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

Challenges and opportunities of defining clinical leptin resistance. J Biol Chem : —

David Stewart
Thursday, July 27, 2017
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  • Sign In. 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.

  • Spontaneous human mononuclear cell cytotoxicity to cultured tumor cells: reproducibility of serial measurements with the use of a chromiumrelease microcytotoxicity assay.

  • Diabetes 51 : —

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Materials and Methods

Food intake and the regulation of body weight. Download PDF. In contrast to earlier studies in the rat 2021no positive cells were found in the PVN. Hypothalamic leptin receptor and signaling molecule expressions in cafeteria diet-fed rats.

STAT3 signalling is required for leptin regulation of energy balance but not reproduction. Thank you for visiting nature. In vivo experiments were performed without blinding of the investigators. To overcome this we injected mice with leptin i. The reason for the selective leptin resistance in the ARC, but not of other brain regions, is unclear. The product leptin-CW was subsequently subjected to anion exchange chromatography Fig.

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Leptin is a 16kDa hormone secreted by adipocytes Zhang et al. Leptin modulates the T-cell immune response and reverses starvation-induced immunosuppression. Insulin-like growth factor-I is an essential regulator of the differentiation of 3T3-L1 adipocytes. Pathology was graded semiquantitatively, as previously described Search Menu. P HFD.

Related articles in PubMed Effect of dietary pumpkin Cucurbita moschata seed meal on layer performance and egg quality characteristics. STAT3 signalling is required for leptin regulation of energy balance but not reproduction. J Neurosci 21 : — Intriguingly though, we see elevated leptin levels in the MBH of both weight loss intervention groups CR and EX4, when compared to the other 3 groups Fig.

Publication types

It also seems feasible to study the in vivo uptake of fluorescently labeled peptide into mouse tissues by using alternative biofluorescence imaging techniques. Moreover, fractions 2 to 4 contained leptin-CW bands that appeared to be larger in size ca. Several recent studies suggest a prominent role of the median eminence and tanycytes in mediating leptin transport to the MBH [ 1736 ]. 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.

  • Reviews in Endocrine and Metabolic Disorders

  • All the authors analyzed the data. Limited food intake will result in lower serum leptin concentrations 38 ,

  • Peripherally applied leptin in rodents induces a central signaling pathway that involves activation of signal transducer and activator of transcription 3 STAT3 8.

  • Adult NG2-glia are required for median eminence-mediated leptin sensing and body weight control.

  • Lung mRNA expression at d 3 p.

  • Advanced Search. Melanocortin receptors in leptin effects.

Sections were endogenous leptin and incubated with biotinylated antirabbit antibodyfollowed by avidin-biotin-complex labeling. 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 moviie in this hypothalamic nucleus. The finding that SOCS-3 is increased specifically in the ARC, but not in other regions of the hypothalamus, is exciting and opens the possibility of a causal relationship because we have earlier demonstrated that SOCS-3 is a potent inhibitor of leptin signaling Supplemental Video S4. Here, we aimed to gain new understanding in leptin BBB transport by visualizing and comparing leptin transport into the brain via whole mouse brain 3D imaging from lightsheet fluorescence microscopy.

Melanocortin receptors in leptin effects. Blood glucose concentrations were significantly greater than lean mice at baseline and at d 3 p. Furthermore, to our knowledge, there are no reports on the effect of diet-induced obesity on infection with influenza virus. High-fat diet treatment for 20 wk revealed that, compared with normal mice, the LepTg mice had an increased susceptibility to diet-induced obesity, as demonstrated by their rate of weight gain, higher accumulation of sc white adipose tissue mass, hypertrophy of adipocytes, and normalization of their reduced metabolic parameters. Mechanisms of leptin action and leptin resistance. Thus, in an obesogenic environment, maintaining lower leptin levels is highly beneficial for both obesity and diabetes management.

It has been previously shown that the leotin of the MBH undergoes vascular remodeling during obesity, which directly influences the accessibility to circulating substances [ 3435 ]. Differential expression of hypothalamic neuropeptides in the early phase of diet-induced obesity in mice. Citing articles via Web of Science Leptin and the maintenance of elevated body weight. All studies were based on power analyses to assure adequate sample sizes, and approved by the State of Bavaria, Germany. Each panel represents one representative animal. Nat Med 2 : —

Introduction

J Clin Invest 99 : — Despite high circulating leptin levels, leptin resistant individuals typically experience a drive to eat extra calories, which impedes sustainable weight loss [ 7 ]. Accordingly, in light of recent and our own findings, little evidence points towards impaired leptin BBB transfer as underlying cause for leptin resistance. It was possible to see the fenestrated blood vessels running along the ME. Tanycytes are specialized ependymal cells that form the blood—CSF barrier in circumventricular organs [ 37 ].

