Increased adipose mass associated with obesity has been linked with a low-grade, chronic inflammatory response, characterized by altered production of adipokines and increases in biological markers of inflammation, such as tumour necrosis factor-α, interleukin-6 or monocyte-chemoattractant protein-1 (MCP-1)plasminogen activated inhibitor (PAI-1), colony stimulating factor (CSF) or inducible nitric oxide synthase (iNOS). However, studies in recent years have revealed that adipocytes are not the major source of inflammatory cytokine secretion from adipose tissue. Non-adipose cells, that constitute the stromal vascular fraction, which includes preadipocytes, endothelial cells, fibroblasts, leukocytes and macrophages seem to be responsible for the chronic inflammatory response observed in obesity. Macrophages residing in lean adipose tissue are characterized by increased expression of genes such as Ym-1, arginase-1 and the anti-inflammatory cytokine IL10. They show an increased capacity for tissue repair and angiogenesis and are commonly described as M2 or “alternatively activated” macrophages. However, in recent years it has been found that the expansion of adipose tissue in obesity is associated with an increased infiltration with macrophages of the M1 or “classically activated” phenotype from the circulation. These macrophages are usually recruited to sites of tissue damage and have been reported to be in a pro-inflammatory state with increased expression of TNF-α and iNOS .
The cellular mechanisms responsible for this enhanced macrophage recruitment remain largely unknown, but it has been suggested that dysregulated adipokine production and increased adipocyte size might contribute to this phenomenon in a crosstalk between adipocytes and macrophages. Adipocyte-derived factors, such as MCP-1 or CSF-1 are overexpressed in obesity and can promote the recruitment of circulating monocytes. Furthermore, obesityis characterized by decreased secretion of adiponectin, which has been shown to exert anti-inflammatory effects on macrophages, whereas the production of the pro-inflammatory adipokine leptin is increased. Another contributing factor might be the increased levels of free fatty acids released from enlarged adipose tissue in
obesity. Recently, it has been demonstrated that saturated fatty acids can act as ligands for TLR-4 and induce the production of inflammatory cytokines from macrophages through the activation of the NFκ-B pathway. In addition, free fatty acids may contribute to the accumulation of bioactive lipids, such as
DAGsand ceramides within the macrophage which are also thought to be an upstream activator of NFκ-B.
10 September 2009
09 September 2009
Obesity Wonder Drug in Development!
(I guess that we can all rest easy and double up on the cookies and hamburgers with this research under way!)
Wonder drug in development to let dieters eat whatever they want - without gaining a single pound
By Fiona MacraeLast updated at 8:07 AM on 04th September 2009
A pill that allows dieters to gorge on junk food without putting on a pound is being developed by scientists. The couch potato's dream, it would allow people to eat all their favourite foods without worrying about their waistline. The wonder drug would also protect against diabetes, liver disease and other debilitating conditions associated with unhealthy eating habits.
The breakthrough hinges on the discovery of a metabolism 'masterswitch' - a gene key to weight control. Mice lacking the gene, known as IKKE, stay slim despite being fed a lard-based diet.
The 'knock-out' mice also free of the liver problems associated with a junk food diet and appear to be protected against diabetes, the journal Cell reports.
Researcher Alan Saltiel said: 'We've studied other genes associated with obesity - we call them "obesogenes" - but this is the first one we've found that, when deleted, stops the animal from gaining weight. 'The fact that you can disrupt all the effects of the high fat diet by deleting this one gene in mice is pretty interesting and surprising.' It is thought that the gene makes enzymes called kinases that help regulate metabolism. Removing the gene - and the kinases - speeds up metabolism, leading to more calories being burnt.
Dr Saltiel said: 'Perhaps most interestingly, the mice burn more calories even though they aren't eating any less or exercising any more.' In the case of people, a drug that cuts kinase levels could allow people to eat fatty and sugary foods without putting on weight. It would also enable them to stay trim without going to the gym. The researchers, from the University of Michigan in the US, are now hunting for such a pill and predict that many others will join the search.
