Friday, February 1, 2013

Why Do We Eat? A Neurobiological Perspective. Part IV

In this post, I'll follow up on the last post with a discussion two more important factors that can affect energy homeostasis and therefore our food intake and propensity to gain fat: age and menopause.


Although it often isn't the case in non-industrial cultures, in affluent nations most people gain fat with age.  This fat gain continues until old age, when many people once again lose fat.  This is probably related to a number of factors, three of which I'll discuss.  The first is that we tend to become less physically active with age.  The second, related factor is that we lose lean mass with age, and so energy expenditure declines.

However, neither of these factors would necessarily lead to fat gain in someone with a robust energy homeostasis system.  Just as some people are highly resistant to fat gain even with massive overfeeding, and others aren't, reducing energy expenditure should only lead to fat gain in a person with a less robust energy homeostasis system.  I think it's pretty clear that just like many things in the body, this system weakens with age, undermining its ability to 'defend' body fatness at a lean level.  We all know people who could sit in front of the TV and eat anything they wanted when they were 22, but 20 years later they put on fat easily.

As we age, the energy homeostasis system seems to become less able to defend against fat gain in an obesity-promoting environment.  As we become truly old however, these systems often break down even further and our feeding systems begin to lose the ability to perform their most important function: keeping us from eating too little.  Obesity is much less common in people over 80 years old, in whom underweight and particularly muscle loss are common problems.


Menopause is a hormonal transition period for women where estrogen levels drop by about 90 percent (among other changes) and body fatness often increases.  The distribution of fat also becomes more 'android', or male-like, with body fat moving from the hips and buttocks to the belly.

Research in animal models has provided a compelling explanation for this.  Researchers have known for a long time that if you remove a female rat's ovaries (ovariectomy), she will become obese, and her body fat distribution will also change to be more male-like.  If you supplement estrogen, you can prevent the fat gain, demonstrating that it's the estrogen itself and not something else about the ovaries that keeps intact female rats lean.  This effect occurs primarily through the estrogen receptor alpha (ERalpha) protein, since mice lacking this receptor develop obesity similar to ovariectomized rats/mice, despite having plenty of estrogen around (1).

When you have an animal model that's obese and you want to understand why, history has shown that the first place to look is in the brain.  It turns out that ERalpha is expressed in the brain, and particularly in a part of the hypothalamus called the ventromedial nucleus (VMN; also abbreviated VMH).  The VMN is a leptin-sensitive brain region that's important for regulating food intake and body fatness (2).  When a female rat is ovariectomized, the decrease in estrogen makes her brain less sensitive to leptin, and decreased leptin sensitivity leads to fat gain (3, 4).  When researchers knock out ERalpha specifically from the VMN, it results in obesity similar to ovariectomized rats (5).  Together, this shows that estrogen promotes leanness by acting on ERalpha receptors in the VMN, and it does so at least in part by increasing leptin sensitivity.

If this is true in humans, then estrogen replacement therapy should prevent fat gain and the redistribution of fat to the belly in women as they go through menopause.  Although the evidence isn't totally consistent due to differences in estrogen dose and study population, overall it supports this idea, particularly as it pertains to body fat distribution (6, 7, 8, 9, 10, 11).

Estrogen replacement seems to carry a real risk of adverse health effects, so most women will choose to avoid it and let nature run its course.  However, knowing that menopause is a risky period for fat gain can help women be vigilant about diet and lifestyle during this important time.


Anonymous said...

Hi Stephen,

I've enjoyed this series and can't wait for your take on gut flora, endotoxemia and weight regulation.

I want to mention that aging tends to be associated with less diverse gut flora which can explain inflammation-induced weight gain.

Likewise, estrogen has well known anti-inflammatory effects on the gut wall. In the absence of VMN ERĪ± dysfunction, perhaps this is a better explanation for why weight gain is common in women after menopause.

As you already know, inflammatory damage caused directly to the hypothalamus is a big part of this picture especially given what we know about endotoxemia and the hypothalamic-pituitary-adreanal axis. I covered this topic here:

I look forward to reading the next installment.

