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Diet induced obese mice retain endogenous leptin action movies: Fluorescent blood–brain barrier tracing shows intact leptin transport in obese mice

Background Citations. In either case, the unraveling of lean individuals with elevated leptin levels might identify them as a new class at increased risk for diet-induced obesity.

Lucas Cox
Monday, July 23, 2018
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  • Due to resolution limitations of the LSFM setup, it was not possible to distinguish whether or not the leptin-CW signal was in the CP interstitium, or had been taken up by the ependymal cells themselves. In contrast, other hypothalamic and extrahypothalamic sites appear leptin responsive, suggesting a state of selective leptin resistance in the brain of DIO mice.

  • Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. A superactive leptin antagonist alters metabolism and locomotion in high-leptin mice.

  • Due to resolution limitations of the LSFM setup, it was not possible to distinguish whether or not the leptin-CW signal was in the CP interstitium, or had been taken up by the ependymal cells themselves.

  • Insulin activation of phosphatidylinositol 3-kinase in the hypothalamic arcuate nucleus: a key mediator of insulin-induced anorexia.

MeSH terms

When compared to other microvessels of the brain, leptin-CW signal is found only colocalized within lectin Supplementary Video SV 5. Close mobile search navigation Article Navigation. For example, the high levels of leptin in obese mice do not result in suppression of appetite as would be expected in lean mice given the same level of circulating leptin. HFD mice had a significantly increased caloric intake Fig.

In the lateral ventricle CP the leptin signal was not only present in the blood vessels, but also outside the capillaries within the CP acion cell layer Fig. Front Neurosci. However, a significant body of evidence points to the ARC as a key site of leptin action to influence energy intake, thus indirectly supporting the hypothesis. For the diet intervention study, DIO mice were subdivided into 4 experimental groups. Stack and overlay pictures were created using ImageJ image analysis software v.

Nat Rev Neurosci. The importance of leptin in the control of systemic energy homeostasis is demonstrated by clinical retaun in people with genetic loss of leptin, which develop hyperphagia and morbid obesity in early childhood that can be reversed by leptin replacement therapy [ 6 ]. Exp Brain Res. We speculate that defects in leptin signaling in neurons within the ARC may play a role in the pathogenesis of leptin-resistant obesity. Introduction Maintenance of energy homeostasis is the keystone in preventing obesity and the metabolic syndrome.

Associated Data

This late response may be due to increased numbers of infected lung cells and obrse of cytokine producing T cells into the lung. These findings challenge the general assumption of reduced leptin action in obesity, and they should be considered in the development of therapies targeting leptin signaling for the treatment of metabolic disease. Skip Nav Destination Article Navigation. Figure 4. Icv LA significantly increased food intake Fig 3jsee also Fig.

These molecules play essential endogenkus in the early inhibition of viral replication 17the stimulation of an inflammatory response 18and recruitment of immune cells to the site of infection The number of the statements may be higher than the number of citations provided by EuropePMC if one paper cites another multiple times or lower if scite has not yet processed some of the citing articles. Leptin resistance not a possible cause of obesity, scientists find. The precipitous diet-induced obesity of the LepTg mice was accompanied with fold and 1. Percentage of survival of lean and obese mice following influenza infection.

Densitometric analysis was performed using ImageJ 1. This effect of leptin is particularly evident in rodents and humans lacking a functional form of the protein, resulting in severe obesity and greatly increased appetite 23. The fact that STAT3 phosphorylation is reduced in DIO mice after administration of a large pharmacological dose of leptin that leads to an increase in serum leptin levels by more than fold not shown suggests that endogenous leptin signaling in the ARC of DIO mice is severely impaired. The remaining authors declare that they have no conflict of interest.

Materials and Methods

Groups with the same character indicate groups that are not significantly different from each other. For example, the high levels of leptin in obese mice do not result in suppression of appetite as would be expected in lean mice given the same level of circulating leptin. A second look at the barriers of the medial basal hypothalamus.