Adult NG2-glia are required for median eminence-mediated leptin sensing and body weight control. Banks WAFarrell CL Impaired transport of leptin across the blood-brain barrier in obesity is acquired and reversible. Sections were washed and incubated with biotinylated antirabbit antibodyfollowed by avidin-biotin-complex labeling. Densitometric analysis was performed using ImageJ 1. Overall, we found that DIO does not prevent the accumulation of leptin in brain areas important for metabolic control.

This may serve as confirmation that the ME was removed. Although the specific function s retaib each nucleus in leptin action is yet largely unknown, injection of small doses of the hormone into the VMH, but not into the ARC, PVN, or DMH, stimulates the sympathetic nervous system Nat Med 10 : — However, the leptin signals required for regulating autonomic function seems relatively intact in DIO mice.

Proc Natl Acad Sci. It should be pointed out that this analysis includes all visible P-STAT3-positive nuclei and disregards differences in signal intensities. Reviews in Endocrine and Metabolic Disorders

SOCS3 expression within leptin receptor-expressing cells regulates food intake and leptin sensitivity but does not affect weight gain in pregnant mice consuming a high-fat diet. Histological examination of WAT Fig. Select Format Select format. Recent history Saved searches.

OB protein binds specifically to the choroid plexus of mice and rats. These reetain appear to mediate leptin transcytosis to the CSF and from there to the arcuate nucleus [ 17 ]. One of five series from each animal was analyzed. Recently, Ladyman et al. These include the lateral hypothalamic area, the paraventricular hypothalamus PVNand the premammilary nucleus PMN of the hypothalamus, the periaqueductal gray and the dorsal raphe DR in the midbrain, and the parabrachial nucleus and the nucleus of the solitary tract NTS in the brain stem 19 — Neuron 23 : — Enhanced leptin sensitivity and attenuation of diet-induced obesity in mice with haploinsufficiency of SOCS

Introduction

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. However, high costs and difficulties in creating the stable peptide tracer conjugates restrict their use to few laboratories specialized in such studies. Leptin caused a 7 fold increase in pSTAT3 levels, which was significantly reduced in all other diet groups Fig. If too much tissue was removed, it will have a concave surface.

Indeed, genetic deletion of the leptin receptor in POMC neurons demonstrates that leptin signaling in these cells is required for normal regulation of body weight homeostasis New issue alert. Moreover, leptin resistance in brain regions located outside the hypothalamus was not examined. Received : 28 February

To remove the MBH the brain actio cut with a scalpel coronally, directly through the center of the hypothalamus. 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 ]. Tanycyte-like cells form a blood—cerebrospinal fluid barrier in the circumventricular organs of the mouse brain. Intriguingly though, we see elevated leptin levels in the MBH of both weight loss intervention groups CR and EX4, when compared to the other 3 groups Fig. Overall, these data highlight the possibility of a non-transport related leptin resistance.

Insulin-like growth factor I mediates high-fat diet-induced adipogenesis in Osborne-Mendel rats. Search Menu. Experimentally induced hyperleptinemia in rodents via exogenous leptin treatment results in a lean phenotype caused by a decrease in food intake and an increase in energy expenditure 14 —

Measurement of protein using bicinchoninic acid. Influenza infection is a major cause retaih morbidity and mortality worldwide. J Am Diet Assoc. Harp, Melinda A. Experimentally induced hyperleptinemia in rodents via exogenous leptin treatment results in a lean phenotype caused by a decrease in food intake and an increase in energy expenditure 14 — Br J Haematol. Monitoring of body weight Fig.

A lacto-ovo-vegetarian dietary pattern is protective against sarcopenic obesity: A cross-sectional study of elderly Chinese people. We speculate that selective diet induced obese mice retain endogenous leptin action movie resistance to the anorexigenic actions of leptin may have been advantageous inudced evolution, thus allowing for rapid accumulation of energy at times of excess food availability and at the same time maintaining other critical leptin-dependent functions. 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. Download PDF. Leptin-induced nuclear translocation of STAT3 immunoreactivity in hypothalamic nuclei involved in body weight regulation. One of five series from each animal was analyzed.

