Autophagy an alternative to vitamin D supplements? / Getting Stronger

An alternative to vitamin D supplements? /  Getting Stronger

Getting Stronger is a blog about the philosophy of Hormetism, based on the application of progressive, intermittent stress to overcome challenges and grow stronger physically, mentally and emotionally. For additional background, click here for the OVERVIEW and AUTHOR pages. 

My recent post on Why I don’t take vitamin D supplements generated a lot of interest and a few misconceptions.  In that article, I did not suggest any practical alternatives to taking high dose vitamin D supplements.  Here I will suggest a way that may provide the benefits of vitamin D without popping any pills, spending all day in the sun, or ingesting copious amounts of fish.

Some readers got the idea that I believe vitamin D is not beneficial, and that I discount the evidence from studies that show the benefits.  I want to dispel that notion.  I do acknowledge the key role that vitamin D and the vitamin D receptor (VDR) play in bone mineralization and regulation of  innate and adaptive immunity, and among other things.  I further acknowledge that many (but certainly not all) studies support an association between higher vitamin D3 levels and reduced incidence of diseases such as cancer.
As I wrote:

Nobody doubts the important role of vitamin D in the body. But are higher levels of a hormone like vitamin D–whether or not provided as a supplement– always a good thing?

My doubts are focused on several points:

• Under-appreciation of the fact that vitamin D is a hormone with diverse and dose-dependent systemic effects, still not fully understood
• Misleading  claims that vitamin D supplementation is “equivalent”  to vitamin D from sun exposure. While the two forms are chemically identical, levels of vitamin D3 synthesized from sun exposure are self-limiting due to feedback regulation.  What happens when we chronically exceed natural limits?
• Inadequate attention to the possible effects of chronic vitamin D supplementation on homeostatic down-regulation of the VDR receptor. See this discussion bv Dr. David Agus of USC medical school.
• Inadequate study of the possible long term adverse effects of chronic vitamin D supplementation. Few studies look beyond 4 years. Hormone replacement therapy was in favor for 50 years before the risks came to light . Things don’t necessarily look any more promising when synthetic hormones are replaced bioidentical hormones.

My article created a dilemma for several commenters. These people acknowledged the risks, but nevertheless cited  benefits they personally experienced  from supplementing with vitamin D–ranging from fewer colds and flu, to relief of autoimmune symptoms, and even lessening of depression.

For these people, a key question remains:

Is there a way to get the benefits of vitamin D supplementation, while avoiding the dependency and risks of taking vitamin D capsules daily for the rest of your life?  While I don’t have a definitive proven answer to that question, recent research leads me to speculate here that there is a promising approach that is within everyone’s reach.

It lies within a powerful natural biological process called autophagy.

What is autophagy?   This term  derives from the Greek roots for “self eating”.  It refers to a process that normal cells in every organism can use to derive energy by breaking down and recycling unneeded or “damaged” components.  Autophagy typically kicks in when a cell is  temporarily deprived of externally supplied nutrients, or subjected to other stresses such as low oxygen, infection and chemical exposure.  In the most common type of autophagy–known as macroautophagy–the cell constructs a special membrane enclosure, called an autophagosome, that floats around inside the cell.  The autophagosome is a kind of miniature recycling factory that detects, engulfs and digests damaged proteins and larger organelle structures.  After trapping the cellular components, the autophagosome fuses with a packet of degradative enzymes, known as a lysosome.  It then degrades these large molecules down to their component amino acids, sugars and fatty acids, which can be used as fuels and building blocks for repair and growth.  This recycling of damaged parts ensures an uninterrupted supply of energy and structural components need by the cell.



But the benefits of autophagy go far beyond fueling the cell, and ridding the cell of useless “junk”. Autophagy’s cellular housekeeping function actively counteracts many of the degenerative processes of aging!



Damage to cell structures and proteins is cumulative, and if allowed to proceed without correction, it can lead to malfunctioning of cellular processes and the genesis of illness. For example, a diet high in reactive sugars such as sucrose and fructose can glycate proteins, creating cross-linked structures known as advanced glycation end-products (AGEs), Similarly, oxidative stress can damage lipid bilayer membranes. The accumulation of these abnormal molecules has been implicated in the genesis of degenerative diseases such as diabetes, Alzheimers, cardiovascular disease and stroke.

Autophagosomes have also been shown to engulf and remove intracellular pathogens, such as the tuberculosis bacterium. Most intriguing, while autophagy regenerates the viability of normal cells, it has been show trigger the self-destruction (apoptosis) of some cancer cells and other abnormal cells.  In short, regular and recurrent autophagy is a key defense against a range of degenerative diseases.
The vitamin D connection.  What does autophagy have to do with vitamin D, you ask?  In mammals, the vitamin D receptor (VDR) sits at the beginning of a important cascade of biochemical pathways. Vitamin D3 or 25-D, from supplements or cutaneous synthesis, is converted to the active 1,25-D form in the kidneys in response to pituitary hormone (PTH).  Renal 1,25-D plays a key role in the regulation of bone mineralization and waste excretion. But the VDR is also distributed to widely in cells throughout the body.  After the kidney has converted vitamin D3 (25-D) to the active form of vitamin D (1,25-D) it is transported through the circulation to extra=renal sites by a protein known as vitamin D binding protein (VDBP).  Within the cell, the active vitamin D  interacts with the VDR to provide local control of a range of metabolic functions, including cellular immunity, anti-inflammatory, anti-infective, and anticancer responses.

And recent research indicates that one of the key functions of the VDR is to regulate autophagy!
Studies by several research groups have elucidated this signaling pathways that connect the VDR and calcium metabolism to autophagy. According to Shaoping Wu and Jun Sun at the University of Rochester Department of Medicine,

The signaling pathways regulated by vitamin D₃ include Bcl-2, beclin-1, mammalian target of rapamycin (mTOR), the class III phosphatidylinositol 3-kinase complex (PI3KC3), cathelicidin, calcium metabolism, and cyclin-dependent kinase (Table 1). These pathways are critical in host defense and inflammatory responses. Hence, vitamin D₃ and autophagy are associated with innate immunity…Vitamin D₃ is a major regulator of calcium metabolism. Increased circulating vitamin D₃ activates VDR, leading to increased intestinal calcium absorption. In excitable cells such as neurons, calcium is released from the sarcoplasmic or endoplasmic reticulum (ER) to activate calcium-dependent kinases and phosphatases, thereby regulating numerous cellular processes, including autophagy. ER calcium induces autophagy when stimulated by vitamin D₃. This process is inhibited by mTOR, a negative regulator of macroautophagy, and induces massive accumulation of autophagosomes in a beclin-1- and ATG7-dependent manner since they are not fused with lysosomes. Vitamin D₃ can down-regulate the expression of mTOR protein, thus inducing autophagy by inhibiting the mTORC1 complex.

