Obesity Linked To Brain Degeneration

In a study just published in the current online edition of the journal Human Brain Mapping, a research team from the University of California at Los Angeles (UCLA) and University of Pittsburgh, compared the brains of people who were obese, overweight, and of normal weight. They used Body Mass Index (BMI) to categorize the weight,normal weight people had a BMI between 18.5 and 25, overweight people had a BMI between 25 and 30, and obese people's BMI was more than 30.
The scientists wanted to see if there was any difference between the brains of those with different BMIs. They discovered that obese people had eight percent less brain tissue than people with normal weight and also people who were only overweight showed a loss of about four percent of brain tissue. By comparing the gray matter and white matter they found that obese people had lost brain tissue in frontal and temporal lobes (parts of the brain critical for memory and planning), the anterior cingulate gyrus (needed for attention and executive functions), hippocampus (critical for long term memory) and the basal ganglia (needed for movement). Overweight people showed less brain loss,mostly in the basal ganglia and the parietal lobe (known as the sensory lobe).

This is a very exciting study that could encourage obese people to lose weight.
According to this study obese people are more prone to Alzheimer's and memory loss. Obesity may also affect the learning power of obese kids, in this case parents will try more to not get their kid become obese.
http://www.naturalnews.com/027046_overweight_obesity_health.html

THE SKY IS FALLING! THE EARTH IS COMING TO AN END!

BREAKING NEWS! ALERT! ALERT!
YOUR MORNING SHOWER COULD KILL YOU!!
The shower you take to limit offensive body odor and get a refreshing morning wake-up call could be dangerous to your health, and could kill you. Non tuberculous mycobacterium (causative of lung disease) and streptococcus (implicated in strep throat, meningitis, or necrotizing fasciitis [it is as ugly as it sounds]) can build up in your showerhead, make you sick, and possibly lead to your death. If you value your health, you should never take a shower again! Or so, that is what the news media would like us to believe.
A study from our friends and colleagues at the Boulder campus published this week in PNAS demonstrated that water coming out the business end of the shower head is dirtier than the water going into the shower head. Mycobacteria and other pathogens can build up in shower head bio-films (a fancy word describing an aggregation of microorganisms in a self arranged matrix), and are then aerosolized in the hot and pressurized water you treasure in the morning. The aerosolized microbial life is then inhaled into the deep lung, where it can release malignant fury. Thus the conclusion that dirty dangers lurk even when you think you are getting clean.
So everyone should stop talking showers, right? Wrong. Fortunately for us young, strong, and healthy grad students, we need not worry, we can continue our normal morning routine of a shower and coffee before the onset of the daily grind. Why? Captain Immunity to the rescue! What the media fails to mention with their attention grabbing headline is that our immune system has been exposed to many if not all of these pathogens previously. As Prof. Cohen mentioned in our first class, you don’t have to look hard to find bacterial flora in and on our bodies. Moreover, the toilet and kitchen counter (and other more typical bacteria laden surfaces) have done a fairly effective job of exposing us already to these pathogens (if you don’t believe me, believe MythBusters http://www.youtube.com/watch?v=TeAOC3A0xJ8. All together now: ewwww!). As we all know, once our body has been exposed to a particular invader, it normally does a decent job of clearing out subsequent invasions by the same pathogen before we get to feeling sick.
The people that need to be worried about this news (and make it a morning bath instead) are those with compromised immune systems. As an example, AIDS causes a reduction in CD4+ helper T cells, resulting in a reduced ability to bind and kill pathogens. As such, even though an AIDS patient may effectively recognize the pathogens inhaled from a showerhead, they lack the ability to fully protect themselves from the pathogen. The incomplete protection will lead to varying severities of illness, and possibly, in the unfortunate case, death.
So, while it is a bit disturbing to think that you are bathing in bacteria, what you see falling isn’t the sky, life will go on, and for the sake of all of our noses, please, continue showering.

For those of you interested in reading the full article it can be found at the following URL: http://www.pnas.org/content/early/2009/09/11/0908446106.full.pdf+html?sid=368e5e90-7301-4346-b3b5-3ccfe88e7d2a

Leptin: an adipokine

Leptin is an important adipocytokine that acts directly on the hypothalamus, and it regulates food intake and energy expenditure. Hypoleptinemia has been linked to weight gain, fat deposition in organs, such as the liver, muscle, and pancreatic islets, clinical features of the metabolic syndrome, and a general proinflammatory state. Leptin is secreted by adipocytes and binds to receptors in the CNS, where it suppresses appetite and decreases food intake. In the peripheral tissues, it enhances
insulin sensitivity in muscle and fatty tissue, while preventing fat storage in organs such as the liver and pancreas.
It functions as a signaling factor that keeps the CNS informed on the status of energy availability in the body. Weight gain and overfeeding increase leptin expression and secretion, and reduced food intake suppresses them.