  • To first test the quality of the tissue isolation method, several individual hypothalamic nuclei were obtained from two lean mice.

  • Adipocytes area px

  • Mol Brain Res. Region specific reduction in leptin-induced phosphorylation of STAT3 in the rat hypothalamus is associated with leptin resistance during pregnancy.

SmithAlexia G. Cytokine regulation of cellular adhesion molecule retaon in inflammation. Altered macrophage-like functions of preadipocytes in inflammation and genetic obesity. While the resistance of obese subjects to exogenous leptin has been widely documented, the action of endogenous leptin to control energy balance in obesity has not been rigorously tested. 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

Brain Behav. Cite Cite Alexia G. Selective induction of monocyte and not neutrophil-attracting chemokines after influenza A virus infection. The extension and relevance of these findings to human obesity hint that, if a subset of individuals are lean because of increased leptin secretion, they may develop an abundance of preadipocytes and small adipocytes, which when exposed to rich-fat diets would undergo rapid differentiation and expansion resulting in severe obesity.

Materials and Methods

Cerebrospinal fluid leptin levels: relationship to plasma levels and to adiposity in humans. About this article. Carlsbad, CA.

Diet-induced obese mice retain endogenous leptin action. 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 Paxinos GWatson C The rat brain in stereotaxic coordinates. Direct double-labeling studies of brain slices are, however, required to fully determine the chemical nature of all leptin-resistant cells in the ARC of DIO mice. Thus, in additional models of obesity, region-specific leptin resistance can be detected. As discussed above, this is likely an underestimate of the actual leptin resistance.

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Molecular cell. The absorbance of the dye at nm diet pills lose weight normalized to the amount of tissue used for the differentiation experiment and expressed as absorbance units per 10 mg of WAT. Read article at publisher's site DOI : They theorized that the body was making extra leptin to combat obesity and that the obese patients must therefore need more leptin than persons of average weight to signal the brain to stop eating. Lung mRNA expression of chemokines in influenza infected lean and obese mice. The observation that both lean and DIO mice had comparable increases in energy intake and BW that were proportional to the doses of antagonist administered peripherally or centrally, demonstrates that both groups experienced substantial restraint of food intake by endogenous leptin, irrespective of their body weight and adiposity. Obesity and cardiovascular disease: pathophysiology, evaluation, and effect of weight loss: an update of the American heart association scientific statement on obesity and heart disease from the obesity committee of the council on nutrition, physical activity, and metabolism.

Because El-Haschimi et al. Differential expression of hypothalamic neuropeptides in the early phase of diet-induced obesity in mice. Revised : 20 July The concept of selective leptin resistance: evidence from agouti yellow obese mice. J Biol Chem : —

MeSH terms

Please review our privacy policy. Recent findings suggest that amylin is able to restore leptin sensitivity and when used in combination with leptin enhances body weight loss in obese rodents and humans. Limited food intake will result in lower serum leptin concentrations 38 ,

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

  • Alexia G. This value was then normalized to total protein in the sample.

  • We thereby aimed to assure an equal distribution of starting body weights at the beginning of jnduced study, which allows for better dissection of longitudinal treatments effects on body weight. However, high costs and difficulties in creating the stable peptide tracer conjugates restrict their use to few laboratories specialized in such studies.

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Pulmonary compartmentalization of interferon and natural killer cell activity. Subject alert. Evidence for this comes from a recent report by Papathanassoglou et al. Article Navigation. However, it should be noted that although the obese mice had a drop in leptin at d 3 p. The expression of cytokines and chemokines during an influenza virus infection occurs in a coordinated and specific cascade.

To first test the quality of the tissue isolation method, several individual hypothalamic nuclei were obtained from two lean mice. By using fluorescently labeled leptin in combination with tissue clearing and light-sheet fluorescence microscopy, we display highest leptin accumulation in the choroid plexus of the ventricular system followed by circumventricular organs such as the ME or SFO. Dense LepR expression is especially found in the choroid plexus CP [ 19 ], an important component of the BBB anchored to the walls of the lateral, central and fourth ventricles. 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.

Associated Data

This is consistent with direct measurements demonstrating reduced whole-brain uptake in obese rodents The reason for the selective leptin resistance in the ARC, but not diet induced obese mice retain endogenous leptin action movie other brain regions, is unclear. 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. Sahu A A hypothalamic role in energy balance with special emphasis on leptin. 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.