Master of Science diet induced obese mice retain endogenous leptin action movies MSc. Moreover, both studies found that the ARC was resistant to leptin, which combined with our data suggest a key role of this nucleus in retakn of leptin-resistant obesity. Protein extraction and western blotting As ME and MBH samples only provide a very small amount of tissue, samples from 2 mice were pooled to provide sufficient protein levels for detection. Proc Natl Acad Sci. Pictures were taken under a bright-field microscope Axioscope, Zeiss, Oberkochen, Germany with a digital camera Axiocam, Zeiss. B, Cumulative food intake during the 4 wk of diet. Earlier studies further reported a complete lack of physiological responses such as weight loss or food intake in DIO mice subjected to intracerebroventricular injections of exogenous leptin, but a low-level preservation of leptin-induced hypothalamic Stat3 activation [ 13 ].

Region-specific leptin resistance within the hypothalamus of mlce obese mice. DIO mice BW Molecular and cellular biology. It is well known that insulin and more specifically IGF-1 play a critical role in preadipocyte differentiation and are necessary for the in vitro differentiation of 3T3-L1 preadipocytes to adipocytes 22 Leptin and Obesity: Role and Clinical Implication.

Materials and Methods

Mol Metab6 1024 Jun View 5 excerpts, cites background. The reduction movoes NK activity in the obese mice is in agreement with previous studies showing that NK cell function is decreased in splenocytes from rats fed a high fat diet 51 Given leptin's influence on immune function, the reduction in leptin may have impaired the innate immune responses in the obese mice.

Dev Cell 2 : — Because El-Haschimi et al. Impaired transport of leptin across the blood—brain barrier in obesity. Notably, the antibody against leptin had a profoundly reduced affinity against leptin-CW Fig.

In contrast, Socs3 expression was significantly increased in vehicle-treated DIO mice in comparison to vehicle-treated lean controls Fig 4d. There were no mmice differences between lean and obese uninfected controls. In addition to antiviral cytokine responses and NK cells, inflammatory responses are a key part of the innate immune response to influenza infection. We found that leptin concentrations in lean mice transiently increased during influenza infection. However in obese animals, these suppressor proteins are persistently elevated 46 Diabetes Care.

UBC Theses and Dissertations

Our findings are further solidified by a recent hypothalamic perfusion study, which revealed no changes in leptin transport kinetics [ 40 ]. Int J Obes Lond. Leptin resistance, defined as the presence of hyperleptinemia and a diminished response to the signaling or weight-reducing effects of recombinant leptin, exists in the majority of obese rodents 12 Methods We developed a novel tool for visualizing leptin transport using infrared fluorescently labeled leptin, combined with tissue clearing and light-sheet fluorescence microscopy. Our measurements were made at a fixed point in time when leptin accumulation reached a maximum in the MBH.

Dietary Patterns in Latinx Groups. Tartaglia LA The leptin receptor. The induction of chemokines is an important component of infection with influenza virus because they function as attractants for immune cells at the site of infection Intradermal lipopolysaccharide challenge as an acute in vivo inflammatory model in healthy volunteers.

Identifying the factors involved in counteracting the effect of leptin during the development of obesity may provide leptln targets to prevent BW gain. All the mice described in this study were males. The melanocortin system plays a critical role mediating the effect of leptin on food intake and BW Seeley et al. Blood glucose concentrations were measured with a Freestyle blood glucose monitor Abbott Laboratories. Student's t test was used for post-hoc comparison between the dietary groups and Tukey's HSD was used for post-hoc comparisons among the days p.

Additional studies will be needed to define the role of GH with respect to IGF-1 in animals chronically responsive to hyperleptinemia. Given leptin's influence on immune function, the reduction in leptin may have impaired the innate immune responses in the obese mice. Lung mRNA expression at d 3 p. Figure 1. Computation of the slope of the increase in body weight of each mouse revealed that the body weight gain of the LepTg mice was 1.

High calorie diet triggers hypothalamic angiopathy. As ME and MBH samples only provide a very small amount of tissue, samples from 2 mice were pooled to provide sufficient protein levels for detection. E, Quantification of data from D. Leptin resistance in diet-induced obese DIO mice is characterized by elevated serum leptin and a decreased response to exogenous leptin and is caused by unknown defects in the central nervous system.

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  • Recent history Saved searches. Figures and Topics from this paper.

  • Use of labeled tomato lectin for imaging vasculature structures.