Source: Am J Med Sci 2009;X(XX):1

Hepatitis C and Interferons

Interferon and the Treatment of Hepatitis C: What Are They? How Can They Be Useful in Treating Disease?

Interferons (INF) are proteins that are produced by a virus infected cell. They are known to interfere with viral replication in previously infected tissue cells. INF-a and INF-b are the molecules thought to have the effect of blocking the spread of viruses to other, uninfected cells.

In this particular blog I would like to discuss INF-a specifically. INF-a is actually a family of closely related proteins. Because of its ability to hinder viral replication, a modified version INF-a is used as a treatment for hepatitis C (HCV). 

HCV is a virus that damages. For reasons that are not understood, viruses in the liver often become invisible to the immune system. This invisibility prevents the immune system from recognizing the virus, thus allowing it to multiple out of control. By giving a hepatitis C infected patient INF-a, it allows their immune system to detect the virus, and it prevents or slows the replication of the virus in the liver.

Specifically, INF-a operates in three ways:

1.     The INF-a attaches to healthy cells to prevent the HCV virus from attacking healthy cells.

2.     It marks the infected cells – this alerts the immune system as to which cells have the HCV virus, and prevents the virus from replicating.

3.     INF-a helps the body rid itself of infected cells, while preventing healthy cells from becoming infected.

Currently, INF-a, coupled with ribavirin, is the standard of treatment for HCV patients. Unfortunately, it only succeeds in clearing the virus in approximately 30-40% of people. This is due to a genotypic interaction which may be discussed in later blogs.

Advantages and dangers of glycemic control

In the diabetes lay article Doctor Hyman clearly preaches the need to address diabetes through diet and lifestyle, a sentiment I throughly agree with. However, he brings up the dangers of insulin and other diabetic medications including the increased the risk of heart attack. According to a recent study at the university of Wisconsin, the use of exogenous insulin does indeed increase the risk of heat attack and CAD. Insulin both exogenous and endogenous causes smooth muscle proliferation in arteriole walls and promotes lipid synthesis which results in lipid lesions in the arteries. Insulin also increases the amount of plasminogen inhibiting factor leading to thrombosis. Despite the slightly elevated risks, glycemic control offers profound benefits regarding the other associated pathologies including retinopathy and neuropathy. For Type 2 Diabetes, lifestyle changes are essential. However the use of insulin and other medications may intervene enough to avoid irrepairable injury allowing the patient to make those changes.

http://care.diabetesjournals.org/content/early/2007/11/19/dc07-1161.full.pdf

Inflammation and the prediction of obesity and diabetes

The fact that obesity, a major risk factor for type 2 diabetes, and diabetes itself, are inflammatory conditions, led to investigations exploring whether inflammatory mediators
predict the development of type 2 diabetes in populations at risk. Several such studies have now confirmed that the presence of inflammation predicts the development of type 2 diabetes. The first of these studies by Schmidt et al. showed that the presence of inflammatory mediators predicted the future occurrence of type 2 diabetes in adults [11] and was part of the larger Atherosclerosis Risk in Communities Study (ARIC). A recent paper from the same study continues this theme by showing that elevated plasma concentrations of sialic acid, orosomucoid, IL-6 and CRP predict type 2 diabetes [12]. An overall inflammation score based on these four indices, the total leucocyte count and plasma fibrinogen concentration, provided an increased
risk of 3.7 (when comparing the highest and the lowest quintiles) in white non-smokers for the development of type 2 diabetes [13]. There are at least three other prospective studies confirming the fact that an increase in inflammatory indices at baseline predicts type 2
diabetes and insulin resistance [14–17]. Similarly, there is also a correlation between fasting insulin concentrations and CRP concentrations in plasma [5,18,19], indicating that insulin resistance and inflammatory processes are related and that in association with the other facts
discussed there might be a causal link. Novel data have now appeared showing that the concomitant presence of promoter polymorphisms of TNF-a (G-308A) and IL-6 (C-124G) in obese subjects with impaired glucose tolerance carry twice the risk of conversion to type 2 diabetes when compared with other genotypes. A G-308A mutation of the TNF-a promoter is associated with increased plasma TNF-a concentrations and a 1.8 higher risk of developing diabetes compared to noncarriers. A C-124G mutation of the IL-6 promoter increases the risk for insulin resistance [20].