To determine whether the preadipocytes and small adipocytes of the LepTg mice were capable of differentiation and growth into lipid filled adipocytes, we recovered the ,ice vascular cell fraction of WAT from normal and LepTg mice and cultured it in vitro to induce differentiation and growth. 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. Smart citations by scite. Influenza infection is a major cause of morbidity and mortality worldwide.

  • 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 ,

  • Quantitation of adipose conversion and triglycerides by staining intracytoplasmic lipids with Oil red O. Related articles in Web of Science Google Scholar.

  • Supplemental Video S3.

  • Food intake and the regulation of body weight. At the end of the diet-intervention study, all mice were first subjected to a single intraperitoneal i.

  • Annual review of physiology. 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.

  • Here, we aimed to gain new understanding in leptin BBB transport by visualizing and comparing leptin transport into the brain via whole mouse brain 3D imaging from lightsheet fluorescence microscopy.

Citing articles via Web of Science Article Google Scholar Comparable leptin protein levels in fiet ME and MBH tissues of lean and obese mice, quantified via western blotting, corroborated the results of our microscopy analyses. Email alerts Article activity alert. You can also search for this author in PubMed Google Scholar. Decreased transport of leptin into the brain has been suggested as one mechanism causing central leptin resistance in obesity 25 ,

Full size image. Brain Res. Accepted : 02 September Int J Obes.

Diabetes 48 : — Our findings provide preclinical evidence that high activity, long-acting leptin analogs are additively efficacious when used in combination with other weight-lowering agents. Living Well.

Other data suggest that defective signaling, rather than reduced leptin transport, precedes development of obesity High calorie diet triggers hypothalamic angiopathy. Mice were injected ip with leptin 5. The finding that SOCS-3 is increased specifically in the ARC, but not in other regions of the hypothalamus, is exciting and opens the possibility of a causal relationship because we have earlier demonstrated that SOCS-3 is a potent inhibitor of leptin signaling

When they treated the mouse withleptin, it stopped eating so much and started losing weight. Ottaway N 1. Google Obeese PubMed. These findings demonstrate that hyperleptinemic DIO mice retain leptin suppression of feeding comparable to lean mice and counter the view that resistance to endogenous leptin contributes to the persistence of DIO in mice. Nat Med 1 : — PLA was dosed based on BW 1. Article Navigation.

Read article actoon publisher's site DOI : Hyperleptinemia is required for the development of leptin resistance. Quantitation of the ORO dye, a measure of triglyceride content of differentiated adipocytes, revealed that the LepTg adipocytes had accumulated 4. This suggestion that our DIO mice have near maximal endogenous leptin action provides a caveat to the therapeutic application of leptin to treat obesity.

For the diet intervention study, DIO mice were subdivided into 4 experimental groups. Info Diabetologie In contrast to earlier studies in the rat 20 obesr, 21diet pills lose weight positive cells were found in the PVN. Interestingly, using Western blotting, they found regional differences in leptin-inducible STAT3 phosphorylation between nonpregnant and pregnant animals, namely suppressed activation in the ARC and the VMH, but not in the DMH or lateral hypothalamus. 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.

To determine whether increased mortality was associated with an increased viral load in the obese mice, we measured lung viral titers at d 3 and 6 p. Recent findings suggest that amylin is able to restore leptin sensitivity and when used in combination with leptin enhances body weight loss in obese rodents and humans. Mol Metab6 1024 Jun Leptin levels reflect body lipid content in mice: evidence for diet-induced resistance to leptin action. Sign In. Perez-Tilve D 1.

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 Socs3, a primary target of leptin. There were no significant differences between lean and obese uninfected controls. Permissions Icon Permissions. Article Contents Abstract.

The extension and relevance of these findings to human obesity hint that, if a subset of individuals are lean because of increased leptin secretion, they may develop an abundance of preadipocytes and small adipocytes, which when exposed to rich-fat diets would undergo rapid differentiation and expansion resulting in severe obesity. 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 contrast, Socs3 expression was significantly increased in vehicle-treated DIO mice in comparison to vehicle-treated lean controls Fig 4d. Cited by: 3 articles PMID: Open in new tab. We thank Drs. J Appl Physiol.

Galbraith Road. J Am Diet Assoc. DIO mife are frequently used as a model of leptin resistance. 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. Google Preview.

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  • See other articles in PMC that cite the published article.

  • The two brain halves are then laid flat, to expose the hypothalamus face upwards. It is relatively clear that overtly obese mice do have reduced whole-brain leptin transport 56but the importance of this result is unresolved.

  • In a first experiment, animals remained on diets for 16 wk Fig. Advanced Search.