  • Based on the known anatomical location of these cells in the ARC of mice, the present data suggest that a significant proportion of these cells are resistant to leptin in DIO mice.

  • In contrast, leptin monotherapy proved ineffective when identical weight loss was induced by caloric restriction alone over a comparable time. View 1 excerpt, references background.

  • Nature reviews. Receive exclusive offers and updates from Oxford Academic.

Materials and Methods. The methods described can be readily adapted to accommodate a imduced of other peptide hormones, which may greatly impact the field of hormonal BBB transport. Sections were washed and incubated with biotinylated antirabbit antibodyfollowed by avidin-biotin-complex labeling. The reason for the selective leptin resistance in the ARC, but not of other brain regions, is unclear.

We found that leptin concentrations in lean mice transiently increased during influenza infection. Note the increased cellularity and the prominent staining of lipids from LepTg mice compared with normal mice. Ottaway N 1. Am J Pathol.

Introduction

Email alerts Article activity alert. Each data point consists of samples from 2 animals, which were pooled due to detection limitations. Leptin resistance, it would appear then, is unlikely to be the result of blunted leptin transport into the MBH.

Google Scholar. Leptin is a 16kDa hormone secreted by adipocytes Zhang et al. Figure 3. Therefore, we measured circulating leptin concentrations in influenza-infected lean and obese mice. Oxford University Press is a department of the University of Oxford. LepTg CFD. Note the increased cellularity and the prominent staining of lipids from LepTg mice compared with normal mice.

However in obese animals, these suppressor proteins are persistently elevated 46 Qiu, B. To determine spontaneous release, 0. Orlando, FL : Academic Press A leptin concentration of 6. Insulin-like growth factor-I is an essential regulator of the differentiation of 3T3-L1 adipocytes.

This was quantified using volumetric calculations based on signal intensity for the ME Fig. The inner CSF—brain barrier: developmentally controlled access to the brain via intercellular junctions. Close mobile search navigation Article Navigation.

Interestingly, LepR was significantly upregulated in both weight loss groups CR and EX4, compared to all groups that did not undergo actioj weight loss Fig. For example, it has been shown that microinjection of small doses of leptin directly into the ARC result in reduced energy intake LH performed in vitro experiments in HEK cells. We therefore conclude that this analysis is likely an underestimate of the degree of leptin-resistant signaling in the ARC of DIO mice.

The cells were grown and differentiated in vitro before staining with ORO for lipid content. These molecules play essential roles in the early inhibition of viral replication 17the stimulation of an inflammatory response 18and recruitment of immune cells to the site of infection A leptin concentration of 6. Email alerts Article activity alert. To determine maximum lysis, 0.

Cited by: 6 articles PMID: A leptin concentration of 6. In contrast, the antagonist increased feeding and BW comparably in lean and diet-induced obese DIO mice, an increase associated with decreased hypothalamic expression of Socs3a primary target of leptin. Copyright notice.

Learn More. These data are discrepant to a previous report that, using essentially the same western blotting methodology, found severely impaired transport of leptin into the MBH of DIO mice compared to lean controls. Disruption of neural signal transducer and activator of transcription 3 causes obesity, diabetes, infertility, and thermal dysregulation. Supplemental Video S1 12M, mov.

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Attribution-NonCommercial-NoDerivatives 4. Mice were dissected and Obese mice retain samples subjected to western blotting a and densitometric analyses b — d for leptin or leptin sensitivity marker pSTAT3. Due to resolution induces of the LSFM setup, it was not possible to distinguish whether or not the leptin-CW signal was in the CP interstitium, or had been taken up by the ependymal cells themselves. J Neurosci 21 : — When compared to other microvessels of the brain, leptin-CW signal is found only colocalized within lectin Supplementary Video SV 5. Protein extraction and western blotting As ME and MBH samples only provide a very small amount of tissue, samples from 2 mice were pooled to provide sufficient protein levels for detection. To overcome this we injected mice with leptin i.

Orlando, FL leptij Academic Press The Journal of endocrinology. Half of the right lobe of the lung was removed at d 0 uninfected3, and 6 p. This reduction may have been due, in part, to the decreased proportion of NK cells in the lungs of obese mice; at d 3 p. J Clin Endocrinol Metab.