A review by Høyer-Hansen et al., of the Institute of Cancer Biology at the Danish Cancer Society, elucidates the mechanisms by which vitamin D (“VD” here) induced autophagy selectively target cancer cells:

VD analogs are potent inducers of autophagy in different cell types, and autophagy is crucial for their cytotoxic activity towards cancer cells….[T]he signaling pathways connecting VD compounds to autophagy induction are similar in breast cancer cells and monocytes [7,12]. Autophagy induction in both cell types relies on an increase in [Ca2+]cyt, which could result from VDR-mediated changes in the expression levels of calcium-regulating proteins and the subsequent endoplasmic reticulum stress.
…Autophagy usually exerts a cytoprotective function in stressed cells; however, in EB1089-treated breast cancer cells, the enhancement of the autophagic response by ectopic expression of Becn1 increases cell death… Importantly, 1a,25-(OH)2D3-treated primary monocytes do not show any signs of cell death even though their autophagy response is similar to that observed in cancer cells. Thus, it is tempting to speculate that 1a,25- (OH)2D3-induced autophagic cell death could be specific for cancer cells; if true, this would represent a new cancer-specific treatment.

The Danish group has also shown that vitamin D acts to contain and eliminate the tuberculosis bacterium by inducing autophagy, perhaps providing an explanation for the historical use of cod liver oil and vitamin D as early therapies against TB  before the advent of antibiotics:

In tuberculosis, M. tuberculosis resides in phagosomes and evades host antimicrobial mechanisms by blocking phagosome maturation and fusion with the lysosome. Ultimately, the host must overcome this evasion strategy to destroy the pathogen. Accumulating evidence suggests that this occurs via the autophagic degradation of bacteria-containing phagosomes and the subsequent killing of the bacteria in autolysosomes. Interestingly, a recent paper links the 1a,25-(OH)2D3- and autophagy-controlled antimycobacterial defense-pathways.

They conclude:

Recent data link autophagy to two of the beneficial effects of VD: the induction of cancer cell death and the clearance of M. tuberculosis. This opens the possibility that autophagy could be a general mediator of the health-promoting effects of 1a,25-(OH)2D3. Accordingly, there is a striking overlap among the diseases promoted by VD deficiency and defective autophagy. The new data linking the two health-promoting pathways open an interesting research field that could lead to new options for the treatment and prevention of many common diseases.

All very interesting. But if the vitamin D receptor is an activator of cellular autophagy, with its many apparent health benefits is there a way to activate the process without taking vitamin D capsules or spending all day in the sun?

How to activate autophagy without vitamin D.   While vitamin D is one potent way to turn on the autophagy switch, it’s by no means the only way. Autophagy is a phenomenon that occurs throughout the animal kingdom, not just vitamin D utilizing mammals like ourselves. For example, Morselli et al. have shown that autophagy is a requirement for the demonstrated life-extending benefits of caloric restriction in nematodes, mice, flies and worms.

In fact there are several ways you can naturally activate autophagy in your body.  It turns out that all of them involve one form of hormesis or another:

• Calorie restriction and intermittent fasting.  In my post on Calorie restriction and hormesis,  I summarized some of the research on calorie restriction in humans, primates and other animals. including the role played by autophagy and other mechanisms.  This is also described in my talk on Intermittent Fasting for Health and Longevity.
• Brief, strenuous exercise.  A 2012 paper in Nature by Levine et al. in mice found that “Exercise is even faster than starvation” at inducing autophagy… “If you just exercise the mice for 30 minutes on a treadmill, autophagosomes start to form. Thirty minutes of running induces autophagy 40 to 50 percent.”
• Hormetic stress in general.   A wide range of short term, intense but sublethal stressors have been shown to activate autophagy via a common pathway.  Criollo et al.  showed that multiple stressors, including nutrient starvation and numerous chemicals, trigger the activation of the IKK (IκB kinase) complex, inducing the classical autophagy pathway involving p53 depletion, mTOR inhibition, AMPK and JNK1 activation, and release of the pro-autophagic protein Beclin-1.  How many of the other hormetic stressors we’ve discussed in this blog– such as cold showers–might effectively activate autophagy?

 
Why I prefer natural stressors.  So perhaps you might be persuaded you to at least consider trying intermittent fasting and exercise (better yet: fasted workouts) to activate your autophagy. If you are one of those who finds that vitamin D helps reduce colds or asthma symptoms — try skipping meals and snacks, and cut back on carbohydrates and excess protein.  I eat one or two small meals a day, mostly low carb or Paleo, and I can’t remember the last time I had a flu or cold.

But taking vitamin D supplements is so much more convenient, right?  I mean — why go to all the effort to subject yourself to uncomfortable hormetic practices when you can just pop a tiny, inexpensive gel capsule once day?  Or even if you go in for exercise and intermittent fasting, why not hedge your bets and throw in vitamin D supplementation too, just to strengthen the brew?
Ultimately a decision like this is a personal one.  You can read all the studies and science that’s out there, but each of us has a different way of balancing considerations of risks and effort, science and intuition.  I can’t make that decision for you.  But I’ll leave you with one thought:

The human species has existed on earth for about six millions years, mammals for 160 million years. Basic cellular defense and repair mechanisms, including autophagy, have played an essential role in protecting us against degenerative diseases during most of that history.  Real world stressors act broadly and in a varied manner. And we have evolved to experience these stressors in their full variety. As Art DeVany likes to point out, real world stressors have  ”fractal” pattern that keeps our metabolisms guessing. To the extent that vitamin D is protective against these diseases, it is likely because vitamin D activates the autophagy signaling pathways. But as David Agus notes in the video I linked above, vitamin D hits a single node in the signaling pathway. Supplementation protocols provide the same fixed amount of vitamin D, day in and day out.

