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.

Age

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

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.