Associated Data

In contrast, other hypothalamic and extrahypothalamic sites appear leptin responsive, suggesting a state of selective leptin resistance in the brain of DIO mice. Mol Metab. Front Neuroendocrinol 24 : 1 —

  • Supplemental Video S1 12M, mov.

  • Challenges and opportunities of defining clinical leptin resistance. Issue Section:.

  • After loading the sample onto the column, the column was washed with 10 column volumes of Buffer A. Food intake and the regulation of body weight.

  • Design and evaluation of GLP-1 receptor G-protein biased agonist with prolonged efficacy on diabetes.

  • J Pept Sci. International Journal of Obesity.

Methods We developed movvies novel tool for visualizing leptin transport using infrared fluorescently labeled leptin, combined with tissue clearing and light-sheet fluorescence microscopy. Alterations at the level of the leptin receptor and at postreceptor steps have been examined to explain this, including down-regulation of ObRb expression 123132 and possible up-regulation of negative signaling regulators such as suppressor of cytokine signaling 3 SOCS-3 1233 — Accordingly, our imaging data are in line with these earlier reports. Hyperleptinemia could even contribute to increased sympathetic activity and arterial pressure in the obese state where there is resistance to the metabolic actions of leptin 57 ,

To arrive at the top five similar articles we use a word-weighted algorithm to compare words from the Title and Abstract of each citation. Inhibition of natural killer cell activity by dietary lipids. Google Scholar Crossref. This discrepancy suggests an age-dependent convergence from multiple neural circuits towards the melanocortin system as the mediator of leptin effects on the homeostatic control of energy balance.

Norman LA 1. Because macrophages are a major contributor to proinflammatory cytokine production, fewer macrophages in the lungs, as well as a decrease in their functional capacity, could explain the reduction in cytokine levels. Lung inflammation contributes to increased mortality in influenza-infected mice. Other contributing factors may involve a shift in insulin sensitivity triggered by hyperleptinemia and a decrease in energy expenditure. View 1 excerpt, cites background. View 2 excerpts, references background and results.

Indeed, LepRa ldptin levels may be the limiting factor for leptin BBB transport rates when endogenous leptin levels are high, or supraphysiological levels of recombinant leptin are administered. Although our study has not directly assessed the issue of reduced transport vs. All studies were based on power analyses to assure adequate sample sizes, and approved by the State of Bavaria, Germany.

In contrast, more common diet induced obese mice retain endogenous leptin action movies of obesity including diet-induced obesity DIOexhibit hyperleptinemia proportional to the amount of body fat stores Frederich et al. Cytokine Growth Factor Rev. Open in new tab Download slide. To determine whether obesity had an effect on the ability of NK cells to lyse a target, isolated lung and spleen cells were analyzed in a standard NK cell cytotoxicity assay 28using 51 Cr-labeled YAC-1 tumor cells ATCC as targets. The induction of chemokines is an important component of infection with influenza virus because they function as attractants for immune cells at the site of infection Percentage of survival of lean and obese mice following influenza infection. Sign In or Create an Account.

DIO mice BW Note the increased cellularity and the prominent staining of lipids from LepTg mice compared with normal mice. In addition to antiviral cytokine responses and NK cells, inflammatory responses are a key part of the innate immune response to influenza infection. Figure 1.

Nutr Neurosci. These data are discrepant to a previous report that, using obeze the same western blotting methodology, found severely impaired transport of leptin into the MBH of DIO mice compared to lean controls. Densitometric analysis was performed using ImageJ 1. Overall, our results support a model whereby leptin bio-distribution in the brain is predominantly facilitated by the CP and LepR-driven transfer from blood into the CSF. Serum immunoreactive-leptin concentrations in normal-weight and obese humans.

Therefore, we measured circulating leptin concentrations in influenza-infected lean and obese mice. Additionally, obese mice had a substantial reduction in NK cell cytotoxicity. PMID: LepTg CFD.

  • Rather, leptin signaling in the ARC is severely decreased, whereas several other sites retain leptin responsiveness. Diet-induced obese mice develop peripheral, but not central, resistance to leptin.

  • Overall, the findings presented here demonstrate comparable endogenous leptin activity in lean and obese hyperleptinemic diet-induced obese mice, despite different sensitivity to exogenously administered leptin. Cite Cite Alexia G.