Our ancestors did not have access to a highly purified, concentrated vitamin D pills to activate their autophagy at a fixed dosage every day.  They did it the old-fashioned way:  they “earned” their autophagy with natural and varied stressors like intense physical activity and more sporadic access to foods (and foods with lower insulin and mTOR activation potential).  And they got their vitamin D from the sun and certain fatty foods — again in a varied pattern.

This old-fashioned way of activating autophagy is a experiment that has been running for millions of years. Chronic, life-long supplementation with high doses of vitamin D is a relatively recent  innovation. Do you want to be so dependent on a single compound you take every day?  What happens if you are away from civilization for a few days without your vitamins?

Hormetic Stress (ie. fasting, cold, intense exercise) and the limbic brain / Getting Stronger

Hormetic Stress (ie. fasting, cold, intense exercise) and the limbic brain /  Getting Stronger

by Todd

#4 04 January 2012 22:07

Hi Ted,

The key fat loss recommendation in this latest article, as well as the previous one (“Obesity starts in the brain”) to apply hormetic stress.

Intermittent fasting, high intensity exercise (not slow aerobics), and cold showers will lower basal insulin, increase BDNF in the brain, stimulate norepinephrine and alter fat metabolism. A secondary recommendation is to minimize (not necessarily avoid) foods that contain compounds known to inflame the hypothalamus — principally high levels of fructose and sucrose, or palmitic acid (found in meat and dairy that is grain-fed rather than grass fed). You can also add anti-inflammatory oils (fish oil, coconut oil) and anti-inflammatory vitamins and minerals (vitamin D, magnesium, zinc) to your diet.

The above recommendations concern direct modification of hypothalamic function. The second main point I made in the article is that regulation of body fat (and other drives) can be changed via “deconditioning” of behavioral responses to cues that are coded in the amygdala.

The most specific advice I can provide is given in my article on the Deconditioning Diet (http://bit.ly/x2EvOh). In short: (1) cut back on carbohydrates and cut out snacks (2) use cue-exposure therapy to extinguish your conditioned cravings; (3) cut out occasional meals and attempt intermittent fasts of 12-20 hours.

Changes to the hypothalamus typically take weeks to months, so don’t expect an immediate benefit. On the positive side, the resulting adaptations are typically quite robust and sustainable.

Hope that helps give you a more specific idea of how to apply these ideas.

— Reply

The Leptin Marketing Miracle | Cogito Ergo Edo

The Leptin Marketing Miracle | Cogito Ergo Edo

It turns out that adipose tissue, something that was previously thought to be a collection of inert bags of triglycerides, is actually metabolically highly active tissue, producing a number of hormone-like substances such as leptin, resistin, adiponectin, tumor necrosis factor alpha, interleukin-6 and so on.  Research is furiously proceeding in this area in the hope that obesity can one day be cured via a pill rather than by taking the apparently onerous step of changing ones behaviour and diet.

Now, when you stop to think about it, hindsight being 20/20, it makes a great deal of sense that adipose tissue needs to communicate with the rest of the body in order to convey long term energy status to the organism.  On my laptop, I can press a button, even when my computer is off, and an led graph display on the side will indicate battery levels.  In addition, there is an icon in my menu bar that shows me whether I am running off mains power, or battery power, as well as the current charge level, assuming that I’m running from the battery.  If the battery ever gets critically low, I get a warning dialog, and my laptop preemptively shuts down to prevent data loss.

Compared to human metabolism, my laptop is ridiculously simple, so, if my laptop battery has this many systems in place to communicate with the user ( the overall brains of the operation ) about energy status, imagine how many equivalents there must be for the biological battery that is adipose tissue to achieve the same thing in an organism. And, of course, it turns out that leptin is merely one of many secretagogues that come from adipose tissue.  These adipose secretions that seem to function as the body’s fuel gauge vary directly with the amount of fat the organism is carrying.  Some of the adipose secretagogues, like leptin and ASP, increase as adiposity increases.  Other secretagogues, like adiponectin, have an inverse relationship with body fat, so that as your fat mass increases, you will produce less and less of adiponectin and its ilk.

Why is Leptin the Poster Child for Adipose Hormones?

When the existence of leptin was first discovered ( 1949 ) and long before it was first isolated ( 1994 ) it was quickly determined that there was a circulating factor the lack of which caused a certain strain of mouse (Ob/Ob) to eat voraciously and thereby become obese.  When the blood of a normal mouse was transfused with that of an Ob/Ob mouse, normal eating behaviour and weightloss ensued in the Ob/Ob mouse.  Understandably, the possibility of developing a therapy that could cure obesity via the administration of this mystery factor raised a great deal of interest.  Coincidentally, and somewhat more subtly, leptin also played very nicely with the dogma that obesity is caused by sloth and overeating, with the slight twist that now it was no longer a character flaw causing it, but rather a hormonal deficiency.  Leptin was also one of the first adipose hormones to be identified, so it stimulated the most interest, due to first mover advantage.

What does it mean to be leptin resistant?

If you’ve ever waited for an elevator and observed an alpha dog type A personality come up and repeatedly mash the already lit elevator call button, although you may not have been aware of it, you were watching a saturable system in action.  That is to say, once the elevator call button has been pressed ( the stimulus ) the response rate of the elevator will not change with any further stimulus ( furiously pressing the call button again and again )  If you happened to be a metabolic researcher, you may even be tempted to say that the elevator had become call button resistant.

In much the same way, the early promise of leptin failed to materialize.  While it was true that administering leptin to an Ob/Ob mouse decreased its appetite, increased its metabolic rate, and caused it to lose weight, this did not prove to be the case with obese, yet genetically normal ( i.e. non Ob/Ob ) mice.  The version of leptin that Ob/Ob mice produce is truncated by a substitution in one of the base pairs, and this reneders it incapable of binding to and activating the leptin receptor in the hypothalamus. This is why administering any normal leptin at all to these mice results in an improvement.  Obese, but otherwise normal, mice don’t have this problem.  They produce plenty of leptin, in fact they seem to produce too much.

