Do you have the keys to your “fat lock-box?”
Lock-boxes have always fascinated me. Lock-boxes with special keys are even more fascinating. The more I’ve learned about fat cells (adipocytes), the more I think about them as special fuel depositories or fat lock-boxes. Before the invention of refrigerators, fast-food, Bisquick and beer, our bodies preserved and reserved fat as a precious commodity.
The body, when given fat with carbohydrates or excess protein, quickly places the fat into a lock-box for safe keeping. It does this for two reasons. First, the body can store fat very efficiently. Second, hormone signals stimulate fat storage when other fuel sources (carbohydrate & protein) are present in excess. The body can access this stored fuel only when the right presentation of hormonal keys are present. Fascinatingly, we now know from recent research, there are actually three types of lock-boxes for fat in the human body (white adipose tissue, brown adipose tissue, and tan adipose tissue).
The greatest challenge for the obesity doctor is getting into the fat lock-box. Some people’s boxes are like the “Jack-in-the-Box” you had as a child – just add a little exercise spinning the handle and the box pops open (These are those people that say, “Oh, just eat less and exercise and you’ll lose weight.”) For the majority of the people I see, it’s more like the lock above with a four or five part key required to turn the gears just right. (And, that key often only seems available on a quarter moon at midnight when the temperature is 72 degrees.) Fat cells, called adipocytes, require four, and possibly more, keys to open them up and access the fuel inside. Exercise is only one of those keys. However, exercise alone often fails.
Over the last 18 months, I have been surprisingly impressed with the results patients have by the addition of both medium chain triglycerides and exogenous ketones. A number of people have asked me, “Why do you encourage the addition of exogenous ketones to a person already following a ketogenic diet?”
Others just accuse me of self promotion, saying, “You’re just trying to sell a product!”
Or they exclaim, “Giving more ketones is just a waste of time and money.”
A few of the uneducated holler from across cyberspace, “You’re just going to cause ketoacidosis!”
Believe me, I’ve heard it all. And, the skepticism is understandable. I work with people every day, looking closely at weight gain/loss, metabolism, cholesterol, blood pressure, inflammation, etc. With any “low-carb” or “ketogenic product,” I test it out on myself and my family, before I offer it to my patients or even consider encouraging its use in my practice. I have this desire to understand “the how” and “the why” before I prescribe the who and when.
The Fat Lock-Box Keys
First , let’s talk about the adipocyte as a fat lock-box – and where you find the keys. Then, we’ll discuss how products may or may not help.
There is only one door INTO the adipocyte for the fat, and the key to that door is insulin. Insulin stimulates an enzyme called lipoprotein lipase that essentially pulls the fat from the cholesterol molecule into the fat cell. Without insulin, fat doesn’t enter the fat cell. As a result, type I diabetics (those that make absolutely no insulin) look anorexic if they don’t take their needed insulin. Insulin is also the first key to the back door on the adipocyte. Actually, if there is too much insulin in the system, fat enters easily through the front door but cannot exit the back door (Picture 1). Insulin seals up the back door so that fat cannot exit very effectively.
That’s why insulin is the master hormone when it comes to obesity. You’ve got to lower the over-all insulin load to get the adipocyte slowing fat entry and increasing fat exit. If you don’t do that, I don’t care how much you exercise, 85% of the population will struggle with weight loss. Hmmm, seems kind a familiar to the last 50 years of our obesity epidemic, No?
The second key to the back door of the fat cells are the catecholamines. These are adrenaline (epinephrine), norepinephrine, adrenocorticotropic hormone (ACTH) and even serotonin. These hormones are produced in the adrenal glands through exercise, fear and even recollection of powerful memories. Medications can also stimulate production of these hormones. The catecholamines stimulate cAMP. cAMP opens the fat cell, releasing fatty acids for fuel.
The thyroid hormone conversion of T4 to T3 also plays a role in uptake of the catecholamines by adnylyl cyclase (AC). Low levels of T3 (like those seen in hypothyroidism or in cases of thyroiditis) also inhibit unlocking of the fat lock-box. Conversion of T4 to T3 is driven by the presence of bile salts in the gut. Increase fat intake increases the presence of the bile salts which naturally leads to better T3 conversion. Hence my constant references to eating more fat and bacon. .