They said: 'The specificity of the apparent actions of IKKE, the nature of the enzyme, and the profound resistance of the knock-out mice to the high-fat diet, make it an especially appealing drug target for the treatment of metabolic disease.' If they do find the right formula, the drug could be on the market within a decade. But with suggestions that such a drug could increase vulnerability to infection, there are many hurdles to be crossed.
The rising tide of obesity has inspired a worldwide search for new weight loss drugs. Scientists at the Salk Institute in California are researching 'exercise in a pill' - drug that gives the benefits of exercise without leaving the sofa. In experiments, a medicine being developed to help heart bypass patients, boosted fat burning and stamina in inactive mice. The drug fooled the muscles into thinking they have exercised long and hard, rapidly burning fat and boosting fitness.
Others are trying to capitalise on the health benefits of red wine to create a fat-burning pill that protects against diabetes.
But obesity experts caution people against pinning their hopes on a quick fix, saying diet and exercise are key in the battle of the bulge.
Internet source:
http://www.dailymail.co.uk/health/article-1211021/Wonder-drug-development-let-dieters-eat-want--gaining-single-pound.html
Wonder drug in development to let dieters eat whatever they want - without gaining a single pound
By Fiona MacraeLast updated at 8:07 AM on 04th September 2009
A pill that allows dieters to gorge on junk food without putting on a pound is being developed by scientists. The couch potato's dream, it would allow people to eat all their favourite foods without worrying about their waistline. The wonder drug would also protect against diabetes, liver disease and other debilitating conditions associated with unhealthy eating habits.
The breakthrough hinges on the discovery of a metabolism 'masterswitch' - a gene key to weight control. Mice lacking the gene, known as IKKE, stay slim despite being fed a lard-based diet.
The 'knock-out' mice also free of the liver problems associated with a junk food diet and appear to be protected against diabetes, the journal Cell reports.
Researcher Alan Saltiel said: 'We've studied other genes associated with obesity - we call them "obesogenes" - but this is the first one we've found that, when deleted, stops the animal from gaining weight. 'The fact that you can disrupt all the effects of the high fat diet by deleting this one gene in mice is pretty interesting and surprising.' It is thought that the gene makes enzymes called kinases that help regulate metabolism. Removing the gene - and the kinases - speeds up metabolism, leading to more calories being burnt.
Dr Saltiel said: 'Perhaps most interestingly, the mice burn more calories even though they aren't eating any less or exercising any more.' In the case of people, a drug that cuts kinase levels could allow people to eat fatty and sugary foods without putting on weight. It would also enable them to stay trim without going to the gym. The researchers, from the University of Michigan in the US, are now hunting for such a pill and predict that many others will join the search.
They said: 'The specificity of the apparent actions of IKKE, the nature of the enzyme, and the profound resistance of the knock-out mice to the high-fat diet, make it an especially appealing drug target for the treatment of metabolic disease.' If they do find the right formula, the drug could be on the market within a decade. But with suggestions that such a drug could increase vulnerability to infection, there are many hurdles to be crossed.
The rising tide of obesity has inspired a worldwide search for new weight loss drugs. Scientists at the Salk Institute in California are researching 'exercise in a pill' - drug that gives the benefits of exercise without leaving the sofa. In experiments, a medicine being developed to help heart bypass patients, boosted fat burning and stamina in inactive mice. The drug fooled the muscles into thinking they have exercised long and hard, rapidly burning fat and boosting fitness.
Others are trying to capitalise on the health benefits of red wine to create a fat-burning pill that protects against diabetes.
But obesity experts caution people against pinning their hopes on a quick fix, saying diet and exercise are key in the battle of the bulge.
Internet source:
http://www.dailymail.co.uk/health/article-1211021/Wonder-drug-development-let-dieters-eat-want--gaining-single-pound.html
08 September 2009
Ab chain KOs?