  • Cerebrospinal fluid leptin levels: relationship to plasma levels and to adiposity in humans. Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, dose-escalation trial.

  • Harp, no conflicts of interest; and M. Email alerts Article activity alert.

In lean mice, circulating serum leptin endlgenous tended to increase transiently following infection; the concentration at d 3 p. The obese mice died at d 8 p. Recommendations of the advisory committee on immunization practices ACIP. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. This has been widely attributed to the development of leptin resistance, a state of impaired leptin signaling proposed to contribute to the development and persistence of obesity. To arrive at the top five similar articles we use a word-weighted algorithm to compare words from the Title and Abstract of each citation. All the mice described in this study were males.

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Matthias H. Nat Commun. Resistance to diet-induced obesity is associated with increased proopiomelanocortin mRNA and retaim neuropeptide Y mRNA in the hypothalamus. Vancouver : University of British Columbia Library. Combined, these data suggest that increased SOCS-3 levels may cause defective leptin signaling in this brain region. The study suggests that the ARC is selectively leptin resistant in DIO mice and that this may be caused by elevated suppressor of cytokine signaling 3 in this hypothalamic nucleus.

  • Interestingly, SOCS-3 is also an inhibitor of insulin signaling 46 — 48and insulin has been reported to require signaling proteins and pathways in the CNS that overlap with those of leptin e.

  • Lung inflammation contributes to increased mortality in influenza-infected mice. The tissue was washed as much as possible from blood, weighed and cut into 4, 8, and 16 mg for the LepTg mice and 4, 8, 16, 32, 64,and mg for normal mice.

  • OB protein binds specifically to the choroid plexus of mice and rats. Two defects contribute to hypothalamic leptin resistance in mice with diet-induced obesity.

  • We did not detect reduced STAT3 activation by leptin in most brain regions after 4 or 16 wk of DIO, arguing against a global defect in leptin transport. HFD mice had a significantly increased caloric intake Fig.

  • Leptin signaling in the hypothalamus: emphasis on energy homeostasis and leptin resistance. Food intake and the regulation of body weight.

Combined, these data suggest that increased SOCS-3 levels may cause defective leptin signaling in this brain region. Molecules that enter the CSF can freely diffuse into many brain regions that line the ventricles [ 20 ]. Brain Res : 89 — Furthermore, isolated tanycyctes display phosphorylation of STAT3 upon leptin stimulation, indicating the expression of the leptin receptor. Two possible transporters responsible for the movement of leptin from the CP to the CSF are low density lipoprotein-related protein 2 LRP2 [ 28 ] or the short form of the leptin receptor LepRa [ 1819 ].

Some features of the site may not work correctly. Am J Physiol. These findings challenge the general assumption of reduced leptin action in obesity, and they should be considered in the development of therapies targeting leptin signaling for the treatment of metabolic disease. In either case, the unraveling of lean individuals with elevated leptin levels might identify them as a new class at increased risk for diet-induced obesity. The diets, which have been previously described 23were obtained from Research Diets.

Nature Med 1 : — Research Needs alert. Transgenic mice overexpressing leptin accumulate adipose mass at an older, but not younger age. Share This Paper. Leptin surge precedes onset of autoimmune encephalomyelitis and correlates with development of pathogenic T cell responses.

For example, it has been shown that microinjection of small doses of leptin directly into the ARC result in reduced energy intake All sections in the series were then carefully examined by dark-field microscopy to assign positive cells diet induced obese mice retain endogenous leptin action movies appropriate nuclei using locations of adjacent landmarks. In contrast, other hypothalamic and extrahypothalamic nuclei remained leptin sensitive. Cloning and distribution of galanin-like peptide mRNA in the hypothalamus and pituitary of the macaque. Each panel represents one animal. The brain plays an important role in orchestrating this homeostasis by receiving inputs from peripheral tissues and responding by regulating various sensations such as reward and satiety. Entry of peroxidase into neurons of the central and peripheral nervous systems from extracerebral and cerebral blood.

