Leptin OverviewI want to start with a short and sweet Leptin overview, which will be new to some and a refresher to others. Leptin is a hormone that structurally belongs to the cytokine family made primarily in white adipose tissue (WAT), but it is also produced in other areas of the body in lesser amounts, like brown adipose tissue (BAT) and skeletal muscle, among others. It’s primary function, particularly for our purposes, is controlling hunger and satiety. When we have optimal Leptin levels in conjunction with optimal Leptin sensitivity, as our energy stores fill up, the "fed state” is signaled and we are no longer driven to eat. When this system becomes dysfunctional, like in obesity or calorie restriction, everything goes haywire and we end up with strong hunger signals even when the body doesn’t need calories.
Like most hormones and adipokines, and pretty much anything responsible for any amount of signaling in the body, we function best when it is at an "optimal” level, we don’t want it super high or super low.
A number of things control the synthesis, release, and sensitivity to Leptin, but there are two main factors to be concerned with. These are fat stores (cell size and number), and energy balance. The important thing to remember is that a calorie deficit causes Leptin to drop, and a calorie surplus causes Leptin to rise. Part of the reason why people tend to hit a wall after extended dieting is this drop in Leptin levels. One of the common ways people deal with this is by implementing regular cheat days where they eat a bunch of carbs and a huge calorie surplus. However, this method is not without drawbacks, and with proper supplementation (Epitome), this becomes unnecessary.
In obesity, we typically see elevated Leptin, which causes reduced sensitivity. The constant over-supply of Leptin causes the receptors to downregulate. So we’ve got plenty of this stuff around, but the body has no idea what to do with it. As an example, let’s say every morning you go into Starbucks to buy coffee. But every time you pull your wallet out, it’s just full of Jordanian Dinar instead of dollar bills. You’ve got like, 100,000 Dinar in there, which is possibly enough to buy the whole coffee shop, but the Baristas have no idea what to do with it so you leave sad and confused with no coffee.
When an individual is obese, or has an endomorphic phenotype (who have similar biochemistry to the obese), and they lose weight, they will experience a major drop in Leptin levels, typically below that optimal window. So take Person A, who is naturally a fairly lean 180lbs, and Person B, who is an endomorph that dieted down from 215 to 180, and Person B is going to have lower Leptin levels and messed up neuroendocrine signaling giving him a strong desire to overeat and get back to that original weight. Even the emotional response to eating is highly controlled by Leptin in the brain, so Person B is getting stronger physiological signals (hunger pangs/fatigue), as well as psychological signals (specific cravings, increased reward response to food). Also chalk up the reduced resting energy expenditure from low Leptin, and you’ve got a brutal combination.Unfortunately this is when the typical person, through their own accord or the advice of their nutrition guru, will often cut calories even more, because if you’re not losing weight, you must be eating too much right? This further caloric restriction drops Leptin even more, and the condition is exacerbated. Also worth noting, with Leptin being tightly linked to the anabolic hormonal cascade of the Fed State (increasing LH which boosts testosterone, increasing GH and T3, decreasing cortisol, etc.) at this point any weight you’re losing is likely to be a high percentage of muscle instead of fat.
Again, one method to attempt to fix this is with a "refeed”, but you’re still sacrificing fat loss during and after the refeed, and the psychological aspect to this type of binge behavior can be quite damaging to many people, making it difficult to stay on a diet. Particularly when Leptin is low and reward signaling is dramatically elevated from food.
Definition of terms
This is a list of terms that, if you scan through first, will better help you understand the ingredients and function. You may want to refer back to it as you read about the specifics of the formula.
SREBP Sterol Regulatory Element Binding Proteins or SREBPs are proteins required for cellular uptake of fatty acids, as well as production of endogenous cholesterol and fatty acids.
SREBP-1a relates to cholesterol, and is regulated by the amount of sterol levels in the cell. This is one of the major reasons why when we eat less cholesterol, our body just produces more, and vice versa.
SREBP-1c relates to glucose, lipids and fatty acids, and is regulated by insulin.