BioStudies: supplemental material and supporting data. A superactive leptin antagonist alters metabolism and locomotion in high-leptin mice. Keyword: Search. Lungs were removed at d 0, 3, and 6 p. Interestingly, obesity is also associated with chronic pulmonary and cardiovascular diseases 15 Ogus, Y.

Search ADS. Interestingly, when comparing leptin-CW accumulation in chow and DIO mice, there appears to be no difference in signal intensities across all areas positive for leptin-CW Attenuation of leptin action and regulation of obesity by protein tyrosine phosphatase 1B. A lacto-ovo-vegetarian dietary pattern is protective against sarcopenic obesity: A cross-sectional study of elderly Chinese people. Indeed, administration of recombinant leptin to obese, hyperleptinemic subjects failed to decrease body weight and food intake 7. All sections in the series were then carefully examined by dark-field microscopy to assign positive cells to appropriate nuclei using locations of adjacent landmarks.

Over-expression of leptin receptors in hypothalamic POMC neurons increases susceptibility to diet-induced obesity. Charles, MO. Conclusion: In response to HFD feeding, the inability to upregulate leptin levels due to partial leptin deficiency protects mice from diet-induced obesity and metabolic dysregulation.

J Diet induced obese mice retain endogenous leptin action movie 20 : — Differential expression of hypothalamic neuropeptides in the early phase of diet-induced obesity in mice. Pictures were taken under a bright-field microscope Axioscope, Zeiss, Oberkochen, Germany with a digital camera Axiocam, Zeiss. We therefore conclude that this analysis is likely an underestimate of the degree of leptin-resistant signaling in the ARC of DIO mice. 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 obtain the best experience, we recommend you use a more up to date browser or turn off compatibility mode in Internet Explorer. San Diego : Academic Press.

Taken together, the study suggests that abnormalities in postreceptor leptin signaling, specifically in the ARC, may play a role in the pathogenesis of DIO in mice. A similar approach, obese mice post mortem, was recently applied to profile the whole body bio-distribution of a fluorescently labeled glucagon-T3 hybride peptide in mice [ 29 ]. Search ADS. 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 ]. Am J Anat. Luke Harrison, Sonja C.

Nature Med 1 : — The publisher's final edited version of this article is available at Cell Metab. However, the inability in partially leptin-deficient mice to fully induce circulating leptin during the development of diet-induced obesity results in reduced food intake and leaner mice with lower body weight compared to their littermate controls. Histology of adipose tissue and liver tissue allowed insights into adipose tissue inflammation and hepatic triglyceride content.

Am J Physiol. In contrast, more common forms of obesity pbese diet-induced obesity DIOexhibit hyperleptinemia proportional to the amount of body fat stores Frederich et al. Skip Nav Destination Article Navigation. The antagonist increased feeding and body weight BW in lean mice, but not in obese models of leptin, leptin receptor, or melanocortin-4 receptor deficiency.

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Abstract The identification of leptin as a mediator of body weight regulation provided much initial excitement for the treatment of obesity. Lung mRNA expression of chemokines in influenza infected lean and obese mice. PMID: Preliminary studies from our laboratory determined that this dose of virus is sufficient to effectively elicit an immune response while causing little mortality in infected control mice. The publisher's final edited version of this article is available at Cell Metab. In this study, we asked whether the LepTg mice would resist the effects of a long-term high-fat diet HFD challenge, reasoning that their continuous response to transgenic hyperleptinemia might protect them against diet-induced obesity DIO.

The finding that SOCS-3 is increased specifically in the ARC, but not in other regions of the hypothalamus, is exciting and opens the possibility of a causal relationship because we have earlier demonstrated that SOCS-3 is a potent inhibitor of leptin signaling 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. Discussion We describe here a novel method of visualizing the transport of leptin across the BBB in mice. 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. A second look at the barriers of the medial basal hypothalamus. Reviews in Endocrine and Metabolic Disorders Banks WAFarrell CL Impaired transport of leptin across the blood-brain barrier in obesity is acquired and reversible.

J Clin Endocrinol Metab. Science News. Blood was drawn into heparinized tubes from the retro orbital sinus under Avertin anesthesia. Total protein was determined by bicinchoninic acid assay, as previously described Smith, Patricia A.

Conversely, when mice lacking leptin were infected, there was no rise in leptin concentrations following infection, and these mice had reduced macrophage function as well as high mortality rate 9. Receive exclusive offers and updates from Oxford Academic. Rivero B 2 .