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Densitometric analysis was performed using ImageJ 1. Maintenance of energy homeostasis is the keystone in preventing obesity and the metabolic syndrome. Foremost, our method does not require radiation and the predicaments associated with it. Oxford Academic. Metabolic analysis by indirect calorimetry showed that PEG-MLA treatment resulted in increased food intake and respiratory quotient without altering body composition or energy expenditure. The effect of leptin is enhanced by microinjection into the ventromedial hypothalamus.

View on PubMed. To inruced whether the preadipocytes and small adipocytes of the LepTg mice were capable of differentiation and growth into lipid filled adipocytes, we recovered the stromal vascular cell fraction of WAT from normal and LepTg mice and cultured it in vitro to induce differentiation and growth. In lean mice, circulating serum leptin levels tended to increase transiently following infection; the concentration at d 3 p. Email alerts Article activity alert. P CFD.

Smith, Patricia A. Mol Metab6 10 dieet, 24 Jun Figures and Topics from this paper. However, in addition to their anorectic effects, these cytokines increase leptin production 4142 ; therefore, leptin concentrations in the lean mice may have been appropriately balanced. Surprisingly, in obese mice serum leptin decreased significantly during infection.

Open in a separate window. Specifically, SOCS1 and 3 are amplified in obese animals and these proteins inhibit signaling by type I interferons 48 Cited by: 3 articles PMID:

To first test the quality of the tissue isolation method, several individual hypothalamic nuclei were action movies from two lean mice. International Journal of Obesity. Design and evaluation of GLP-1 receptor G-protein biased agonist with prolonged efficacy on diabetes. Tanycytic VEGF-A boosts blood—hypothalamus barrier plasticity and access of metabolic signals to the arcuate nucleus in response to fasting. Our data suggest that leptin resistance in the ARC could be important for development of DIO, but the underlying mechanism causing decreased activation of STAT3 has remained unresolved. A recent study by Balland and colleagues describes a dissection method to separate the ME from the MBH, thus excluding circulating signals and allowing the measurement of proteins found only within the MBH and not within the ME [ 17 ]. DIO in mice has earlier been associated with a dramatic loss of total hypothalamic STAT3 signaling 12but potential regional differences within the hypothalamus were not examined.

Paul T. Serum immunoreactive-leptin concentrations in normal-weight and obese humans. This may relate to our data showing that sndogenous increase in SOCS-3 appears to be restricted to the ARC and that earlier studies have used whole hypothalamic tissue, which may have prevented detection of changes in the subregion. How leptin is transported across the BBB and to its responder neurons, defined by their expression of the leptin receptor LepRis still a matter of debate [ 14 ]. Nat Rev Endocrinol.

This suggests the existence of leptin resistance in hyperleptinemic obese subjects. Next, if labeling with the fluorescent dye is successful and the labeled peptide remains bioactive, modern imaging techniques can be applied to visualize the transport route of fluorescent peptides into the brain. Open in new tab Download slide. Citing articles via Web of Science

However, as shown by our study and outlined in Fig. Due to the conflicting nature of the literature regarding leptin transport and uptake in obese animals [ 12172526 ], we aimed to confirm our findings using an additional, more quantitative method. This is mainly supported by leptin transport studies that used radioactively labeled leptin and showed a decrease in blood—CSF leptin ratios, suggesting blunted leptin transport kinetics and thus a cause for leptin resistance [ 12 ].

Histochemistry 97 : — For the obede of the slopes of weight gain on the HFD, the individual slope of the body weight curve of each mouse on the HFD was obtained from the equation of the linear curve fit. Science : — These molecules play essential roles in the early inhibition of viral replication 17the stimulation of an inflammatory response 18and recruitment of immune cells to the site of infection Antiviral and proinflammatory cytokine mRNA production in the lungs of the infected mice was markedly different between obese and lean mice.

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The latter would indicate a specific uptake, due to the fact that the ependymal diet induced obese mice retain endogenous leptin action movies are connected by tight-junctions and thus form the blood—CSF barrier in the CP. Email movoes Article activity alert. Overall, our findings suggest a crucial role for the CP in controlling the transport of leptin into the cerebrospinal fluid and from there to target areas such as the MBH, potentially mediated via the leptin receptor. Results Fluorescently labeled leptin allows for visualization of leptin distribution in the whole mouse brain To visualize how exogenous leptin distributes in the brain after injection i. Despite high circulating leptin levels, leptin resistant individuals typically experience a drive to eat extra calories, which impedes sustainable weight loss [ 7 ]. However, high costs and difficulties in creating the stable peptide tracer conjugates restrict their use to few laboratories specialized in such studies. Mol Cell.