AMPKAdenosine monophosphate-activated protein kinase, or AMPK, is basically the cellular signaling equivalent of exercise. Once activated, it triggers fatty acid oxidation and the generation of ketone bodies, inhibits cholesterol synthesis and lipogenesis, stimulates skeletal muscle glucose uptake, and favorably modulates insulin secretion. Increasing AMPK activation can actually repair damaged insulin signaling.
Fat loss and fat gain are moderated by numerous complex mechanisms, and AMPk is a key player in this flux. Appropriate levels of AMPk activation are great for fat loss.
AMPK phosphorylates, and inhibits the aforementioned SREBP-1c (1). Without adequate AMPK activation, SREBP-1c reacts to glucose elevations causing lipogenesis and lipid accumulation.
When looking at fat loss research, data on Type II Diabetes is an interesting and highly relevant place to look, even for those lacking the clinical symptoms. One of the ways the drug Metformin works (most people with T2DM are prescribed this right off the bat), is through AMPK activation.
To reiterate, activation basically has the same effect as exercise, from a fat loss/metabolic perspective.
PTP1BProtein-tyrosine phosphatase 1B (or PTP1B) is an enzyme found in the endoplasmic reticulum of cells. This enzyme relates to insulin signaling, in that, suppressing it improves insulin sensitivity. When mice have this enzyme knocked out, insulin sensitivity is enhanced and they become resistant to obesity (2). And what’s really cool about that, is that the enhanced insulin sensitivity and increased glucose disposal is tissue specific to skeletal muscle, not fat (3).
LPSLipopolysaccharides (or LPS), are molecules consisting of a bonded lipid and carbohydrate produced from bacteria in the body. These are also referred to as endotoxins. LPS act as potent immune stimulating signals, interacting with monocytes and macrophages. They interplay with many inflammatory cytokines like TNF-a, various interleukins and TGF-b (4).
In overweight and obese folks, LPS are consistently elevated due to bacterial imbalance of the gut microbiome. The inflammatory stress from LPS can contribute to intestinal permeability, also known as Leaky Gut Syndrome. This is a double-whammy, as the increased permeability allows LPS to freely enter the bloodstream and cause more problems.
cAMPCyclic adenosine monophosphate (or cAMP) is made from ATP, acting as a 2nd messenger for things like epinephrine and glucagon, which can’t pass through plasma membranes themselves. It is closely involved in regulating glucose and glycogen, as well as lipid metabolism.
PhenotypeGenetics + Environment = Phenotype
Genetics = what your parents gave you.Environment = food, exercise, supplements, behavior psychology.
EndomorphThe classic round body type that has a hard time losing fat. The CICO (calories in/calories out) model of weight loss typically doesn’t get the job done for this person. You’re frequently hungry when you shouldn’t be. Diets work initially then you hit a wall after a short phase of progress. Getting motivated to exercise is challenging due to physiology as much as psychology (your body, through many intricate hormonal processes, makes you feel tired as to conserve energy, which then, downstream tells your brain to stay on the couch and eat more food).
BA directly acts on SREBPs, resulting in some highly favorable effects. By inhibiting the maturation of SREBP, it decreases the body’s endogenous production of cholesterol and fatty acids. It has been shown, in vivo, to ameliorate diet-induced obesity by decreasing lipid content in the serum as well as at the tissue level, and by improving insulin sensitivity.
It also was found to reduce the size and improve stability of atherosclerotic plaques, also through the SREBP route (5,6). In addition to inhibiting the maturation of SREBP, it also knocks it out on multiple levels by suppressing mRNA expression, translocation to the nucleus, and target gene expression in hepatocytes (7).
Excessive fat (triglyceride) accumulation in the liver is a major problem for people with endomorphic tendencies. In fact, Non-Alcoholic Fatty Liver Disease (NAFLD, which is defined by excessive fat storage in the liver) is a rapidly increasing diagnosis that likely relates, at least in part, to climbing rates of obesity. As far as large scale data goes, the last estimate (which is surely pretty conservative now) was that about 20% of U.S. residents have NAFLD, which is associated with diabetes, insulin resistance and obesity (8). Point being, as an endomorph, the likelihood of your liver over-storing triglycerides is quite high, which can lead down a pretty unforgiving path, not only from an overall health & longevity perspective, but also due to the downstream signaling effects on appetite regulation and body composition. BA has been shown, in vivo, to suppress excessive triglyceride accumulation and lipogenesis in the liver. This is accomplished by SREBP suppression, as well as AMPK activation (7).
