Well, as some background, there are 2 well characterized nuclear estrogen receptors: ERα and ERβ. These function as classic nuclear steroid receptors by binding to response elements in target genes and ultimately altering transcription (genomic effects). But these receptors can also move to the plasma membrane and activate signaling cascades upon ligand binding (non-genomic rapid effects). Furthermore, there is some suggestion that a newly described g-protein coupled receptor (gpr30) also binds estrogen, again initiating signaling cascades.
Right. I guess the major misconception is that estrogen is all bad, because it is actually quite protective, at least in terms of preventing metabolic pathology. One of the things that estrogen does in humans is promote subcutaneous fat storage (versus the bad stuff – visceral), particularly butt and leg fat. While this isn’t necessarily good for physique-enhancement, it is actually the safest place to store body fat and is probably the reason that females are protected from metabolic disease compared to men.
Yes, and not only adipose tissue my friend…but my thesis work is actually aiming to get a better understanding of estrogen’s role in skeletal muscle physiology, a surprisingly understudied area. We have found that estrogen increases LPL in muscle, while decreasing it in fat tissue. This results in a partitioning of fatty acids away from adipocytes and towards skeletal muscle where these FFA’s are likely oxidized. In support of this, we also saw that estrogen increased muscle PPARα expression (a master regulator of fat oxidation). Furthermore, we found that estrogen and a metabolite of estrogen (2-hydroxyestradiol) can rapidly activate AMPK in muscle, another mechanism for increasing fat oxidation, as well as Akt, an important signaling molecule in the insulin cascade.
So, estrogen receptors are clearly expressed in skeletal muscle, and there are obvious gender differences in terms of muscle quality and quantity. Now clearly testosterone plays a role here, and probably progesterone as well, but estrogen is quite important too.
Well, for one thing, expression of ERs in muscle is way less than say uterine tissue. Now, from the limited studies that have been done to look at ERs in muscle, there actually don’t seem to be major differences between the genders. Males definitely express estrogen receptors, and estrogen is important to male physiology in that males with rare genetic estrogen deficiencies (aromatase or ERα deficiency) have profound glucose and lipid metabolism impairments and are quite insulin resistant. Interestingly, endurance trained males have higher muscle expression of both ERα and ERβ, probably due to higher type I fiber percentage. (Muscle expression of both receptors is higher in type I oxidative fibers.) But the relative expression and importance of ERα and ERβ in muscle is still quite unclear.
In terms of adipose tissue, it has been shown that female ERα expression is higher than ERβ in omental fat, but ERβ expression is higher than ERα in subcutaneous depots. And women with higher ERβ expression in omental fat tend to have greater adiposity. Just a correlation of course, but it’s possible that ERβ opposes ERα in adipose tissue.
Right! And actually the newest line of thinking is not so much that visceral is bad (again, metabolically speaking), but that subcutaneous is actually good! But that is a whole different story….So getting back to muscle, one of things that estrogen has been shown to do in rodents is activate myogenic satellite cells in response to muscle damage, thereby facilitating muscle recovery from exercise. Interesting! Now a lot of my work is not yet published, so I can’t say too much. But have no doubt; ovarian hormones likely have significant effects on skeletal muscle!
YES!
When we initially discussed this some time ago, my diagnosis was incorrectly determined to be Type 2. This after I showed up at the doc’s office having had blood sugar over 600 mg/dl (as high as a glucometer can read) for at least 8 hours. After going home with Metformin and no referral to an endocrinologist, I took it upon myself to seek a 2nd opinion and an immediate shot of insulin. Thankfully I did, as it turns out I’m actually a true Type 1, meaning auto-antibody positive and no insulin production, and now I have a great doc to refer people I don’t like. But back to the now, it’s been CRAZY having diabetes! With all of my knowledge, it’s still been a daily struggle to keep my blood sugar in check. I have a whole new respect for the pancreas, that’s for sure! Regardless, I’ve really tried to focus on it as a learning experience, which it TOTALLY has been. My biggest battle came this spring when I started my attempt to get super lean for summer. To my surprise and remarkable frustration, the body fat just wasn’t melting off as it has every year prior when I would stick to a clean nutrition plan (notably pre-insulin therapy). As frustrating as this has been, it has ended up being somewhat serendipitous in that I have come to discover my new favorite hormone – a hormone that I sadly knew very little about prior to my diabetic struggles. It turns out that the pancreatic ß-cell makes 2 hormones. That’s right…not just the well appreciated insulin, but also the much lesser talked about cousin of insulin called amylin!
