INT102935

Context Info Confidence 0.60 First Reported 2002 Last Reported 2010 Negated 7 Speculated 4 Reported most in Body Documents 31 Total Number 35 Disease Relevance 18.47 Pain Relevance 5.24

signal transduction (Lep) extracellular space (Lep) extracellular region (Lep) intracellular (Lep) lipid metabolic process (Lep)

Anatomy Link Frequency body 4 fat 3 plasma 2 sympathetic 2 cartilage 1 Lep (Mus musculus)

Pain Link Frequency Relevance Heat cytokine 135 100.00 Serotonin 2 99.54 Cholecystokinin 112 99.08 Inflammation 111 98.64 Osteoarthritis 379 98.36 Intracerebroventricular 18 97.20 Hippocampus 40 96.16 endometriosis 3 95.36 tolerance 67 94.68 Kinase C 4 93.84

Disease Link Frequency Relevance Heat Obesity 1591 100.00 Body Weight 248 100.00 Disease 60 99.36 INFLAMMATION 135 98.64 Aging 249 98.40 Osteoarthritis 316 98.36 Diabetes Mellitus 157 97.52 Ganglion Cysts 1 97.52 Targeted Disruption 155 97.12 Endometriosis (extended) 6 95.36

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Key:

Protein

Mutation

Event

Anatomy

Negation

Speculation

Pain term

Disease term

CONCLUSIONS: Our data suggest that kinin B(1) receptors participate in the regulation of the energy balance via a mechanism that could involve the modulation of leptin sensitivity.

Regulation (modulation) of leptin

1) Confidence 0.60 Published 2008 Journal Diabetes Section Body Doc Link 18332096 Disease Relevance 0 Pain Relevance 0

Besides, these data suggest that the leptin receptor may be regulated in a similar way to other cytokine receptors, such as the IL-2 receptor (CD25).

Spec (may) Regulation (regulated) of leptin associated with cytokine

2) Confidence 0.54 Published 2010 Journal Mediators of Inflammation Section Body Doc Link PMC2846344 Disease Relevance 0 Pain Relevance 0.12

Serotonergic activation rescues reproductive function in fasted mice: does serotonin mediate the metabolic effects of leptin on reproduction?

Regulation (effects) of leptin associated with serotonin

3) Confidence 0.45 Published 2002 Journal Biol. Reprod. Section Title Doc Link 12021050 Disease Relevance 0 Pain Relevance 0.38

The relevance of osteocalcin in the leptin-dependent sympathetic regulation of insulin secretion was also verified in vivo.

Regulation (regulation) of leptin in sympathetic

4) Confidence 0.45 Published 2008 Journal The Journal of Cell Biology Section Body Doc Link PMC2606962 Disease Relevance 0.55 Pain Relevance 0.03

Short-term leptin treatment did not affect resting cell length in either young or aging C57 and ob/ob mice (Fig. 3A).

Neg (not) Regulation (affect) of leptin associated with aging and obesity

5) Confidence 0.45 Published 2010 Journal PLoS ONE Section Body Doc Link PMC2852499 Disease Relevance 1.28 Pain Relevance 0

Short-term leptin treatment (1.0 nM) failed to affect resting cell length in either low or high fat diet groups at both ages.

Neg (failed) Regulation (affect) of leptin in fat

6) Confidence 0.45 Published 2010 Journal PLoS ONE Section Body Doc Link PMC2852499 Disease Relevance 0.89 Pain Relevance 0

To test the potential role of leptin in the pathogenesis of osteoarthritis, an in vitro study was conducted using porcine cartilage explants to determine the effects of physiologic levels of leptin on cartilage matrix turnover and inflammation.

Spec (determine) Regulation (effects) of leptin in cartilage associated with inflammation and osteoarthritis

7) Confidence 0.45 Published 2010 Journal Arthritis Res Ther Section Body Doc Link PMC2945020 Disease Relevance 0.44 Pain Relevance 0.22

It is well documented that STAT3-dependent signaling, which in turn promotes changes in gene transcription, plays an important role in a number of leptin driven hypothalamic functions including body weight regulation, lactation and regulation of thyroid function (Bates and Myers, 2004).

Regulation (regulation) of leptin in thyroid associated with body weight

8) Confidence 0.43 Published 2007 Journal Mol Cell Neurosci Section Body Doc Link PMC1995039 Disease Relevance 0.10 Pain Relevance 0.05

Moreover, the rate of leptin transport varies between brain regions and is also dependent on the plasma levels of leptin.

