffle formation. Here we monitor the effects of leptin on DC migratory capacities, focusing on the intracellular signaling driving cytoskeleton rearrangement. We found that leptin increases immature DC migratory performance both by favoring cytoskeleton dynamics and by up-regulating CCR7 surface expression, thus favoring chemotactic responsiveness. We found that in immature DCs, leptin activates cofilin, favoring the turnover of actin microfilaments, and, by triggering Vav phosphorylation, promotes Rac1 activation. Finally, we found that in immature DCs, leptin up-regulates interleukin-12p70 production on CD40 stimulation and, more importantly, increases their capacity to stimulate activation of autologous CD8(+) T cells. Taken altogether, the findings herein highlight the potential use of leptin as an adjuvant tool in vaccination protocols employing ex vivo-generated autologous DCs.