It was this over production of leptin that led to the formulation of the idea that what was happening was that despite the stimulus ( leptin ) the response, decreased appetite and increased metabolic rate, failed to materialize.  Further research also showed that injecting leptin directly into the brain of obese, but otherwise normal, mice did show some results, while infusing leptin into the blood stream did not, suggesting that some transport mechanism from the blood across the blood brain barrier was being saturated.  Despite repeatedly mashing the elevator call button, the elevator fails to arrive any sooner.

More support was provided for the leptin resistance hypothesis with the discovery of the Db/Db mouse.  Like the Ob/Ob mouse, the Db/Db mouse exhibits a ravenous appetite and is morbidly obese. In direct contrast, however, transfusing the blood of a normal mouse with that of a Db/Db mouse does not improve the ravenous appetite or weight gain of the latter.  Moreover, the reverse transfusion of Db/Db blood in a normal mouse causes it to stop eating and eventually starve to death.  Apparently, the Db/Db mouse secretes an over abundant circulating factor to which its body is incapable of responding.

It turns out that the Db/Db mouse has a genetic defect in the hypothalamic leptin receptor.  As a result, despite producing bucketloads of leptin, the hormone is incapable of binding to the damaged receptor and activating it.  Unfortunately, in this case,  there is no therapeutic approach that is possible, as we are essentially dealing with irreversible brain damage.

But you are not a mouse, although, if you are a mouse and are reading this, well done you!!  For those of us who are not mice, the principal effect of being leptin resistant would result in a higher appetite than is warranted by the degree of body fat that we are carrying – hyperphagia:

The concept of leptin resistance was originally proposed to explain the observation that elevated leptin did not reduce food intake or prevent body weight gain in obese humans.  However, it is now recognized that resistance to leptin action may be primarily centered within the neuronal pathways regulating food intake and that other leptin responsive processes remain intact in the obese state. - Adipose Tissue In Health and Disease, Todd Leff, p. 190

Which is to say that, according to leptin researchers, given the amount of excess fat that an obese individual is carrying, they ought to be eating a whole lot less than they actually do.  We’ve heard this before : overweight is caused by over eating, apparently, but in this case the over eating is due to assumed leptin insensitivity.

How do normal people become leptin resistant?

The $65,000 question is how does one go from having a normal response to leptin to being leptin resistant?  Well, something had to happen to elevate leptin levels and repeatedly press the already lit leptin elevator call button ( the saturation model ).  And how do we get increased leptin levels?  By increasing adipose tissue mass.  Which means that because we got fatter, we became leptin resistant, not the other way around.  You may want to pause here and go over that again.

But wait, it actually gets a little more complicated:

Leptin resistance is commonly associated with hyperleptinemia … suggesting that leptin causes its own resistance. This concept was further supported in rats receiving prolonged central leptin infusion:  Even though these animals initially lose weight, their body weights normalize over time despite ongoing leptin treatment.  In this state, even additional acute leptin injections failed to induce any anorexigenic effect. – Frontiers in Eating and Weight Regulation, Wolfgang Langhans, p. 129

So, effectively, these researchers artificially elevated the leptin of rats by directly injecting it into their brains, bypassing any potential saturation effects at the blood brain barrier transport level.  After an initial weightloss period, the  weight of the rats stabilized.  At that point, they increased the  leptin dose, but this basically had no effect, no additional weightloss occured, or, in science speak, this “failed to induce any anorexigenic effect.”

Hang on to your hats, folks, because we’re not done yet:

In contrast, low leptin levels (e.g. in mice after prolonged fasting) as well as lack of leptin ( Ob/Ob mice ) increases leptin sensitivity … The evolutionary adaptiveness of a leptin-driven feedback mechanism in which low body weight ( low leptin levels ) produces the most potent anorexigenic effect seems questionable.  A potential explanation for this is that leptin action may be less important in times of plenty, but be critical to coordinate reproductive behaviour with information about body fat stores in states of scarcity.

Translation: it seems that we have a paradox where the ability of leptin to affect feeding behaviour, that is, to curb appetite and increase metabolic rate, works best at low body weights?!  But this doesn’t make sense.  Or does it?

From an evolutionary and energy balance perspective does it matter to you that you have 60 vs. 70 days worth of stored body fat?  Would your driving behaviour change if you had 7/8th of a tank of gas instead of it being full?  Personally, I wouldn’t give it a second thought.  How about if the needle was on empty and the gas light was illuminated?  Well, that’s an altogether different beast, now, you’d think about every time you touched the accelerator, you’d start obsessing over traffic lights, coasting as much as possible to conserve momentum, and frantically looking for the nearest gas station.  Or, to bring the analogy home, from a survival of the organism and species perspective, it is far more important to take action when you have low stores of body fat and low levels of leptin than it is to address states where leptin levels are high. If you are an organism living in a temperate climate, low leptin levels indicate that you may not survive the winter, whereas high leptin levels suggest that you may be on your way to all of the metabolic syndrome problems in a couple of decades, but at least you are pretty likely to live to see next Spring.  Faced with the choice, I’d rather be fat and alive  than skinny and dead.

Is leptin an obesity or starvation signal?

You can never be too rich or too thin.

- Wallis Simpson

It is extremely important, although virtually impossible, to try to escape the cultural biases that one brings to the research table.  An egregious example where this did not happen comes from a 2004 review of the state of leptin research from the journal Cellular and Molecular Life Sciences:

Circulating leptin serves to communicate the state of body energy repletion to the central nervous system (CNS) in order to suppress food intake and permit energy expenditure.

These authors, because they are preoccupied with obesity and adiposity, have framed the role of leptin as preventing obesity, or in their words, suppressing food intake.  In so doing, however, they are led directly into the paradox of leptin resistance, where high leptin levels fail to achieve the presupposed function of suppressing food intake.  This closely parallels the saturated fat theory of coronary heart disease which had researchers run headfirst into the French paradox, where high saturated fat intake did _not_ result in a higher incidence of CHD!  In that case, rather than abandon their untenable assumptions about the role of fat in CHD, researchers grasped at straws and came up with resveratrol and red wine.  You would think that we would have learned from that experience and be far more willing to question our base assumptions in the face of contradictory evidence.  Unfortunately, it seems that in the case of leptin, we are repeating the pattern.