TRENDS in Immunology Vol.25 No.1 January 2004

Milk Products, Insulin Resistance Syndrome and Type 2 Diabetes

A growing body of evidence suggests an inverse relationship between calcium and vitamin D status and dairy food intake and the development of the insulin resistance syndrome (IRS) and type 2 diabetes mellitus (t2DM). Observational studies show a consistent inverse association between dairy intake and the prevalence of IRS and
t2DM. In a systematic review of the observational evidence, the odds for developing the IRS was 0.71 for the highest dairy intake (3–4 servings/d) vs. the lowest intake (0.9 –1.7 servings/d). Few interventional studies have been conducted to evaluate the effects of dairy food intake on the management of prevention of IRS or t2DM. Intervention studies that have examined the independent effects of dairy intake on
specific metabolic components of the IRS including blood pressure and obesigenic parameters have shown favorable effects that support the observational findings albeit the results have been less consistent. Many metabolic and dietary factors appear to influence the degree to which dairy affects IRS metabolic parameters
including calcium and vitamin D intake status, BMI, ethnicity and age. Overall, the intake of low-fat dairy products is a feature of a healthy dietary pattern which has been shown to contribute to a significant extent to the prevention of IRS.

Journal of the American College of Nutrition, Vol. 28, No. 1, 91S–102S (2009)

What is pointed out by this paper I think is really good. This doesn't mean that people should be consuming more dairy servings than what is suggested for their age and gender, but consuming the adequate amount would help them if they have insulin resistance. But I think, they should also be aware of their renal function as if there is a dysfunction it might increase the formation of renal stones.

Folic acid supplementation on insulin sensitivity and inflammatory markers

Inflammation plays a pivotal role in the atherosclerotic process, and some chemokines seem to be crucial in the pathogenesis of vascular damage. High-serum homocysteine, recently recognized as an independent risk factor for vascular disease might increase cytokine and chemokine levels, thus amplifying endothelial damage; moreover, it might worse insulin resistance, thus further contributing to enhance cardiovascular risk. The effect of folic acid supplementation in improving in vivo endothelial function is still debated.
Subjects receiving folic acid supplementation showed a decrement of homocysteine and an amelioration of insulin sensitivity; this treatment was also associated with a significant drop in the circulating concentration of monocyte chemoattractant protein-1, interleukin-8 and C-reactive protein, in the absence of any significant variation of BMI or fat mass.
In healthy overweight subjects a short-term folic acid supplementation reduces the circulating level of some inflammatory mediators independently of weight change, thus suggesting a potential therapeutic role for folic acid in the protection from atherogenesis and cardiovascular diseases.

International Journal of Obesity (2006) 30, 1197–1202.

On the other hand it has been shown that increased folic acid supplementation can increase the chance of colorectal and prostate cancer. Specially if a person already has a precancerous lesion, folic acid supplementation would increase the chance of malignancy in these lesions.
For this study, I think, we can't just tell people to consume more folic acid. We already know about the increase of the risk of cancer, which is a big problem and most of the breads and cereals are already fortified with folic acid in U.S. So we can't have people increase their folic acid intake.

Klotho, atherosclerosis

Disruption of klotho gene expression causes multiple aging phenotypes including arteriosclerosis, pulmonary emphysema, osteoporosis, infertility, and skin atrophy. Although klotho supplementation has been shown to improve the aging phenotype of klotho deficient mice which as would be expected , it remained to be addressed whether klotho supplementation in a heterogeneous experimental animal of vascular dysfunction would improve vascular function which is a prerequisite to address the generality of the effects of klotho on the vasculature.klotho gene transfer improves endothelial function and increases NO metabolites strongly suggests a direct and possibly cooperative regulatory pathway between NO and klotho in the vasculature. Equally important is the finding that klotho gene expression improved blood pressure and induced vascular remodeling.

These findings strongly suggest an underlying role of the klotho gene product in the regulation of endothelial function and of atherosclerosis. Vasodilatation induced by endothelium-derived NO has been reported to be impaired in hypertension , diabetes mellitus and hyperlipidemia . These observations lead to the hypothesis that a decrease in the klotho gene expression may be atherogenic due to direct or indirect involvement with reduced NO production in these common diseases. findings collectively show a coupling between klotho gene expression and NO as a general phenomenon in vascular diseased states which establishes and confirms a regulatory interactive pathway between NO and klotho in the vasculature. Although the cellular and molecular mechanisms of the relationship between klotho and regulation of NO need to be clarified in further studies, involvement of the klotho gene in decreased NO formation by down-regulated eNOS or accelerated degeneration of NO by NO scavenger such as superoxide anion are plausible regulatory pathways.

