Eat proteins read estrogens, said the liver

Is the liver a reproductive organ?

As you know, I was working with these glowing-in-the-dark ERE-Luc mice, in which the reporter luciferase is expressed under estrogen receptor (ER) activity. ER is supposed to be more involved in reproduction than in nutrition, however, the liver of these ERE-Luc animals was always brighter in the morning than in the afternoon. The higher luciferase activity in the morning was not due to some circadian regulation but was more related to food intake. In fact, mice eat during the night, therefore in the morning they were in a fed state and in the afternoon in a more fasting state. After some control experiments, I find out that some non-identified food component was activating the hepatic estrogen receptor, hence nutritional cues were causing high luminescence into the liver. This was particularly evident when animals were fed with soy-milk: surprisingly, we found that common soy-phytoestrogens like genistein and daidzein were playing a minor role in this activation, but something else in the food matrix was responsible for ER activation (Rando et al., Toxicol Appl Pharmacol. 2009 237(3):288-97). What was going on?

Consider that soymilk is a high-protein nutrient. In a paper published yesterday in Cell Metabolism, using synthetic diets we demonstrate that dietary amino-acids regulate the activity of the estrogen receptor (ER). As a result of ER activation, hepatic IGF-1 secretion in the blood is increased. IGF1 plays a key role in uterine physiology. We observed that calorie restriction or selective ablation of ER in the liver decreased blood IGF1 to levels inadequate for the correct progression of the estrous cycle in the uterus. In a few words, our results suggest that the liver connects feeding to reproduction by sensing the availability of dietary proteins, an essential building block for the growth of the fetus and the subsequent production of the milk.
Looking at the calendar, we think the moon is the
fertility gatekeeper. However, in mice, the ovulation
calculator for optimal fertility is more based
on dietary proteins (the cheese) sensed in the liver
like an 'estrogen' hormone.
Our data challenge the well established paradigm on how the nutritional status affects reproductive activity. It is current belief that the organs responsible for energetic homeostasis signal the nutritional status to the brain neuroendocrine system, which, in turn, regulates the activity of reproductive organs via hormone gonadotropin synthesis and release (i.e., the hypothalamus-hypofisys-gonad axis). We have described a more direct signaling system where the estrogen receptor present in liver is the sensor of nutrient availability and controls, via IGF-1 secretion, the progression of the estrous cycle in reproductive organs. In this context, the trigger of ER activity is not its cognate hormone (the estrogen) but are some dietary proteins. So, in case of severe malnutrition, protein shortage cannot induce liver ER activity and its permissive signalling to reproductive organs. This can help to eludidate why anorexic women and women with liver disease have also troubles with menstrual cycles.

EDIT: You can read an interview of my former boss on Science Daily, and two post-publication review at F1000 by Alan McNeilly and by Albert Ricken. Beware, it is written that proteins influence the transcription of ER: this is not exactly true, ER is a transcription factor and dietary proteins influence the ER transcriptional activity by a mTOR dependent ER phosphorylation, not the expression of the ER gene itself.

--- References to the original research --- ---

Rando G, Ramachandran B, Rebecchi M, Ciana P, & Maggi A (2009). Differential effect of pure isoflavones and soymilk on estrogen receptor activity in mice. Toxicology and applied pharmacology, 237 (3), 288-97 PMID: 19361539

Della Torre S, Rando G, Meda C, Stell A, Chambon P, Krust A, Ibarra C, Magni P, Ciana P, & Maggi A (2011). Amino Acid-Dependent Activation of Liver Estrogen Receptor Alpha Integrates Metabolic and Reproductive Functions via IGF-1. Cell metabolism, 13 (2), 205-14 PMID: 21284987