Figure 1. Thus, although the increase in baseline Socs3 levels exhibited by DIO mice may attenuate the effect of exogenously administered leptin, explaining the lack of expected hypophagia or activation of Diet induced obese mice retain endogenous leptin action movie signaling cascade, our results suggest that DIO mice do not experience reduced endogenous leptin action, and in fact demonstrate that it plays a critical role preventing further BW gain. To determine whether obese mice had significantly elevated lung pathology compared with lean mice, we examined lung tissue following infection. T-tests were used for comparison of two groups and two-way ANOVA with or without repeated measures and Sidak multiple comparison tests were used for post hoc comparisons. Lung mRNA expression of chemokines in influenza infected lean and obese mice. Rivero B 2. Experimentally induced hyperleptinemia in rodents via exogenous leptin treatment results in a lean phenotype caused by a decrease in food intake and an increase in energy expenditure 14 —

  • Search Search articles by subject, keyword or author. Two defects contribute to hypothalamic leptin resistance in mice with diet-induced obesity.

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  • Immunogenicity and efficacy of orally administered inactivated influenza virus vaccine in mice.

Maintenance of energy homeostasis is the keystone in preventing obesity and the metabolic syndrome. Neurobiol Aging. Chemical hybridization of glucagon and thyroid hormone optimizes therapeutic impact for metabolic disease. Membranes were blocked in Tris-buffered-saline with 0. Dye solution not used for coupling was diluted to the same absorption value as that of the coupled leptin sample and used as a control. Leptin signaling in the hypothalamus: emphasis on energy homeostasis and leptin resistance.

To visualize how exogenous leptin distributes in the brain after injection i. Indiced protein binds specifically to the choroid plexus of mice and rats. Consistent with these results, immunohistochemical IHC studies demonstrate rapid activation of STAT3 by leptin in hypothalamic and extrahypothalamic brain regions of rats and mice. Pictures were taken under a bright-field microscope Axioscope, Zeiss, Oberkochen, Germany with a digital camera Axiocam, Zeiss. Recombinant mouse leptin was from Dr. One of the most widely used models of leptin resistance and human obesity is DIO in mice and rats.

Ip PLA or icv LA increases food intake and diet induced obese mice retain endogenous leptin action movie weight in wildtype mice but not in obese melanocortin 4-receptor deficient mice The melanocortin system plays a critical role mediating the effect of leptin on food intake and BW Seeley et al. 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. Google Scholar Crossref. However, the inability in partially leptin-deficient mice to fully induce circulating leptin during the development of diet-induced obesity results in reduced food intake and leaner mice with lower body weight compared to their littermate controls.

Lung viral titers were determined by a modified tissue culture infections dose 50 TCID 50 using hemagglutination as an endpoint, as previously described Diabetes Care. Leptin also plays a role in reproduction 4immunity 5and bone metabolism 6. Sign In or Create an Account. T lymphopaenia in relation to body mass index and TNF-alpha in human obesity: adequate weight reduction can be corrective.

Preliminary studies from our laboratory determined that this dose of virus is sufficient to effectively elicit an immune response while causing little mortality in infected control mice. Leptin regulates proinflammatory immune responses. Half of the right lobe of the lung was removed at d 0 uninfected3, and 6 p. Inhibition of natural killer cell activity by dietary lipids. Given the lack of an early proinflammatory response in obese mice, it is plausible that leukocytes from the obese mice no longer respond to leptin. Skip Nav Destination Article Navigation.

  • The design of barriers in the hypothalamus allows the median eminence and the arcuate nucleus to enjoy private milieus: the former opens to the portal blood and the latter to the cerebrospinal fluid.

  • Identifying the factors involved in counteracting the effect of leptin during the development of obesity may provide efficacious targets to prevent BW gain. Individuals lacking circulating leptin are hyperphagic and obese, features that can be reversed with administration of exogenous leptin Halaas et al.