Now that we’re talking about the liver and AMPK (the exercise mimetic), BA has also been shown to have an inhibitory effect on liver glucose production through AMPK activation (9). Now, hepatic (liver) glucose production is a normal function that keeps blood glucose stable when you’re not shoving carbs in your mouth, so its not necessarily/inherently a bad thing. The problem arises in the endomorphic phenotype when this system becomes dysfunctional and the liver over-produces glucose causing hyperglycemia and/or above optimal fasting glucose levels. When fasting glucose is high, the body doesn’t have any urgency to use fatty acids as fuel, so fat burning, in the eyes of your body, becomes an unnecessary and useless endeavor. To illustrate this point, when two groups of insulin resistant mice were given a diet that should make them fat and sick, the ones receiving BA saw a decrease in blood glucose, triglycerides, and insulin resistance by 34%, 59%, and 38%, respectively (9).
Along these lines, another study looked at mice fed a fattening diet for 15 weeks. One group had BA added to their diet, the other did not. The BA group showed significantly decreased body weight, less abdominal fat accumulation, lower blood glucose, less plasma triglycerides and cholesterol, increased plasma Leptin, and an optimized ratio of amylase:lipase enzymes favoring fat metabolism over carbohydrate (10).
Oh but there’s more, so much more. BA is also a PTP1B inhibitor, which optimizes Leptin signaling and increases insulin sensitivity (11). It has been shown to modulate cAMP, resulting in a strong lipolytic boost in adipose tissue, while directly preventing absorption of lipids from the small intestine resulting in a pronounced anti-obesity effect (12).
In line with the inflammation/obesity link, some brand new research on Betulin demonstrates that it inhibits NF-kB, a protein complex that becomes activated in response to things like stress, elevated ROS, oxidation of LDL cholesterol, and various inflammatory cytokines (13). Elevated NF-kB causes a host of inflammatory related problems, and the Endomorphic Phenotype is more susceptible to this cascade.
To return the focus to Leptin, one of the major problems with potent Leptin sensitizers is that while they improve Leptin resistance, they tend to do this at the expense of lowering Leptin levels, which throws a figurative wrench in the Leptin associated fat loss effect. As a refresher, we will typically see elevated Leptin levels in the overweight and obese, but a decreased Leptin sensitivity. Weight loss in and of itself will drop Leptin levels, and coupled with a Leptin sensitizer, Leptin would likely drop below optimal levels. When this happens, you start to see a decrease in thyroid output, increased hunger, lower energy expenditure in skeletal muscle, and other problems.
Knowing this problematic limitation, researchers out of Yeungnam University in South Korea designed an experiment using a Leptin sensitizer in combination with a stimulant of endogenous Leptin to see if there was any synergy. They chose BA for their Leptin sensitizer, along with something called Orthosiphon Staminus (OS) as the Leptin stimulant, knowing that OS increases Leptin expression in vivo and in vitro.
Mice were given a fattening diet for 6 weeks, in conjunction with 2 weeks of BA, OS, both, or neither. The subjects receiving BA, OS, or neither, didn’t see a significant body weight reduction, but the combination of BA+OS significantly reduced bodyweight over the other groups suggesting a synergy in line with the proposed hypothesis between these two ingredients (14).
Now, keep in mind this was only two weeks worth of supplemental intervention, so its likely that more time on BA alone would have shown results in line with the previously mentioned studies. That being said, it’s pretty interesting that a positive effect on weight loss was seen so rapidly in the combination group. Which brings us to our next ingredient…Orthosiphon Stamineus (ethanolic extract)Orhosiphon Stamineus (OS) is a tropical herb, commonly consumed in Southeast Asia as a tea for it’s anti-inflammatory, analgesic (pain-reducing), and kidney health properties (15–17). On the general health front, it has also been shown to be a liver protecting agent, purportedly through it’s direct antioxidant capabilities in liver cells (17,18).