The remarkable thing about all of this is how easy it is to dispense with the leptin resistence paradox while maintaining almost the exact structure of the original statement:

Circulating leptin serves to communicate the state of body energy reserves to the central nervous system (CNS) in order to promote food intake and enhance energy conservation.

With this framing, all the observed data is easily explained.  The body is fanatically worried about the possibility of starvation, so when leptin levels fall dangerously low, thereby indicating a starvation state, the brain makes you ravenous, and dials down energy expenditure.  Conversely, when there are “adequate” levels of circulating leptin, the body has a nice energy reserve, and there is nothing to do.  Dialing back appetite is not necessary, because the body does not care what it looks like in the mirror, it is only concerned with survival.  As far as your metabolism is concerned, Wallis Simpson was a collossal idiot.

How do we deal with leptin resistence?

If we are dealing with a saturable system, there are only two general approaches we can take to bring the system into the responsive state: we can either attempt to manipulate the level of the stimulus, or the response.  Of the two, manipulating the response requires us to have a very good understanding of all of the aspects governing the behaviour of the system.  Essentially, we have to crack open the black box and figure out what makes it tick.  In contrast, manipulating the stimulus, assuming that we can correctly identify it, is relatively straight forward, we can effect change completely oblivious as to why the system is resonding.  As soon as we lower or raise the stimulus to the responsive range of the system, we’re good to go.

Lessons learned from hyperinsulinemia

Keep in mind that we’ve seen this play out before, but under the guise of insulin resistence.  In that case, the primary causal factor, as outlined by Gary Taubes in Good Calories, Bad Calories, was excessive carbohydrate consumption and its impact on insulin:

“Carbohydrate is driving insulin is driving fat,” is how George Cahill, a former professor of medicine at Harvard Medical School, recently described this …

This should not be very controversial: carbohydrate consumption leads to increased blood glucose levels which cause insulin levels to rise, and the corresponding increase in insulin directs all tissues capable of doing so to absorb the glucose.  Eventually, if this persists, tissues will reach a limit to their capacity to absorb blood glucose and the glucose absorption system will be saturated, becoming incapable of responding to the insulin signal.

Armed with this information, we then know how to modulate the insulin stimulus: we reduce carbohydrate and other insulinogenic nutrients ( whey, for instance ) in our diet. In so doing, we reduce the insulin stimulus and move the whole system back into the sensitive part of the curve.

But, in the case of hyperleptinemia and leptin resistence, the fundamental stimulus for increased leptin production is … increased adipose tissue.  This in turn suggests that we need to reduce fat mass in order to reduce leptin and thereby move the whole system into the responsive part of the curve!  And how should we accomplish this?  To paraphrase George Cahill :

Carbohydrate is driving insulin is driving fat is driving leptin is driving leptin resistence.

It turns out that the solution for leptin resistence is exactly the same as for insulin resistence!

The Leptin Marketing Machine

More generally, any diet that reduces fat mass, whatever its details may be, will make you leptin sensitive.  This is fantastic news if you want to set yourself up as a diet guru, especially if your diet  pitch hinges on leptin sensitivity.  Leptin is novel, and novelty sells.  So, in the finest tradition of magicians, you misdirect the audience with all your talk about leptin so that they do not notice the standard calorie restricted, or paleo, or ketogenic, or, God help you, vegan diet up your sleeve.  Were you to try to market the “Slight tweak on the paleo diet, diet”, nobody would bite.  Instead, talk about leptin, the hypothalamus and the neuroendocrinology of leptin, plasma membrane fatty acid binding proteins, AMPK, and so much more.  You can easily fill a few hundred pages with the details.

Further, you can also differentiate and brand your approach with irrelevant details, which really do not have any material impact on the diet.  You can have your clients wave a dead chicken over every meal while facing the temple of the oracle at Delphi ( once they figure out in which direction Delphi lies ), or have them eat 70 grams of protein within 30 mins of waking.  The dirty little secret is that if we are speaking of calorie restricted diets, which is what the word diet has come to mean, they all work.  Even those monumentally stupid diets like the Twinkie Diet or the All Potato Diet will work as long as they restrict calories.  This buys you a lot of latitude to fiddle with the details.

So leptin becomes part of the smoke and mirrors being used to sell a particular collection of dietary principles, supplements, or other weight loss talismans.  You may think that I’m overstating my case, but you can already find “The Leptin Boost Diet” in your local bookstores.  When you consider that obesity is supposedly the result of leptin insensitivity to the already over boosted leptin levels, it would seem that boosting leptin levels yet higher still might not be the optimal approach.  So, whoever came up with the title for this book probably hadn’t read it. This has the whiff of smoke and mirrors about it, and that’s being charitable.

Alternatively, if you are not keen on reading, you can now address your leptin issues with a pill, “clinically proven” to work.  Of course, the clinic in question was in Cameroon, because, apparently, researchers were unable to find 92 obese subjects in North America on which to perform their study.  Or, perhaps the researchers were motivated to go to Cameroon by other reasons?  We can only speculate, but we can at least take a look at the miracle ingredients:  pomegranate extracts, beta carotene, carob, blue green algae, guar gum and konjac.  Those last two are quite interesting, because they both are indigestible fibre.  If you read the patent application, the formulation is basically 30% guar gum and 50% konjac.  It is fairly well known that soluble fibre increases satiety, increases gastric emptying time, and basically interferes with absorption of nutrients from the digestive tract by creating an indigestible gel.   This idea of filling your digestive system with zero calorie bulk is not new, but, whether or not this is a worthwhile thing to do in order to involuntarily reduce caloric intake and lose weight is debatable.  What is certain, however, is that the mechanism of operation has very little to do with leptin.

Once the novelty of leptin wears off, and in this internet driven micro-attention span age, it surely will, then it will be up to resistin, or adipsin, or ASP, or any one the myriad adipose secretagogues to step into the diet marketing spotlight.  It will not be long before “The Resistin Advantage Diet (RAD)” hits the shelves.  I’m seriously thinking of getting copyright or a trademark on that just to prevent some marketing wonk from actually producing such a monstrosity.  I will confess to having a morbid curiosity with respect to what the marketing wonks will do with interleukin-6.  It does have an ominous Death Star sound to it …I like to imagine James Earl Jones intoning “I’m your father Interleukin-6!”

Well, then, what diet should I follow?