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Within the hypothalamus, dense staining in the PMN and scattered staining in action movie lateral hypothalamic area was also detected. Leptin bands were detected by either immunolabeling with a leptin antibody red or infrared fluorescence green. LH conducted immunohistochemical stainings. Supplemental Video S3. Despite recent progress in the understanding of leptin signaling circuits in the brain, molecular mechanisms underlying the development of leptin resistance are still unknown. In further direct support of the hypothesis of a causal relationship between increased SOCS-3 and reduced leptin-stimulated STAT3 phosphorylation in obese mice are our recent data from studies of mice that are heterozygous for a SOCS-3 gene deletion

Behavioral and endocrinological effects of single injections of monosodium glutamate in the mouse. All mice were housed individually. It has been previously shown that the vasculature of the MBH undergoes vascular remodeling during obesity, which directly influences the accessibility to circulating substances [ 3435 ]. These changes include an invasion of fenestrated vessels from the ME into the ARC, allowing for an increase in peripheral hormone visibility to the arcuate neurons [ 36 ]. Design and evaluation of GLP-1 receptor G-protein biased agonist with prolonged efficacy on diabetes. Labeled leptin combined with tissue clearing and light-sheet fluorescence microscopy allows for 3D visualization of leptin distribution in the intact mouse brain.

Eur J Nucl Med. Insulin and leptin revisited: adiposity signals with overlapping physiological and intracellular signaling capabilities. Cell Metab. Membranes were then washed and incubated with secondary antibodies antirabbit-horseradish peroxidase coupled, ,; Bio-Radwashed and developed by enhanced chemiluminescence ECLplus, Amersham, Piscataway, NJ and x-ray films Amersham.

Accepted : 02 September Leptin serves as an adipostat, i. However, different results were detected in the VMH and the DMH between the two studies and actlon with the present study. Because the stimulation of STAT3 phosphorylation is markedly attenuated in response to a large pharmacological dose of leptin after only 6 d of HFD, it is likely that the arcuate nucleus is severely leptin resistant to endogenous leptin and that this resistance is present even before the onset of obesity.

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Melanocortin receptors in leptin effects. THE BINDING OF the adipocyte-derived hormone leptin 1 to its signaling competent receptor Acttion 2 in the arcuate nucleus 3 initiates a cascade of neuronal events aimed at the regulation of food intake and the adipose mass. Cited by: 6 articles PMID: Once infected, an appropriate coordination of both innate and adaptive immune responses is necessary for elimination and recovery from the virus. Lung inflammation contributes to increased mortality in influenza-infected mice.

Localization of leptin receptor mRNA and the long form splice variant Ob-Rb in mouse hypothalamus and adjacent brain regions by in situ hybridization. Am J Anat. We developed a novel tool for visualizing leptin transport using infrared fluorescently labeled leptin, combined with tissue clearing and light-sheet fluorescence microscopy. Reviews in Endocrine and Metabolic Disorders

  • Interestingly, because some CNS sites retain leptin responsiveness in DIO mice, it is possible that a HFD induces region-specific leptin resistance in the CNS that allows some aspects of leptin action to be unaffected, although other processes are attenuated.

  • 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.

  • More recent work points towards lepti crucial direct involvement of endothelial cells of the BBB as major mechanism of leptin transport [ 18 ]. 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.

Clin Endocrinol Oxf. The publisher's final edited version of this article is available at Cell Metab. Changes in the expression of any of these molecules can alter subsequent immune responses J Clin Endocrinol Metab. Totowa, NJ : Humana Press ; — Nature medicine. Figure 1.

How can we reconcile the apparent discrepancies between our results and previous reports, mostly based on radioactive tracer studies, which obesf diminished leptin BBB transport in a state of obesity [ 12 obese mice, 17 ]? These data suggest that leptin action in the ARC, but not in other hypothalamic or extrahypothalamic leptin-responsive brain regions, is specifically impaired in DIO mice. All studies were based on power analyses to assure adequate sample sizes, and approved by the State of Bavaria, Germany. The methods described can be readily adapted to accommodate a plethora of other peptide hormones, which may greatly impact the field of hormonal BBB transport. In a study of 4 wk, when increased body weight, energy intake, and hyperleptinemia is also present Fig.

Selective induction of monocyte and not neutrophil-attracting chemokines after influenza A virus infection. Nature medicine. These findings demonstrate that hyperleptinemic DIO mice retain leptin-suppression of feeding comparable to lean mice, and counter the view that resistance to endogenous leptin contributes to the persistence of DIO in mice.

Diabetes 51 : leptin action Here, we aimed to gain new understanding in leptin BBB transport by visualizing and comparing leptin transport into the brain via whole mouse brain retaln imaging from lightsheet fluorescence microscopy. Selective leptin resistance: a new concept in leptin physiology with cardiovascular implications. Eur J Nucl Med. If too much tissue was removed, it will have a concave surface. Direct double-labeling studies of brain slices are, however, required to fully determine the chemical nature of all leptin-resistant cells in the ARC of DIO mice. Interestingly, LepR was significantly upregulated in both weight loss groups CR and EX4, compared to all groups that did not undergo profound weight loss Fig.

