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Crosstalk of Estrogen and Leptin in the Hypothalamus

Gao Q, Horvath T. Crosstalk between estrogen and leptin signaling in the hypothalamus. Am J Physiol Endocrinol Metab. 2008 Mar 11 [Epub ahead of print]

Comparative Medicine, Yale University, New haven, Connecticut, United States.

Obesity, characterized by enhanced food intake (hyperphagia) and reduced energy expenditure that results in the accumulation of body fat, is a major risk factor for various diseases including diabetes, cardiovascular disease and cancer. In the United States, more than half of adults are overweight and this number continues to increase (Flegal et al., 2002). The adipocyte secreted hormone, leptin, and its downstream signaling mediators play crucial roles in the regulation of energy balance. Leptin decreases feeding while increasing energy expenditure and permitting energy-intensive neuroendocrine processes (such as reproduction). Thus, leptin also modulates the neuroendocrine reproductive axis. The gonadal steroid hormone, estrogen, plays a central role in the regulation of reproduction and also contributes to the regulation of energy balance. Estrogen deficiency promotes feeding and weight gain, and estrogen facilitates and to some extent mimics some actions of leptin. In this review, we examine the function of estrogen and leptin in the brain, with a focus on mechanisms by which leptin and estrogen cooperate in the regulation of energy homeostasis. Key words: estradiol, leptin, crosstalk.

My comments: Ok, this is a bit of a technical paper but rather than focus on the detail pieces, I want to use it to try and clear up some big misconceptions that exist in the fitness and dieting world.

First things first, let me talk about leptin and the hypothalamus. I feel like I’ve been thumping on about leptin for years now, probably because I have. In many ways, it is the single most important hormone when it comes to problems with dieting and body recomposition. Released from body fat (and scaling frighteningly well with body fat levels), leptin signals the brain about two things which are

  1. How much fat you’re carrying
  2. How much you’re eating

This is important because knowing these two things is crucial for your body to be able to adjust things like metabolic rate, appetite, hormones, etc. Now, originally leptin was thought to exist to prevent obesity; this turns out to be incorrect. Rather, leptin exists to prevent starvation and the fall in leptin is what coordinates most of the bad things that happen on a diet.

Metabolic rate falling, dropping T3, increasing cortisol, increased appetite…all coordinated by the fall in leptin when you diet. Towards this end, while studies have routinely shown that increasing leptin in fat people does little, other studies find that replacing leptin to pre-diet levels on a diet raises metabolic rate and thyroid levels and increases fat loss.

Although leptin affects other tissues such as skeletal muscle, fat cells and the liver, most of its central action occurs in the brain, at the level of the hypothalamus. By exerting its signal there, leptin does what I talked about above. Recent work has also found that leptin can ‘rewire’ the brain (at least in rats) to increase the amount of a compound that does help to inhibit appetite. Outside of cases where leptin is massively elevated chronically (causing problems), leptin is one of the good hormones.

Which brings me to estrogen and the topic of this paper. In the world of bodybuilding and dieting, estrogen is usually painted rather broadly with the brush of ‘bad’. The old (and incorrect) idea is that estrogen is responsible for women’s fat problems. Estrogen makes you store fat, estrogen gives you fat legs, estrogen makes you crazy (ok, the last one is partially true). And there’s some truth to all of that. But there’s a lot of non-truth. Women seem compelled to try and banish estrogen (seriously, some use that terminology), figuring if they get rid of it, the fat will melt off.

As it turns out, estrogen is fairly schizophrenic in the female body in terms of how it impacts fat loss. As I discuss in The Stubborn Fat Solution estrogen can both positively and negative affect body fat levels in women. For example, estrogen stimulates fat oxidation during exercise. It can also limit fat mobilization from fat cells (through various mechanisms). The hows and whys of the differences aren’t important here, just realize that estrogen isn’t ‘bad’ in the sense that most think.

Consider for example this simple fact: if estrogen were THE source of women’s dieting problems, then women whose estrogen levels have fallen to very low levels (as occurs with amenorrhea or when they diet to low levels) should have an easier time losing fat. Yet nothing could be further from the truth. Or consider this: when a woman enters menopause (and her estrogen and progesterone levels drop to extremely low levels), she often gains body fat. If estrogen were the problem, neither of these things should be the case.

And this week’s paper goes a long ways towards explaining why. In addition to its schizophrenic effects on other tissues of the body, estrogen affects the brain. And, in the context of this paper, it turns out that estrogen is having a lot of signalling effects in the hypothalamus that are IDENTICAL to leptin’s (which, as I outlined above, are nothing but good). I’d note, tangentially that other studies suggest that estrogen improves the brain’s sensitivity to leptin, meaning that it makes leptin work better.

Of more importance, as stated, estrogen and leptin appear to show a great deal of similarity of the signals that they send in the brain which is what this paper details.

Somehwhat like leptin, estrogen can actually reduce food intake and body fatness levels in both animals and humans. As I noted above, postmenopausal women often gain fat and estrogen replacement causes them to lose that body fat. There is some evidence that metabolic rate may go down after menopause, and this may also be fixed by estrogen replacement.

Of some interest, empirically some contest prep coaches feel that the reason many anti-estrogen drugs (such as Nolvadex) are effective is because they exert a pro-estrogenic effect in some tissues (this little bit of strangeness, whereby a supposed anti-estrogen compound can have pro-estrogenic effects is explained in The Stubborn Fat Solution book).

Additionally, a deficiency in the level of aromatase (the enzyme that converts testosterone to estrogen) has been shown to cause a number of hormonal problems along with infertility in both sexes; clearly estrogen is crucial to normal functioning.

As mentioned above, recent work in rats has found that leptin ‘rewires’ the hypothalamus to express more of the neurons which release the ‘good’ hormones (in terms of appetite control). Estrogen has been found to do the same thing. Both estrogen and leptin also activate those same neurons, increasing levels of the hormone in question (it goes by the abbreviation POMC for pro-opiomelanocortin). I’d note that recent work suggests that it is the drop in estrogen (rather than the increase in progesterone) that is responsible for the increase in appetite during certain parts of the menstrual cycle. That is, normal or high estrogen levels blunt appetite.

The paper gets into a number of molecular details beyond the above but it’s not really relevant. My main point here is that

  1. Estrogen and leptin appear to have interacting and overlapping roles in the brain in terms of reducing appetite and body fat.
    Estrogen is certainly not ‘bad’ in any sense in terms of its impact on body weight and body fat regulation. Certainly some of its physiological effects are negative but there are also extreme positives to estrogen in the body. The idea that simply eliminating estrogen will solve women’s fat or weight problems (or solve lower body fat problems) is simply silly, reductive, and nonsensical.

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