Basically, amylin is co-secreted with insulin acting to ultimately help control glycemia post-prandially. It does this in 3 ways:
- Slowing gastric emptying
- Inhibiting gluconeogenesis
- Sending the brain signals of satiety.
Well, us type 1’s who don’t have beta cells also don’t produce amylin. The result of this is high post-prandial glucose spikes and increased fat storage.
Let me explain my theory on the fat storage phenomenon…normal people produce insulin in the pancreas, which directly feeds the liver, so the liver actually sees more insulin than the periphery and gets a clear signal to shut down glucose production (release of stored glucose). My insulin however, now gets to the periphery from my subcutaneous injection site. Therefore my liver gets less insulin than necessary to completely inhibit gluconeogenesis (I would be severely hypoglycemic if I tried to give enough insulin to completely shut down hepatic glucose production). The end result is that I have to give MORE insulin to overcome the hepatic production and maintain euglycemia and “tight control” of my diabetes. Now, lipogenic pathways are notorious for being super-sensitive to insulin (hence why severely insulin resistant individuals can still put on the fat!), so in the face of all the insulin I have been pumping to maintain euglycemia, it is actually no wonder that getting super lean has been tougher for me this year! In terms of my diabetes control, obviously a huge concern, my A1c is still not optimal despite normal glucose readings pre and 2hrs post eating. I suspect this is because of high post-prandial glucose spikes. Normal people don’t go above 120 mg/dl, but I soar up past 200 mg/dl every carb meal! Good thing I dose some antioxidants… Well now for the good news… a few weeks ago I started injecting symlin (an amylin analogue) with meals. It’s only been a couple weeks, but WOW! My glycemic control is amazingly better! I bet my A1c is plummeting as we speak! It will take some more time to assimilate my fat loss data, but I am optimistic. I almost feel like normal person again! FYI, yo-yoing glucose levels over a range of 250 mg/dl throughout the day is NOT fun!
That’s a great question, but I don’t know the answer. It’s actually possible because I suspect amylin would suppress appetite in lean people too. I don’t know of any studies done yet in non-diabetic lean individuals, but I know they have given it to non-diabetic obese individuals and seen significant weight loss. It may eventually be approved as an obesity treatment, possibly in conjunction with other neuro-modulators.
I was doing in vitro studies with fat cells and muscle cells to try to reproduce some data showing that cinnamon increases insulin sensitivity. Cinnamon had been shown to inhibit a phosphatase that de-activates the insulin receptor, and possibly even bind to the insulin receptor itself. We never really got convincing data. Human studies have been conflicting, some showing beneficial effects of the spice, and others not reporting much going on. I suspect that cinnamon does some good things, but it depends on the extract, and the effects are small so you’d need a lot of cinnamon!
My pleasure, thanks for digging me out of the lab to share some knowledge with M&M!
*Nicole will be available all month in the Inner Circle for discussion of this article as well as any other questions that may arise. Nicole’s Published Research: Publications: D’Eon TM, Rogers NH, Stancheva ZS, Greenberg AS. Estradiol and the Estradiol Metabolite, 2-Hydroxyestradiol Activate AMP-Activated Protein Kinase in C2C12 Myotubes. Obesity 2008, in press (Epub April 10, 2008). Rogers NH, Obin MS, and Greenberg AS. Chapter 4: Obesity and Adipokines. In Contemporary Endocrinology: Treatment of the Obese Patient. Editors: Kushner R and Bessenden DH, p69-85, 2007 Humana Press Inc, Totowa, NJ Souza SC, Chrisofolette MA, Ribeiro MO, Miyoshi H, Strissel KJ, Stancheva Z, Rogers NH, D’Eon TM, Perfield JW, Imachi H, Obin M, Bianco AC, Greenberg AS. Perilipin regulates the thermogenic actions of norepinepherine in brown adipose tissue. J Lipid Research, June 2007; 48(6):1273-9.Abstracts: Rogers NH, Perfield II JW, Strissel KJ, Obin MS, Greenberg AS. Ovariectomy in mature mice does not increase food intake, but increases adiposity and adipose tissue inflammation. To be presented at NAASO 2008. Rogers NH, Perfield II JW, Strissel KJ, Obin MS, Witczak CA, Goodyear LJ, Greenberg AS. Chronic estrogen deficiency in mice alters FoxO1 signaling in a mixed fiber skeletal muscle. To be presented at ENDO 2008. Rogers NH, Witczak CA, Goodyear LJ, Greenberg AS. Estrogen rapidly phosphorylates AMPK, Akt, and AS160 in isolated rat soleus muscles. Experimental Biology, 2008.
