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by subcosmos 3216 days ago
Hi, Endocrinologist and obesity specialist here.

Let me confidently assure you that inflammation in the hypothalamus is a dominant feature of obesity, and obesity is currently one of the top diagnosed medical problems in America. This stuff isn't hypothetical, but well accepted within the clinical research field for metabolic disorders.

Please don't recommend laymen avoid reading articles like this. That's rather senseless. While this stuff hasn't become standard in medical school curricula yet, it definitely will be some day, particularly when we are more confident in interventions that prevent hypothalamic gliosis.

EDIT: also, don't discount hypothalamic inflammation based on what you know about encephalitis. Some parts of the hypothalamus (the arcuate nucleus, in particular) are highly susceptible to inflammation because they are surrounded by a characteristically porous part of the blood brain barrier (behind the hypophyseal portal system). This allows bulky blood-born protein hormones (like leptin and insulin) to make it into the sensory neurons.

Indeed this part of the brain doesn't become red and painful, but something more relevant happens. Microglia surround the neurons responsible for appetite suppression and kill them off, which permanently changes the body fat setpoint that the brain strongly defends. There is definitely a profound and sometimes irreversible loss of function here, and that's the current focus in research. Hopefully some day we will find ways to drive repair of these circuits.

4 comments

> Let me confidently assure you that inflammation in the hypothalamus is a dominant feature of obesity

I certainly believe you (I'm not qualified to agree or disagree, as I'm not a specialist like you). The point of my rambling comment is to make sure the readers understand that the kind of inflammation we're talking about here is very removed from what people usually think about when they think of inflammation.

> Please don't recommend laymen avoid reading articles like this. That's rather senseless

Hm... Here I'll have to disagree. I think medical research should be consumed rather judiciously, especially by laymen or by doctors that are not specialists in the research area in question.

I'd rather have people read distilled accounts of research (textbooks, meta-analysis, etc.) than studies in knockout mice.

EDIT: Answering your edit. I'm not discounting anything. I think the study is as relevant as it gets for a study in mice, and the role of hydrocarbons of the diet is an important one. After all, is it just calories in VS calories out or is there something else?

I do understand what the study is talking about when it talks about microglia and inflammation. I'm merely trying to answer the question about "What is inflammation IRL" in a way that laymen may understand - most people don't know that microglia are derived from cells of the immune system (in a sense, they are the "inflammatory cells" of the brain), and can't draw the parallel between neutrophils and monocytes happily blasting away through the extra celular matrix under the skin in search for pathogens and microglia killing healthy neurons.

In no way I want to be skeptical of the article or discount the importance of its findings. I only want to draw the distinction between the "naïve" idea of inflammation and the kind of inflammation the article is talking about.

EDIT2: The poster asked why he didn't feel "inflammed". He would certainly feel "inflammed" if he had an encephalities, so there is definitely some confusion here. My comparison between this "low level" inflammation and encephalites was meant to highlight that. Do you think I was unclear?

I concede with many of your points. We are living in an era where nutritional dogma is really strong in a lot of areas, and I think research articles like this do drive lots of amateur dietary advice from people who over-interpret it.

Pardon my passionate writing, obesity is a personal matter for me. I'm looking forward to it being pushed further out of the lab and into the clinic, but I'm not sure what those steps look like just yet.

More important is the focal nature of this specific kind of inflammation. It is also not quite a typical inflammatory response if just messing with adhesion factor and AGE receptor changes it this much. (Different from even chronic inflammation.)
I'm in medical school right now, we talked about metabolic disorders and the role of the hypothalamic nuclei in obesity. Wouldn't be that hard for a medical student who remembers what microglia are to extrapolate from there. I also agree that laymen can indeed read these kinds of articles, if comfortable with the content. If not, there's plenty of secondary sources commenting on these new findings.
The one prospective test to be run in humans (interventional study) is if we have some potent AGE formation inhibitor and what that would do to prevent obesity. People working on SENS might be the ones to ask (esp. GlycoSENS).

Expensive to run of course.

> Hopefully some day we will find ways to drive repair of these circuits.

Any idea on how we may do it? AFAIK, currently we have no good mechanisms to "repair" individual brain circuits: even in strokes, we mainly exercise the affected area so that neural plasticity repurposes other neurons (usually in the cerbral cortex) to take over lost functions.

Does the hypothalamus have this degree of plasticity?

I saw a study once that raised mice on both standard and high fat chow. Predictably the high fat fed mice developed central obesity. (High fat diets are still a reliable way to make a mouse fat).

They then put the fat mice back on the normal chow, and they lost weight, but importantly they didn't ever reach the healthy weight of the mice fed on normal chow from the start.

The explanation they offered was that the GABAergic Agrp/NPY neurons (that promote hunger and lower metabolism) had formed stronger connections, and many of the Glutaminergic POMC/Cart neurons (that promote satiety and increase metabolism) had died off.

Whenever I go digging for this study I can't find it. Allison Xu's lab however has written a few studies now talking about this neural subtype ratio in various models, as well as the inflammatory mediators linked to their changes over time. http://www.pnas.org/content/110/8/E697.long

Im not sure about the plasticity questions, or neural regeneration, but that would be ideal if possible. I have however seen more crude suggestions for treatment that involve killing off neurons in the hypothalamic nuclei that promote hunger and feeding using techniques such as gamma knife radiotherapy. https://www.ncbi.nlm.nih.gov/pubmed/15695926

But it would be a LONG time before that becomes a viable surgery in humans!

Thanks. I'll read these papers he I have the time. I agree that gamma knife surgery on the hypothalamus is probably not yet ready for prime time (and it might never be if we can find something better)
Hi,

Endocrine patient here.

I've seen some research that suggests a phenomena of hypothalamic obesity due to decreased oxytocin secretion. Know much about this?

Could Inflamation of the hypothalamus decrease / increase sensitivity of the negative feedback mechanisms of the endocrine systems that are controlled via the hypothalamus / pituitary?

Thanks for your input doc.