Gabriella Kadar said...

Hi Stephan,

not only does lack of estrogen result in abdominal fat increase but it also causes fat to increase in the 'jowls'. Menopausally estrogen decreases but testosterone remains and is responsible for male pattern fat distribution. I think this is why women don't catch up to men in regards to heart disease until menopause. The recently reported Swedish study on sleep apnea proved that the incidence of sleep apnea sky rockets in women post menopausally.

What I haven't read anything about is the causative factor for male pattern fat distribution in young females. They develop PCOS and have the telltale fat hump in the C8 region along with persistent acne in the lower half of the face. What could be responsible for this? The fat hump remains even if the woman loses excess weight. I have not read anywhere why the incidence of this situation appears more common today than in the past. There is something about the current diet that was not present in the past. I don't think it is just hypercaloric intake.

There are plenty of obese young women who do not have fat necks, for example. As estrogen levels decrease (late 30s, early 40s) these women exhibit a gradual fat redistribution also, middle age acne and excess facial hair development.

Don't men become obesity prone as well once their testosterone levels begin to decline? Doesn't excess fat generate its own estrogen in these fellas?

Anonymous said...

Dear Stephan,

thank you so much for writing this series!

Here's a related question that's been bugging me, and I think you're just the person who might know: How does the body (i.e., the brain) decide how much energy to spend? I suppose it's related to energy availability and to motivation to pursue goals. But what I don't know, is what's in control: does increasing energy availability increase energy expenditure by increasing efforts for desire-satisfaction, or does increasing motivation to pursue goals increase appetite?

Another way to ask the question is, what are the neural correlates of the subjective feeling of “having lots of energy”? We all know people who eat a lot of calories, but feel energy-depleted (even though there are goals they'd like to pursue), and other people who accomplish more the more they eat, with all the extra energy going into higher perceived energy-levels, which seem to drive activity/creativity/useful work. What accounts for the difference? Genetics, psychology, composition of nutrients and anti-nutrients in the diet, or inflammation/disease triggering resting/recovering behavior in favor of active behavior. I'd really like to know.

G said...

Hi Stephan,

I really enjoyed this series.

I have seen you mention a few times now that research shows moderate exercise is better for your health than intense exercise.

I hope at some point you will have the time to review this research for your readers. I - for one - am very curious.


G said...
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Gretchen said...

Someone has come up with a conjugate of estrogen and GLP-1 and claims it doesn't have the side effects of regular estrogen.

Grinch said...

"Menopausally estrogen decreases but testosterone remains and is responsible for male pattern fat distribution. I think this is why women don't catch up to men in regards to heart disease until menopause"

estrogen replacement does not help reduce heart disease after menopause so it is unlikely to have anything to do with reduced estrogen. The more likely factor is iron status, which greatly increases after menopause.

Logan said...

This series was very interesting, thanks so much for sharing your knowledge and insights!

I think you mentioned in part III that much weight is put on around the holidays. It reminded me in many religious traditions there is usually a period of fasting before
any feasting and this is frequently repeated throughout the year. From my own tradition (Catholicism) advent and lent are two such examples of several weeks of fasting before the feast. Might these periods traditionally have given enough time for people to reset their "set points" before a time of indulgence? Does it work that way?

Gabriella Kadar said...

Dave, is the iron status your theory? Postmenopausal women don't get abnormally high iron levels.

The sleep apnea study seems to be a more physically direct means by which heart disease occurs.

The Womens' Health Initiative study has been given the boot. The subjects in the study were women who in many cases were as much as 10 to 20 years postmenopausal. They had no problems with going through menopause. Altering a condition of homeostasis is not healthy and if the study proved anything it is that.

Newer studies have shown that women who are taking hormone replacement from late periomenopause are benefiting. Seems hormones are hot therapy again.

agen sbobet said...

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Jane said...