To revisit the inflammation-obesity connection, this interplay between inflammatory signaling and bodyfat storage is a self-perpetuating cycle that needs to be managed, particularly in Endomorphs. The collective data on OS is pretty clear about it’s anti-inflammatory effect, which seems to be mediated largely by it’s ability to block the negative effect of LPS, even when cells are directly stimulated with LPS (19,20,17). As you might recall, management of LPS is critical for proper immune function, and OS has been shown to additionally optimize this by favorably modulating the immune system through proliferation of peripheral blood mononuclear cells (PBMCs) (21).
Glucose control (fasting and post-prandial) is typically a problem for the overweight/obese/endomorph. OS has been shown to lower blood glucose without elevating insulin. It does this, at least in part, by inhibiting two enzymes, alpha-glucosidase and alpha-amylase (22,23).
OS hits most of the things in our Definition of Terms section at the beginning of the article pretty hard. It decreases the expression of SREBP-1c, giving it anti-adipogenic properties. It increases hormone sensitive lipase (HSL, a key player in fat burning) through the cAMP pathway. It hits AMPK from multiple angles; by directly increasing phosphorylation as well as upregulating something called carnitine palmitoyltransferase 1-a, which enhances fat oxidation through the AMPK pathway. It also inhibits glucose uptake into fat cells by decreasing phosphorylation of insulin receptor substrate (24).
Additionally, OS has been shown to be a mild diuretic and anorectic, supporting water loss and appetite control (17,25).
Throughout this writeup we have focused on obese/endomorph phenotypes, since these issues are a huge social problem approaching epidemic proportions. So, what about lean individuals (sub 12%), you ask? Well, as touched on earlier OS functions on the Leptin system in a very unique way - normalization. For the Obese/Endomorph, this means lowering levels to within normal, but for the truly lean (and my hats off to you), this would function to raise Leptin level also to within normal. No longer will you find yourself up at 2am sleep-eating some Little Debbie Zebra Cakes, or contemplating capital murder to get to a plate of pasta. For the lean individual, you should be able to maintain your leanness with a minimum of effort, or even consider attempting single digits (this will be made easier with the addition of Leptigen Basic, but that’s for another time.)
Queen Bee AcidQueen Bee Acid (or QBA), also known as 10-dydroxy-2-decenoic acid, is a bioactive medium chain fat found in Royal Jelly. In the larvae stage, bees fed Royal Jelly grow into Queen Bees instead of worker bees. Queen Bees are much larger and live several years, while worker bees only live about six weeks (26). The growth promoting property of Royal Jelly likely comes from a protein called royalactin, which is not part of the lipid fraction where the QBA is found. The life extension property is likely found in the QBA however, as worms given QBA live about 12% longer (27). This may have something to do with improving cell membrane resistance to peroxidation, at least in part, but this hasn’t been tested in humans yet.
The main reason for the inclusion of QBA in the Epitome formula is that it appears to be a super AMPK activator. So again, with increased AMPK you get an exercise mimetic and increased fat oxidation. In addition, this boost in AMPK from QBA has been shown, in vitro and in vivo, to enhance glucose uptake in skeletal muscle independently of insulin for better nutrient partitioning (28).
QBA also has an interesting effect on the brain, in that it has been shown to increase neuron growth similar to endogenous BDNF and the omega-3 fatty acid DHA (29). Similar to Orthosiphon, QBA also acts as an anti-inflammatory through favorable modulation of LPS signaling (30). It also acts as an anti-inflammatory in a second way, through inhibition of something called Histone Deacetylase (HDAC), which is also inhibited by the ketone body b-hydroxybutyrate. HDAC inhibitors are also looked at for prevention and treatment of cancer, as well as mood stabilization.
Some other side-notes on general benefits, QBA has been shown to boost collagen production, help with skin aging, and reduce joint destruction in Rheumatoid Arthritis (31–33).