Subsequently, leptin is transported via tanycytes into the cerebrospinal fluid CSF of the ventricular space, from where it then laterally diffuses into the MBH [ 17 ]. Skip Nav Destination Article Navigation. Identification of SOCS-3 as a potential mediator. National Center for Biotechnology InformationU. Impaired transport of leptin across the blood—brain barrier in obesity. In order to visualize the lectin Thermo Fisher Scientific Inc.

As discussed above, this is likely an underestimate of the actual leptin resistance. Mol Cell 1 : — Impaired transport of leptin across the blood-brain barrier in obesity is acquired and reversible. Hypothalamic tanycytes are an ERK-gated conduit for leptin into the brain. Gut-brain cross-talk in metabolic control. This significant impairment is likely because the Western blotting analysis, compared with counting of positive cells by IHC, also measures partial decreases in STAT3 phosphorylation in individual cells. Because leptin acts on several brain nuclei both within and outside the hypothalamus 21we hypothesized that some sites within the CNS may remain leptin sensitive in DIO mice.

The importance of the current findings is underscored by the fact that millions of people worldwide are affected by influenza infection every year and the universal prevalence of obesity has reached epidemic proportions. Intradermal lipopolysaccharide challenge as an acute in vivo inflammatory model in healthy volunteers. Smith, no conflicts of interest; P. NK cells assist in eliminating infected cells and help limit viral spread until a specific cell-mediated response can be assembled Receive exclusive offers and updates from Oxford Academic.

The reason for this discrepancy is unclear but may relate to the fact that we have used pharmacological doses of endogenous leptin action, and it cannot be ruled out that a lower amount of recombinant leptin would result in reduction of stimulated STAT3 phosphorylation in some brain regions of DIO mice in addition to the ARC. The Src-family kinase Lyn in immunoreceptor signaling. This suggests the existence of leptin resistance in hyperleptinemic obese subjects. Mol Metab. Profound weight loss induces upregulation of LepR in the CP and increased leptin accumulation in the MBH To gain further insight into how leptin resistance may affect leptin transport, we designed a diet intervention study. Adult NG2-glia are required for median eminence-mediated leptin sensing and body weight control. Nat Protoc.

Insulin activation of phosphatidylinositol 3-kinase in the hypothalamic arcuate nucleus: a key mediator of insulin-induced anorexia. Indeed, LepRa expression levels may be the limiting factor for leptin BBB achion rates when endogenous leptin levels diet induced obese mice retain endogenous leptin action movies high, or supraphysiological levels of recombinant leptin are administered. Moreover, we compared leptin levels in the ME and MBH of DIO mice subjected to weight loss by either modest dieting, profound calorie restriction or repeated treatment with exendin-4, to clarify whether altered leptin transport into the MBH can explain the superior restoration of leptin sensitivity by pharmacology [ 22 ]. Sahu A A hypothalamic role in energy balance with special emphasis on leptin. Open in new tab Download slide. As indicated in Fig.

Densitometric analysis was performed using ImageJ 1. PEG-MLA treated mice also displayed decreased whole-body insulin sensitivity, moives endogenous hepatic glucose production HPGand impaired insulin mediated suppressed of HPG as determined by euglycemic-hyperinsulinemic clamps. Role of signal transducer and activator of transcription 3 in regulation of hypothalamic proopiomelanocortin gene expression by leptin.

Paul T. Time-resolved hypothalamic open flow micro-perfusion reveals normal leptin transport across the blood—brain barrier in leptin resistant mice. As indicated in Fig. J Neurosci 21 : — After loading the sample onto the column, the column was washed with 10 column volumes of Buffer A.

Oxford University Dlet is a department of the University of Oxford. Laboratory propagation of human influenza viruses, experimental host range, and isolation from clinical material. Mice housing, procedures, and handling were in agreement with institutional guidelines and were approved by the University of California-San Francisco Animal Care Committee. Article Navigation. The Journal of endocrinology. Search articles by 'Lee Ann Norman'.

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