This is a question that deserves much more time and space than I have to devote to it here and now.  Suffice it to say, though, that you should try to eat a sane diet!  Sanity, here, would require that the diet that you ultimately pick helps you to attain your goals, and, most importantly, that you could conceivably sustain indefinitely.  However, what that practically means for a given individual is very difficult for me to predict from behind my keyboard, especially as the diet will vary according to ones goals.  Although it should not need to be said … one size cannot possibly fit all.   And, as much as it pains me to say it,  please note that this does not rule out in any way selecting a “leptin reset” diet as the preferred approach. 

Apart from the marketing malarkey, if the underlying diet is sound, then I cannot object overmuch.  I will object, however, to wrapping a sound diet in irrelevant detail in an attempt to brand and differentiate yourself.

Posted by pklopp on Mar 17, 2012 in Endocrinology, Metabolism | 3 comments

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The 14-percent advantage of eating little and then a lot: Is it real?

Health Correlator: The 14-percent advantage of eating little and then a lot: Is it real?

Monday, July 16, 2012

When you look at the literature on overfeeding, you see a number over and over again – 14 percent. That is approximately the increase in energy expenditure you get when you overfeed people; that is, when you feed people more calories that they need to maintain their current weight.

This phenomenon is related to another interesting one: the nonlinear increase in body weight and fat mass following overfeeding after a period starvation, illustrated by the top graph below from an article by Kevin Hall (1). The data for the squares on the top graph is from the Minnesota Starvation Experiment (2). The graph at the bottom is based mostly on the results of a simulation, and doesn’t clearly reflect the phenomenon.

Due to the significant amount of weight lost in what is called above the semistarvation stage (SS), the controlled refeeding period (CR) actually involved significant overfeeding. Nevertheless, weight was not gained right away, due to a sharp increase in energy expenditure. That is illustrated by the U-curve shape of the weight gain in response to overfeeding. Initially the gain is minimal, increasing over time, and continuing through the ad libitum refeeding stage (ALR).

Interestingly, overfeeding leads to increased energy expenditure almost immediately after it starts happening. It seems that even one single unusually big meal will significantly increase energy expenditure. Also, the 14 percent is usually associated with meals with a balanced amount of macronutrients. That percentage seems to go down if the balance is significantly shifted toward dietary fat (3), probably because the metabolic “cost” of converting dietary fat into body fat is low. In other words, large meals with a lot of fat in them tend to cause a reduced increase in energy expenditure – less than 14 percent. Shifting the balance to protein appears to have the opposite effect, increasing energy expenditure even more, probably because protein is the jack-of-all-trades among macronutrients (4).

The calorie surplus used in experiments where the 14 percent increase in energy expenditure is observed is normally around 1,000 calories, but the percentage seems to hold steady when people are overfed to different degrees (5) (6). Let us assume that one is overfed 1,000 calories. What happens? About 140 calories are “lost” due to overfeeding.

What does this have to do with eating little, and then a lot, in an alternate way? It allows for some reasonable speculation, based on a simple pattern: when you alternate between underfeeding and overfeeding, you reduce food consumption for short period of time (usually less than 24 h), and then eat big, because you are hungry.

It is reasonable to assume, based on the empirical evidence on what happens during overfeeding, that the body reacts to “eating big” as it would to overfeeding, increasing energy expenditure by a certain amount. That increase leads to a reduction in the caloric value of the meals during overfeeding; a reduction of about 14 percent of the overfed amount.

But the body does not seem to significantly decrease energy expenditure if one reduces food consumption for a short period of time, such as 24 h. So you have the potential here for some steady fat loss without a reduction in caloric intake. Keeping a calorie intake up above a certain point is more important than many people think, because a calorie intake that is too low may lead to nutrient deficiencies (7). This is possibly one of the reasons why carrying a bit of extra weight is associated with increased longevity in relatively sedentary populations (8).

Is this 14-percent effect real, or just another mirage? If yes, what does it possibly translate into in terms of fat loss?

More on these issues is coming in the next post.

18 comments:

js290 said...

Ned, it should be clear to anyone with some formal mathematics (and/or engineering) training that energy input and energy output are coupled; they can't be treated independently. So any model that tries to decouple these two variables is inherently wrong. The other detail that people miss is when the body will use the energy we ingest. So, even if dietary fat doesn't necessarily provide the maximal increase in energy expenditure, what's important is the ability to ultimately tap the stored fat for energy. As Dr. Rosedale puts it, people don't get fat by eating it, they get fat by not being able to burn it.

July 16, 2012 8:08 AM

igel said...

people on warrior / leangains protocols (myself included) can definitely say that it is NOT a mirage: fasting and then eating big is a cool way to burn fat and build muscle (if one intends to do so) simultaneously

July 16, 2012 8:35 AM

Ned Kock said...

Hi js290. So, would you say that the effect is real, or a mirage? Also, the loss due to EE seems to be lower if the overfeeding is significantly shifted toward dietary fat.

July 16, 2012 4:39 PM

js290 said...

Ned, I would say it's absolutely real. If we can believe that metabolism is slowed by reducing energy input, then it stands to reason that metabolism can be accelerated by increasing energy input. Obviously the relationship is nonlinear; therefore I'm not surprised that dietary fat may have a different effect on energy expenditure. Practically, it doesn't really matter the exact function. As long as the hormones and enzymes are biased towards burning more fat than they store, fat mass will be lost.

July 16, 2012 9:02 PM

vaporizers said...

These are fantastic stuff you shared here.

July 17, 2012 3:36 AM

Ned Kock said...

What I find interesting about this effect js290 is that the body does not seem to significantly decrease energy expenditure if one reduces food consumption for a short period of time, such as 24 h. So you have potential here for fat loss if you alternate between lower and higher calorie intake, as long as you do that in short enough windows of time (less than 24 h). This may be an explanation to the effect that igel mentioned in his comment, associated with some IF approaches.

July 17, 2012 6:34 AM

David Isaak said...

Hi, Ned-- Have you seen this? http://www.sciencedaily.com/releases/2012/07/120702162153.htm Of course, people are fond of noting that people aren't rats--and we really aren't fruit flies! (And, of course, a calorie is no longer a calorie, either. Odd that Bray would be the one to prove it: http://rdfeinman.wordpress.com/2012/03/19/bray-et-al-shows-that-a-calorie-is-not-a-calorie-and-that-dietary-carbohydrate-controls-fat-storage/ )

July 17, 2012 8:54 PM

js290 said...