Dave & Gabriella

'Estrogen deficiency has been regarded as the main causative factor in menopausal symptoms and diseases. Here, we show that although estrogen decreases by 90%, a concurrent but inverse change occurs in iron levels during menopausal transition. For example, levels of serum ferritin are increased by two- to threefold from before menopause to after menopause. This observation has led us to hypothesize that, in addition to estrogen deficiency, increased iron as a result of menopause could be a risk factor affecting the health of postmenopausal women. ..'

Gretchen said...

Stephan, Do you know if anyone has researched why women in nonindustrial cultures do *not* gain fat in middle age?

Is food distributed according to need and it's assumed older people need less? Are they slower to get food out of a communal pot? It might also be interesting to study weight in cultures in which the men eat first and the women share what's left.

An interesting aside. We had a pair of cats, and the male cat always ate first. Except when the female was pregnant. Then he let her eat first.

Travis Culp said...

Were the increase in iron status the cause, I'd expect a correlation to show up in epidemiology studies.

Tomas said...

I think that in menopause both estrogen and progesterone drop dramatically, and progesterone moreso so in effect we see a higher estrogen to progesterone ratio. The studies that have shown no fat gain involved replacement of both hormones...
anyone please correct me here if I am wrong

Jane said...



Atherosclerosis is a progressive inflammatory disease [637-667] characterized by the accumulation of both oxidised lipids and various fibrous elements in arteries, often as plaques [668; 669]. Iron and oxidised lipids are both found in atherosclerotic lesions [106; 670-677], and iron depletion by dietary or other means delays this [678-681]. There is a correlation between iron status and atherosclerosis [671; 682-691], plausibly caused in part by the known ability of poorly liganded iron to effect lipid [683] and protein peroxidation, and by the effects of primed neutrophils [692] and transferrin [664]. In this context, exogenous ferric iron is deleterious to endothelial function [693], while iron chelation improves it [694-697]. However, phlebotomy provided no clinical benefit here [698]. Note that iron levels in plaques correlate with the amount of oxidised proteins therein [675], and that in one study [672], the EPR-detectable iron (essentially Fe(III)) in atherosclerotic tissue was seventeen times greater than that in the equivalent healthy tissue; this is not a small effect.
...It has been pointed out that many measures of iron stress are inappropriate, since it is only the redox-active form of iron that is likely involved in oxidative stress. Serum ferritin is considered by some to be the most reliable marker of iron status in general [787], although it is not well correlated with iron distribution in the heart [788]. What is clear, however, from the above is that deranged iron metabolism is intimately and causally involved in the formation of atherosclerotic lesions, and that appropriate iron chelation can help both to prevent and to reverse this.

Jin said...

If the main production of progesterone occurs by the corpus luteum at ovulation, how do we know it isn't the drastic decrease in progesterone which leads to fat gain?

Puddleg said...

An oldie but a goody:
Clara M. Davis and the wisdom of letting children choose their own diets

Puddleg said...

The original paper:

For the self-chosen diets, the average distribution of calories per kilogram of body weight
(regardless of variations in children's age) was protein 17 per cent, fat 35 per cent. and carbohydrate 48 per cent. The individual range for the protein in the group was from 9 per cent to 20 per cent.

Meals were often combinations of foods that were strange indeed to us, and would have been a dietitian's nightmare-for example, a breakfast of a pint of orange juice and liver; a supper of
several eggs, bananas and milk.

Gabriella Kadar said...

In cachexia, the ferritin levels become extremely high. Same with starvation due to muscle wasting.

Is it possible that -Some- but not all post-menopausal women experience an increase in ferritin due to loss of muscle mass? After all, the body does store what it does not need in regards to iron.

Ferritin, when it is very low indicates a lack of dietary iron or bleeding. But high ferritin is another pathology altogether.

As an aside, recently there has been a report that post menopausal women with low thyroid levels LIVE longer. It is suggested that thyroid replacement should not be given to this cohort. Well, isn't that just great? It appears that quality of life doesn't matter.

Peter said...
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Peter said...

A bit off topic, but nevertheless a small breakthrough in endocrinology, with an important health-promoting message.

Tropical Plants Made Our Ancestors Hungry For Sex

The link for the article was too long. It was published in the above online source, you can google it.

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