[subcosmos]

Hi. Neuroendocrinologist here. Body fat is regulated by specialized circuits in the hypothalamus. We now know that inflammation of these central nuclei is a key feature of weight gain in both animals and humans.

There are two sets of neurons: those that promote feeding and slow metabolic rate, and those that suppress feeding and increase metabolic rate. The former class of neurons is GABAergic (inhibitory in neuroscience) and the latter is glutaminergic (stimulatory). Generally in animal experiments, the gabaergic neurons that drive feeding and conserve stored energy outnumber the glutaminergic neurons by a great deal, and over the lifespan of an organism, they increase in number.

Its been noted in some animal models that weight loss interventions are not permanent because they lead to alterations in this circuit to further promote weight gain and energy conservation. This may be why most humans also regain weight after losing it. If you think about it, it makes sense for most control loops in the body to "fail safe", IE, its much preferrable to gain weight than starve to death. This circuit thus fights to preserve fat mass.

Some "food for thought"

https://www.ucsf.edu/news/2017/07/407571/brains-immune-cells...

https://www.ucsf.edu/news/2015/02/123466/ucsf-researchers-re...

[allover]

Sure but that's all still about 'overeating' and 'hunger' (you feed a mice high fat foods, it triggers overeating)?

So it's still the case that if you keep your calorie intake below your TDEE, you won't regain the weight, whereas a lot of weight re-gainers like GGP claim some vague 'endocrine/metabolic' thing, when we have no evidence for that.

[manmal]

Thanks for the clarification! Do you think rapid weight loss could lead to HPA axis dysfunction as a result, i.e. lowered corticosteroid output (what some call adrenal fatigue, but is actually regulated by the hypothalamus)?

[subcosmos]

I don't focus on the whole HPA axis much, and in general the "adrenal fatigue" phrase doesn't have a great reputation among most of my colleagues. I hesitate to write it all off though.

From my diabetes work, its clear that corticosteroids definitely have a strong role in the development of metabolic syndrome, but I'm not sure about its ties to hypothalamic functioning. In the hypothalamus, the effects can be a lot more direct. Eventually its decision-making feed into the sympathetic/parasympathetic nervous systems which directly regulate metabolism and fat release in peripheral tissues. IE, your fat and muscle cells take direct neural firings from the autonomic nervous system as marching orders of whether or not its time to store energy or burn it.

So if the central neurons in the hypothalamus adjust to promote a higher setpoint body weight, that central point in control will direct weight gain via many downstream factors, some of which may be hormonal. Right now a central focus in research is figuring out why the hell the hypothalamus is driving the setpoint higher and higher. It seems like inflammation there might be a strong culprit.

Hopefully someday we will figure out what about our mass produced consumables are gumming up the works there.