Inflammation & Medications
The third key is an inhibitory effect on adenylyl cyclase (AC) activity by alpha and beta adrenoreceptors, adenosine, prostaglandins, neuropeptide Y, peptide YY, HM74-R & nicotinic acid. These inhibitory and inflammatory hormones produced in the brain, gut and other areas decrease cAMP activity in the fat cell and slow fat loss. The fancy long names are all hormones causing inflammation. Of note, many are also stimulated by medications including blood pressure lowering drugs. Check with your doctor if the medications you are taking may be causing weight gain, or halting your weight loss.
Please note that the first three keys have effect on the cAMP pathway for release of fat from the adipocyte. These three keys turn on or off effective function of cAMP leading release of fatty acids from the fat cell.
The fourth key follows a separate pathway. This is why I’ve clinically seen patients experience weight loss even in the presence of higher insulin, inflammatory disease or hypothyroidism. This key activates release of the naturitic peptides (ANP, BNP). These hormones are released from the heart when it squeezes more powerfully. As the cardiac muscle contracts, it releases ANP & BNP hormones. These hormones stimulate the cGMP pathway in the adipocyte. It then activates hormone sensitive lipase (HSL) and perilipin to release free fatty acids. Again, this pathway is separate from the pathway by which the first three keys released fat. Exercise increases heart contractility, but is inhibited by high insulin levels. However, ketones themselves also stimulate this increased contractile effect.
Hypothalamus-Pituitary-Gonadal (HPG) Axis & Testosterone
There actually is a fifth key not referenced above. The fifth key to the fat lock-box amplifies testosterone’s presence through the HPG axis. Insulin resistance and leptin resistance lower testosterone in men and raise it in women, causing poly-cystic ovarian syndrome (PCOS). Normalizing insulin levels (with a ketogenic diet) while at the same time increasing ketones as the primary fuel powerfully resets the HPG axis through a complex series of hormonal reactions. Growth hormone is balanced and testosterone returns to a normal range.
Clinically, 60% of the people I see in the office have abnormal testosterone due to insulin resistance. This leads to hypogonadism in men and PCOS (abnormal periods, facial hair growth and/or infertility) in women. Restricting carbohydrates and maintaining nutritional ketosis by diet and/or addition of exogenous ketones has a powerful corrective factor in these people.
Testosterone influences the up-regulation of the alpha & beta adrenergic receptors (the 2nd & 3rd key above). Hence, if your testosterone is low, it has a suppression on the way that the catecholamines influence fatty acid release from the fat cells. If your testosterone and growth hormone are normal, muscle development and adrenaline stimulus from exercise helps amplify the use and mobilization of fat from the fat cell. In people with insulin resistance and leptin resistance, exercise and the catecholamines don’t have the same fat burning effect.
What Does This Actually Mean?
Yes, I have greatly simplified a series of very complex hormonal pathways in the explanation of the keys above. Why do you think understanding obesity has been so difficult? Think of your adipocytes as a fat lock-box.
What’s even more important is the knowledge that the fat cell DOES NOT open or close because of calories. There is no dogmatic calorie-meter on the wall of the fat cell. There is no calorie key to the fat lock-box. Really, . . . in the 50 years of studying fat, researchers haven’t found one. (Prove me wrong when you show me an electron micro-graph of a calorie-meter in the wall of a cell). Science has demonstrated multiple times that the lack of food from starvation or excessive fasting suppresses thyroid function (an inhibitory effect on key #3). Restricting calories actually inhibits fat loss in many people.
The fat lock-box keys I refer to above are hormone responses to the presence of macro-nutrients (food). That means, first reduce your carbohydrate intake by eating real food from good sources. You can learn how to get started by registering for my FREE six part weight loss mini-course. Second, be as active as you can. Third, reduce stress and medications that have inhibitory effect on catacholamines. Fourth, balance your thyroid. And, fifth, get into ketosis and consider adding exogenous ketones to your dietary regimen. It really is that simple.
(For those of you that still believe there is a calorie key – or just need something to do while in the bathroom):
- Lafontan et al. Arterioscler Thromb Vasc Biol. 2005
- Lenard NR, Obesity, 2008
- Li XF et al, Endo (April 2004) Vol 145
- Liu YY& Brent GA, Trends Endocrinol Metab. 2010 Mar; 21(3): 166–173
- Max Lafontan et al. Arterioscler Thromb Vasc Biol. 2005;25:2032-2042
- Skorupskaite K et al, Hum Rep Update, Mar 2014, vol 20