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Our 3D imaging revealed leptin accumulation predominantly in the CP of the ventricular system, an ependymal secretory organ designed to transfer molecules from the blood to the CSF. Several cell types such as pericytes and astrocytes contribute to the architecture and mogie of the blood—brain barrier BBBwhich ultimately protects the brain from neurotoxins while governing the passive diffusion of gases and hydrophobic molecules as well as the active transport of hydrophilic nutrients, amino acids and large-scale peptide hormones [ 23 ]. Equally impressive is the finding that treatment with recombinant leptin reverses the obese phenotype in leptin-deficient humans 4. Hypothalamus as an endocrine organ. Rather, leptin signaling in the ARC is severely decreased, whereas several other sites retain leptin responsiveness.

Brain Res : 89 — New Engl J Med. Because the stimulation of STAT3 phosphorylation is markedly attenuated in response to a large inruced dose of leptin after only 6 d of HFD, it is likely that the arcuate nucleus is severely leptin resistant to endogenous leptin and that this resistance is present even before the onset of obesity. Elements of artwork used in Fig. 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. A sample of the cortex was also collected.

Norman LA 1. Search articles by 'Nickki Ottaway'. Leptin sensitivity can be restored by reducing circulating leptin levels within a physiologically healthy range and is a viable antiobesity and antidiabetic strategy. Endocrinology : — This suggestion that our DIO mice have near maximal endogenous leptin action provides a caveat to the therapeutic application of leptin to treat obesity.

In Fig. Hypothalamus as an endocrine organ. Pal RSahu A Leptin signaling in the hypothalamus during chronic central leptin infusion. Accepted : 02 September

We speculate that defects in leptin signaling in neurons within the ARC oobese play a role in the pathogenesis of leptin-resistant obesity. These changes include an invasion of fenestrated vessels from the ME into the ARC, allowing for an increase in peripheral hormone visibility to the arcuate neurons [ 36 ]. Download citation. Int J Obes. Membranes were blocked in Tris-buffered-saline with 0.

Obesity has been associated with immune dysfunction 1 — 3. Data Data behind the article This data has been text mined from the article, or deposited into data resources. To determine whether circulating glucose and insulin concentrations were affected by infection, mice were food deprived for 8 h and blood samples were collected prior to infection after 22 wk on the diet and at d 3 and 7 postinfection p. Europe PMC requires Javascript to function effectively.

To determine whether circulating glucose and insulin concentrations were affected by infection, mice were food deprived for 8 h and blood samples were collected prior to infection after 22 wk on the diet and at d 3 and 7 postinfection p. Select Format Select format. As expected, baseline leptin concentrations were higher in obese mice than in lean mice Fig. The extension and relevance of these findings to human obesity hint that, if a subset of individuals are lean because of increased leptin secretion, they may develop an abundance of preadipocytes and small adipocytes, which when exposed to rich-fat diets would undergo rapid differentiation and expansion resulting in severe obesity. Because the innate immune response also activates and polarizes the appropriate cell mediated response, these data indicate that overall immune function may be affected by obesity.

Figure 2. However, the hyperleptinemia characteristic of most forms of obesity, whether in animal models or individuals 9fails to result in similar effects and is thus attributed to leptin resistance. J Nutr Biochem. The combined leptin levels of the LepTg mice, however, were fold over those of normal mice. Interestingly, obesity is also associated with chronic pulmonary and cardiovascular diseases 15 This study clearly shows obesity can cause T cells to become insensitive to leptin and suggests that other cells of the immune system would be similarly affected. Individuals lacking circulating leptin are hyperphagic and obese, features that can be reversed with administration of exogenous leptin Halaas et al.

Accordingly, the CP has been strongly linked to leptin transport into the brain [ 21 ]. Time-resolved hypothalamic open flow micro-perfusion endogneous normal leptin transport across the blood—brain barrier in leptin resistant mice. Eur J Nucl Med. Our post mortem imaging approaches were based on LSFM as well as confocal microscopy to combine whole brain 3D imaging with subsequent high resolution imaging in brain slices. Modulation of tanycytic tight junctions in the ME was shown to increase leptin transport into the MBH [ 17 ]. The methods described can be readily adapted to accommodate a plethora of other peptide hormones, which may greatly impact the field of hormonal BBB transport. ME median eminence, MBH mediobasal hypothalamus.

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