Another interesting finding is that klotho gene transfer significantly prevented perivascular fibrosis in the coronary arteries as chronic inhibition of NOS with L-NAME has been reported to be associated with an increase in wall thickening and coronary perivascular fibrosis in the rat heart. These histological findings also further support an association between NO and klotho. NO and klotho, although speculation, an increase in systemic NO production may be involved in reduction in medial hypertrophy of aorta and coronary perivascular fibrosis.Some studies indicate that supplementation of the klotho gene restores endothelial-dependent aortic dilatation and accelerates systemic NO production, resulting in a decrease in blood pressure and vascular remodeling. klotho gene therapy is a potentially viable and novel therapeutic strategy for preventive treatment of atherosclerotic cardiovascular diseases.
Vol. 276, No. 2, 2000 BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS

Serum FGF21 ,Obesity

Serum FGF21 levels in overweight/obese subjects are significantly higher than in lean
individuals.
Serum FGF21 correlates positively with adiposity, fasting insulin, and triglycerides but negatively with HDL cholesterol . The increased risk of the metabolic
syndrome associated with high serum FGF21 is over and above the effects of individual components of the metabolic syndrome. In vitro study detected a differentiation-dependent expression of FGF21 in 3T3-L1 adipocytes and human adipocytes. In db/db obese mice, FGF21 mRNA expression was markedly increased in both the liver and adipose tissue compared with that in their lean littermates. Furthermore, FGF21 expression in subcutaneous fat correlated well with its circulating concentrations
in human.FGF21 is a novel adipokine associated with obesity-related metabolic complications in humans. Diabetes 57:1246–1253,2008

Interesting Quote.

So while we were having our discussion two weeks ago about people expecting a 'wonder' drug of some sort that would cure obesity and/or diabetes (which seems to be in the pipes if you read some of the other blogs) I kept thinking of a quote that I had heard of a few years back and wanted to share it all with you:

“Formerly, when religion was strong and science weak, men mistook magic for medicine; now, when science is strong and religion weak, men mistake medicine for magic.”
-Thomas Szasz

Just some food for thought.

Systemic Inflammation: whats Obesity got to do with it?

If you find obesity and its associated comorbidities then inflammation is sure to be close by. The connections between these three spin such a web it is hard to tell where the start, middle, and end of the obesity web are. For example, does obesity cause comorbidity and inflammation independently or are the three dominoes in a line. To further complicate the predicament classically associated obesity comorbidities can be caused by inflammation without obesity. For example, the gram negative bacteria cell associated lipopolysaccharide, activating the tried and true TLR->NFKB->gene expression->cytokine pathway ( or down regulation of PAPP-gamma according to the literature you read, both of which suppress GLUT 4 by different means) results in type 2 diabetes. Wow, if that doesn’t make you scratch your head I don’t know what will, and it gets better. Preadipocytes can exhibit phagocytic activity, secrete cytokines, and can become adipocytes or macrophages. At this point you should be having a mid-life immunologic crisis. Rest assured though, with reductionism to the rescue we will tackle the inflammation obesity predicament piece by piece, one at a time. For example obesity can cause fat deposition in the liver. Many proinflammatory cytokines such as CRP are produced by the liver (one possibility for the source of chronic inflammation.).

Sometimes the obesity web actually makes sense. In the obese state a large number of macrophages infiltrate the adipose tissue possibly to clear necrotic adiposity. Secreting TNF-alpha the macrophages inhibit insulin receptors and suppress GLUT 4 expression causing insulin resistance. According to Ping et. al. in the obese state macrophages in adiposity are in the M1 polarization alternatively macrophages in the lean state are of the M2 polarization suggesting obesity is proinflammatory. Macrophages in the proinflammatory state also cause atherosclerosis.

To be a large cell such as a growing adipocyte you need a lot of oxygen. One theory to the systemic inflammation associated with obesity is that as adipocytes get too large they no longer receive adequate oxygen. They might die because of it causing the large influx of macrophages which in turn cause inflammation. Or alternatively they might release cytokines to self induce insulin resistance so they wont get any larger which causes a secondary systemic inflammation.

Systemic inflammation associated with obesity is multifaceted. Macrophages and adipocytes are the primary source of the inflammation but there are many secondary and treachery contributors making pointing the finger to the culprit difficult but this knowledge helps to delineate solutions to the problem.

-Randy, who has a serious case of blogitis and is amused that despite agreeing with his 495 partner Elham to blog on different topics still managed to cover the same material. Seriously, not my bad yall.

Citations:
Jia0, Ping. "Adipose inflammation: cause or consequence of obestiy-related insulin resistance." Diabetes, Metabolic Syndrome, and Obesity Dove Medical Press 2008;1 25-31

O'rourke, Robert. "Inflammation in obesity-related diseases." Surgical Research Review
Mosby inc 2009; 255-259