Ned, it is indeed interesting. I kind of also wonder whether the increase in energy expenditure associated with a "balanced diet" as opposed to a higher fat diet has more to do with the body trying to rid itself of excessive glucose. That is, while one's metabolism is functioning properly, the body will increase energy expenditure by burning off the glucose. But, if the metabolism is operating sub-optimally, the excessive glucose goes into storage. Whereas with with fat, the body is primed to use it for fuel at any time, so an increase in energy expenditure beyond that of a "balanced diet" is not as necessary. It'll increase some because there's more energy to be used, but the body isn't as "panicked" about it. Also, I'm also a bit of an unqualified skeptic when people claim that low carb, per se, breaks their thyroid function, and is somehow restored by introducing dietary glucose. I have to wonder whether people with these experiences simply were not eating enough. And, the re-introduction of carbs simply meant a total increase in energy input. In other words, would they have experienced similar improvements in thyroid function by simply eating more?

July 17, 2012 10:59 PM

Evelyn aka CarbSane said...

Hi Ned, I have to look for it but I came across a study that demonstrated EE actually increases early in a fast. I tend to think if this is true, it goes away with habituation, so erratic IF may be better. That's just a hunch though.

July 18, 2012 3:57 AM

Ned Kock said...

Hi David, thanks for the link. This reminds me of the earlier post on BMI and mortality: http://bit.ly/NWbeMY

July 18, 2012 5:24 PM

Ned Kock said...

I think those are good points js290. There is one problem with a very high fat, low carb diet – neither liver nor muscle glycogen will be properly replenished. Depending on the amount of glycogen depleting exercise done, that type of diet may be unsustainable.

July 18, 2012 5:30 PM

Ned Kock said...

Hi Evelyn. And I am not even considering that possible increase in EE during a fast (or period of calorie restriction), only the one resulting from overfeeding later on.

July 18, 2012 5:32 PM

Jeffrey of Troy said...

This seems to me, as igel alluded to, to support IF + "overfeeding" when you do eat, just enough so that the daily avg over a week or so = what you would have gotten if you did neither. Same calories, different apportionment. Specifically, eat big (esp pro) post-workout (recovery's where you make your gains). But if you ate that big all the time, you'd gain both muscle and fat, like many powerlifters.

July 18, 2012 6:05 PM

David Isaak said...

>>Hi David, thanks for the link. This reminds me of the earlier post on BMI and mortality... Yes, indeed, I thought of your post immediately.

July 18, 2012 7:20 PM

js290 said...

Ned, that's why I go two weeks between glycogen depleting activity. ;-) http://www.youtube.com/watch?v=fQra-ME7vIo#t=47m13s

July 18, 2012 7:47 PM

SEAJ said...

I am curious how the body knows its in a calorie surplus. I would speculate that its the abundance of specific nutrients.. maybe amino acids or glucose levels that cause the effect. Maybe supplementing whole foods with more rapidly digesting amino acids and or sugars at a caloric deficit could simulate the effect.

July 20, 2012 1:15 PM

Ned Kock said...

Hi SEAJ. That is one of the crucial questions, which goes unanswered in the pubs that provide evidence for the 14-percent effect. Well, at least the ones I reviewed.

July 21, 2012 7:45 AM

Introducing Bulletproof Intermittent Fasting: How to Lose Fat, Build Muscle, Stay Focused & Feel Great The Bulletproof Executive

» Introducing Bulletproof Intermittent Fasting: How to Lose Fat, Build Muscle, Stay Focused & Feel Great The Bulletproof Executive

By Dave Asprey

If you want to lose fat and improve your health as fast as possible, without feeling mentally slow, it’s hard to beat Bulletproof Intermittent Fasting.

Plain intermittent fasting has become popular in biohacker circles because it shows tremendous promise for fat loss, preventing cancer, building muscle, and increasing resilience. The most popular site that covers plain intermittent fasting is Leangains.com.  It’s totally worth a visit. The basic idea behind plain intermittent fasting is to eat all of your daily food in a shortened period (8 hours in the case of Lean Gains) and fast the rest of the time. For reasons we will get into below, this tells your body to simultaneously build muscle and burn fat.  It really works.

The problem is not everyone does well with fasting. If you’re a busy entrepreneur or even a student who needs to be in a high performance state all day, dealing with hunger can be a distraction. It’s much worse for those with an impaired metabolism (i.e. the people who need to lose weight). If you have more than 30 pounds of extra fat or if you’re facing diabetes, it can be hard to skip meals and still get things done.

Bulletproof Intermittent Fasting is a biohack that changes that and makes it possible to lose fat and build muscle faster than plain intermittent fasting… without feeling hungry or tired.

Introducing Bulletproof Intermittent Fasting

Bulletproof Fasting is the same as intermittent fasting, except you consume a cup of Bulletproof Coffee in the morning. The healthy fats from grass-fed butter and MCT oil give you a stable current of energy that sustains you through the day. The ultra low toxin Upgraded Coffee Beans optimize brain function and fat loss with high octane caffeine. The MCT oil also serves to increase ketone production and boosts your metabolic rate by up to 12%. This drink is so filling, we’ve had clients who drank one cup of Bulletproof Coffee in the morning and didn’t feel like eating until mid afternoon. Adding extra MCT oil will promote ketogenesis (the formation of ketones) and provide more of a mental kick.

For optimal results, you should be following the green side of Bulletproof Diet in conjunction with this protocol. Bulletproof Fasting will not save you from the effects of Poptarts and fried Oreos.

Bulletproof Intermittent Fasting: Mental Performance Protocol

Goal: Improve and/or sustain mental performance while getting more benefits than plain intermittent fasting.

Step 1: Finish dinner by 8 pm

No snacking after dinner – go to bed whenever you want.

Step 2: Drink Bulletproof Coffee in the morning

Bulletproof Coffee is a mix of brewed Upgraded Coffee Beans, grass-fed butter, and pharmaceutical grade MCT oil. You can find the complete recipe here. Don’t mess around with cheap coffee, which will sabotage your efforts since 91.7% of green coffee has mycotoxins in it.