Regulation (dependent) of leptin in brain

9) Confidence 0.43 Published 2007 Journal Mol Cell Neurosci Section Body Doc Link PMC1995039 Disease Relevance 0.09 Pain Relevance 0.30

We had previously shown that fasting could regulate hypothalamic gene expression in insulin-deficient mice even though in these mice fasting did not influence plasma leptin or insulin [5].

Neg (not) Regulation (influence) of leptin in plasma

10) Confidence 0.42 Published 2003 Journal BMC Physiol Section Body Doc Link PMC179893 Disease Relevance 0.32 Pain Relevance 0

Interestingly, a lowered leptin level after 48- hour food deprivation affected expression neither of CCK-A receptor [23] nor CART in nodose ganglion neurons [24].

Neg (neither) Regulation (affected) of leptin in ganglion associated with ganglion cysts and cholecystokinin

11) Confidence 0.39 Published 2008 Journal BMC Neurosci Section Body Doc Link PMC2587474 Disease Relevance 0.28 Pain Relevance 0.81

After delivery the leptin values dropped to non pregnant levels (NP) in CBA/J x DBA/2 and control CBA/J x BALB/c matings (Fig 2C).

Regulation (control) of leptin

12) Confidence 0.33 Published 2010 Journal PLoS ONE Section Body Doc Link PMC2965104 Disease Relevance 0.62 Pain Relevance 0

It is responsive to peripheral stimuli such as leptin.

Regulation (responsive) of leptin

13) Confidence 0.31 Published 2007 Journal Nutr Metab (Lond) Section Body Doc Link PMC2018708 Disease Relevance 0.18 Pain Relevance 0.11

However neither leptin nor adiponectin concentrations correlated with the angiogenic response, nor find confirmation in microarray results showing down-regulation of the leptin signaling by JAK-STAT pathway in animals on HF diet.

Regulation (regulation) of leptin

14) Confidence 0.27 Published 2009 Journal Lipids Health Dis Section Body Doc Link PMC2674043 Disease Relevance 0.37 Pain Relevance 0.07

mice and in ob/ob mice treated with the sympathomimetic isoproterenol supports the view that osteocalcin is in vivo a significant mediator of the leptin-dependent sympathetic regulation of insulin secretion.

Regulation (sympatheti) of leptin in sympathetic associated with obesity

15) Confidence 0.27 Published 2008 Journal The Journal of Cell Biology Section Body Doc Link PMC2606962 Disease Relevance 0.75 Pain Relevance 0.03

To add further credence to the notion that sympathetic signaling in osteoblasts contributes to the leptin regulation of insulin secretion, we performed two other experiments.

Regulation (regulation) of leptin in osteoblasts

16) Confidence 0.27 Published 2008 Journal The Journal of Cell Biology Section Body Doc Link PMC2606962 Disease Relevance 0.47 Pain Relevance 0.13

mice had a normal body weight but harbored a significant increase in serum insulin levels, indicating that in vivo there is a significant neuronal contribution to the leptin regulation of insulin secretion (Fig. 1 O and Fig.

Regulation (ptin regul) of leptin in body associated with body weight

17) Confidence 0.27 Published 2008 Journal The Journal of Cell Biology Section Body Doc Link PMC2606962 Disease Relevance 0.26 Pain Relevance 0.05

Given the pleiotropic effects of leptin in regulating appetite, skeletal metabolism, fertility, and many other physiologic functions, however, targeting leptin directly may prove overly complex as an osteoarthritis therapy.

Regulation (targeting) of leptin associated with osteoarthritis

18) Confidence 0.27 Published 2010 Journal Arthritis Res Ther Section Body Doc Link PMC2945020 Disease Relevance 1.88 Pain Relevance 0.58

Indeed, leptin was the only cytokine or adipokine that was altered by the high-fat diet.

Regulation (altered) of leptin in fat associated with cytokine

19) Confidence 0.27 Published 2010 Journal Arthritis Res Ther Section Body Doc Link PMC2945020 Disease Relevance 1.53 Pain Relevance 0.83

The present study does not allow to conclude whether the observed effects are due to an independent effect of leptin and NO via the sympathetic nervous system or due to an interaction between the signalling cascades of both molecules.

Neg (independent) Regulation (effect) of leptin in sympathetic nervous system

20) Confidence 0.27 Published 2010 Journal PLoS ONE Section Body Doc Link PMC2881035 Disease Relevance 0.58 Pain Relevance 0.04

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