I wanted to throw out a question to see if anyone with a little more clinical or immunology experience might know the answer - Are there many (or any) knockout mutations of antibody light or heavy chains?
With the redundant nature of the chains, it seems that a single KO would have little phenotypic effect, but then, consequently, double KO offspring would be without antibodies - which doesn't, as far as I know, happen all that often.
The only phenotypic effects I could imagine would be a decline in the number of B-cells that develop viable antibodies (a ~50% reduction for a heavy KO, and ~12% reduction for a light KO, if my math is right), or a reduction in the potential antibodies due to a reduction in allotypic variation (eg, a mother and fathers V12 regions might be different), but neither of those effect seems like they would be evolutionarily disadvantageous enough for KOs to be entirely absent.
Also, if anyone feels like doing a little math, I calculated that ~17% of B cells would develop valid antibodies, but Prof. Cohen mentioned that only ~1/27 do. If the prob. of a single H chain working is 1/9 (since there are 2 recombinations) and a single L is 1/3 (since there's no D region):
(1-(8/9)^2)(1-(2/3)^4) = 16.9%
Is my math wrong, or my understanding of what's going on?
Thanks for any input...
With the redundant nature of the chains, it seems that a single KO would have little phenotypic effect, but then, consequently, double KO offspring would be without antibodies - which doesn't, as far as I know, happen all that often.
The only phenotypic effects I could imagine would be a decline in the number of B-cells that develop viable antibodies (a ~50% reduction for a heavy KO, and ~12% reduction for a light KO, if my math is right), or a reduction in the potential antibodies due to a reduction in allotypic variation (eg, a mother and fathers V12 regions might be different), but neither of those effect seems like they would be evolutionarily disadvantageous enough for KOs to be entirely absent.
Also, if anyone feels like doing a little math, I calculated that ~17% of B cells would develop valid antibodies, but Prof. Cohen mentioned that only ~1/27 do. If the prob. of a single H chain working is 1/9 (since there are 2 recombinations) and a single L is 1/3 (since there's no D region):
(1-(8/9)^2)(1-(2/3)^4) = 16.9%
Is my math wrong, or my understanding of what's going on?
Thanks for any input...
Questions/Clarification From This Week's Readings
So I was a little unclear about a couple of the learning objectives from this week's reading
Unit 5 Question 7 sks us to "Calculate the minimal number of genes required to code for a million different antibody molecules based on the outdated concept of 'ong gene one H or L chain.'"
In the text, to make a hundred trillion antibodies it takes 10^14 genes. So I'm going to go ahead and assume that this is the correct formula to follow to calculate the number of genes required to make a million antibodies. So could the answer be 2*10^3?
Unit 6 Question 12 on the asks us to "discuss how complement is important in immunity to bacteria even if the bacteria are resistant to lysis by C9."
To my understanding, both C9 AND C8 form lesions on the target cell membrane, which causes the target cell to lyse. Is the answer to this question just that it's not that big of a deal if the bacteria is resistant to lysis by C9 because C8 can also cause the target bacteria to lyse? (I am a little suspicious because that seems a bit too obvious/simple...)
Thanks for the help whoever responds to this post!!!
Unit 5 Question 7 sks us to "Calculate the minimal number of genes required to code for a million different antibody molecules based on the outdated concept of 'ong gene one H or L chain.'"
In the text, to make a hundred trillion antibodies it takes 10^14 genes. So I'm going to go ahead and assume that this is the correct formula to follow to calculate the number of genes required to make a million antibodies. So could the answer be 2*10^3?
Unit 6 Question 12 on the asks us to "discuss how complement is important in immunity to bacteria even if the bacteria are resistant to lysis by C9."
To my understanding, both C9 AND C8 form lesions on the target cell membrane, which causes the target cell to lyse. Is the answer to this question just that it's not that big of a deal if the bacteria is resistant to lysis by C9 because C8 can also cause the target bacteria to lyse? (I am a little suspicious because that seems a bit too obvious/simple...)
Thanks for the help whoever responds to this post!!!
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