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Confused about neuroendocrinology and weight loss

Answered on August 19, 2014
Created March 29, 2011 at 4:26 PM

So, in doing some reading about the relationship between neuroendocrinology and weight loss, I have come across some unanticipated findings. First, the background:

Hypothalamic inflammation interferes with insulin and leptin signaling. It is believed to be a cause of obesity. Tumor necrosis factor-alpha (TNF-a) is believed to be at least partially responsible for creating an inflammatory state in the hypothalamus. In addition, stearic acid (a ubiquitous saturated fat) is believed to have a similar effect on hypothalamic inflammation as does TNF-a.

TNF-a is produced by the innate immune response to lipopolysaccharides (fat + carb), AKA endotoxin, which are commonly thought of as comprising the outer membrane of gram-negative bacteria. These bacteria trigger an immune response that increases TNF-a, thereby increasing hypothalamic inflammation and promoting imbalance in the pathways between the brain and the liver and pancreas that leads to improper regulation of homeostasis (increasing energy intake and decreasing energy expenditure largely through reduced thermogenesis in brown adipose tissue).

So, you would think that in order to reduce hypothalamic inflammation, you would want to downregulate TNF-a production. A reasonable place to start might be to reduce lipopolysaccharides, perhaps by somehow reducing gram-negative bacteria (you could also use some heavy duty drugs like infliximab, but that is impractical for most without serious autoimmune diseases and the side effects might be nasty).

However, some research suggests that a HIGH fructose diet is effective in attenuating endotoxicity by increasing plasma tryglycerides AND nitric oxide production. But other research suggests that fructose, through its ability to increase uric acid, actually decreases NO.

So here's where I'm lost. Why does a high fructose diet (seemingly paradoxically) promote changes (protection against LPS endotoxicity) that reduce hypothalamic inflammation (downregulation of TNF-a production) - a condition that is seemingly at the heart of disordered energy intake/expenditure? Would excess fructose intake in the short-term be expected to alleviate hypothalamic inflammation? What is the relationship between fructose, uric acid, and nitric oxide that might explain the apparent discrepancy in terms of the effect of fructose on NO. Does anyone know of other research that may shed some light on this confusing area?

461281c9092d3cb306b46831064e2fc4

on March 29, 2011
at 05:58 PM

Ok, but nevertheless there is evidence to suggest that in otherwise healthy overweight individuals, inflammation in the hypothalamus caused by TNF-a is affecting the neuroendocrine system and preventing weight loss. In that "environment," one potential method for reducing inflammation is to seek ways to reduce the excess TNF-a. Just to clarify, this isn't about leptin specifically, but about how the entire neuroendocrine system works together. That's what I'm seeking to understand more about.

2f54dbe892ec89b12d1db686568e885a

(919)

on March 29, 2011
at 05:28 PM

Beats me........

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3 Answers

4
Ed71ab1c75c6a9bd217a599db0a3e117

(25482)

on March 29, 2011
at 05:21 PM

TNF alpha is a pleomorphic chemical......its acts based upon the envirnoment it is in. For example it is vital in the immune reaction of autophagy or apoptosis for cancer elimination when it is needed. But when you get a spike of TNFalpha due to hepatic or hypothalamic dysfunctional signalling it can cause cancer.......hence why I tell everyone context matters huge. Chemicals can have equal and polar opposite reaction in the body based upon the current state of the cell. And palmitic acid is the real problem in leptin signalling. It is the cause of leptin resistance centrally and peripherally. That is generated by de nove lipogensis from excess carbohydrate metabolism especially from fructose.

461281c9092d3cb306b46831064e2fc4

on March 29, 2011
at 05:58 PM

Ok, but nevertheless there is evidence to suggest that in otherwise healthy overweight individuals, inflammation in the hypothalamus caused by TNF-a is affecting the neuroendocrine system and preventing weight loss. In that "environment," one potential method for reducing inflammation is to seek ways to reduce the excess TNF-a. Just to clarify, this isn't about leptin specifically, but about how the entire neuroendocrine system works together. That's what I'm seeking to understand more about.

0
8fb965cf6e3162ed278d14316c1f0f4d

(0)

on August 22, 2011
at 07:03 PM

High fructose does indeed promote lipid production as it bypasses PFK in the liver and adds an almost unregulated energy source in the form of DHAP and GA that are converted into acetyl co-A through 1 and 2 steps respsectively. Dyslipidemia is largely responsible for the decreased insulin resistance by inhibiting normal mitochondrial oxidation. Insulin resistance is also contributed by elevated postprandial endotoxin levels that are observed after hgih fructose feeding. Chronic fructose can alter your gut ecology and the host microbe interaction resulting in a more permeable gut border. That allows for more bacterium particles or endotoxins to enter your blood stream. A common clinical solution for too much LPS (septic shock) is to treat with intralipid. Endotoxins readily interact with lipid molecules and therefore intralipid sequesters much of the endotoxin load. A chronic high fructose diet is not normally attainable in nature, but it there is a possiblity that adaptation mechanism for fructose rich diets could be its lipogenicity.

0
4494ee5074820a88bbd45f908168a7c3

on April 11, 2011
at 04:05 AM

Have you ever been to Hyperlipid? It's an informational goldmine! Even if you don't agree with his conclusions, the explanations of biological processes are amazing. http://high-fat-nutrition.blogspot.com/

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