Drink as much Bulletproof Coffee as you like in the morning. You can have another cup before 2:00 PM if you get hungry. No coffee after 2:00 PM or you won’t sleep.

Step 2.5 (optional) – Work out

This is not necessary to gain muscle and lose fat, but it helps. If you’re going to work out, lift something heavy right before you break the fast in step 3. I’d suggest high intensity weight training. Shorter and harder is better than longer exercise. You will need to sleep more if you exercise.

Step 3: Do not eat until 2pm

This means you’ve not had anything to eat except Bulletproof Coffee for 18 hours.  This should occur from the time you wake, through the morning, and into the afternoon. If 18 hours is too long, start with a shorter fast and increase from there.

Step 4: Eat as much Bulletproof food as you like for 6 hours (until 8 pm)

The number of meals you eat during this time is irrelevant, as is the amount of calories.
Here is a sample day of Bulletproof Intermittent Fasting:

8:00 AM: Drink Bulletproof Coffee.
2:00 PM: Break fast with foods from the Bulletproof Diet.
8:00 PM: Eat your last meal before beginning the fast.

Bulletproof Intermittent Fasting extends your life, improves brain function, and makes you more resilient on all levels. Even if you just start drinking Bulletproof Coffee for breakfast in place of the watery bags of sugar we call fruit, you can take advantage of some of these benefits. Once you start Bulletproof Intermittent Fasting, you will have gained an unfair advantage on your peers in health, longevity, and performance.

Benefits of Plain Intermittent Fasting

Animal studies (thanks Wikipedia!)

• “Reduced serum glucose and insulin levels and increased resistance of neurons in the brain to excitotoxic stress“^[2]
• “Enhance[s] cardiovascular and brain functions and improve[s] several risk factors for coronary artery disease and stroke including a reduction in blood pressure and increased insulin sensitivity” and that “cardiovascular stress adaptation is improved and heart rate variability is increased in rodents” and that “rodents maintained on an IF regimen exhibit increased resistance of heart and brain cells to ischemic injury in experimental models of myocardial infarction and stroke.”^[3]
• May “ameliorate age-related deficits in cognitive function” in mice^[4]
• Correlation with IF and significantly improved biochemical parameters associated with development of diabetic nephropathy^[5]
• Resistance in mice to the effects of gamma irradiation^[6]
• Lifespan increases of 40.4% and 56.6% in C. elegans for alternate day (24 hour) and two-of-each-three day (48 hour) fasting, respectively, as compared to an ad libitum diet.^[7]
• Rats showed markedly improved long-term survival after chronic heart failure via pro-angiogenic, anti-apoptotic and anti-remodeling effects.^[8]

Human studies

• Alternative day fasting (ADF) may produce significant improvements in several markers such as LDL cholesterol in as little as eight weeks.^[10]
• “may effectively modulate several risk factors, thereby preventing chronic disease, and that ADF may modulate disease risk to an extent similar to that of CR”.^[11]
• Serum from humans following an IF diet had positive effects (reduced triglycerides in men and increased HDL in women, as well as reduced cell proliferation and increased heat resistance) in vitro on human hepatoma cells.^[12]
• IF confers protection from toxic chemotherapy treatments, allowing higher doses and therefore more effective treatment for cancers.^[13]
• IF may function as a form of nutritional hormesis.^[14][15]

Reasons Bulletproof Intermittent Fasting Works Better

Reason #1: Tripling down on mTOR.

mTOR sounds like it should be the name of a hero in a Japanese comic book, but it’s a little more important than that. mTOR stands for “Mammalian Target of Rapamycin.” It’s one of those things that only a biohacker (or a fat person) could get excited about.  mTOR is a major mechanism that increases protein synthesis in your muscles. Both exercise and coffee raise cellular energy use while simultaneously inhibiting your muscle building mechanisms (mTOR) for a brief period, which causes it to “spring back” and build even more muscle as soon as you eat.

There are 3 known ways to raise mTOR. Intermittent fasting, exercise, and coffee (or more weakly, chocolate, green tea, turmeric, or resveratrol)




Bulletproof Fasting hits all 3 ways to compress mTOR, causing a bigger rebound and better use of your food for muscle building. I used Bulletproof Intermittent Fasting occasionally during my 4500 calorie per day no exercise long term experiment, and ended up looking like this after doing it for 4 days per week for 2 weeks. Keep in mind that I used to weigh 300lbs, and I hadn’t worked out for 18 months when this photo was taken.

Plain intermittent fasting doesn’t use coffee, so it only hits one, or possibly 2 of the 3 possible mTOR triggers. Bulletproof Intermittent Fasting works better because it can use all 3 mechanisms, but it works very well (as you can see) with just coffee and intermittent fasting. The cool thing is that an all fat breakfast (like Bulletproof Coffee) doesn’t make your body think it’s broken the fast, so you get the benefits of the fasting anyway. It’s awesome!

Reason #2: Ketosis

Plain intermittent fasting helps you enter ketosis (fat burning mode that’s good for your brain) but then you end ketosis if you eat carb-containing foods at the end of the fast. Using MCT in your Bulletproof Coffee increases the speed at which you go into ketosis, so it fuels your brain, and it helps you stay in ketosis even in the presence of some carbs in your diet. MCT is noticeably better than just grass fed butter in my coffee for this effect.

Reason #3: You’ll actually do it because you feel awesome

Let’s face it. You’re not a super athlete. You’re not a model or a professional body builder. You have work to do at your day job and being hungry, sluggish, and cranky all morning during a fast is not fun or good for your career. It’s easier, and far more pleasant to do a Bulletproof Intermittent Fast than a plain one. I’ve done plain ones and enjoy them to be honest, but they are even more enjoyable with Bulletproof Coffee. Plus, I get better results with the coffee protocols.

Reason #4: Metabolic hacking

Coffee increases your metabolism by up to 20 percent. Plain intermittent fasting doesn’t. This combination is superior.

That just about covers it.  If you benefit from this Bulletproof Intermittent Fasting Protocol, please leave a comment here or on the Bulletproof Forum.  The next article on Bulletproof Intermittent Fasting will show you the protocol that produced 75 pounds of weight loss in 75 days.

Intermittent Fasting and Diurnal Cortisol - Kindke's Scrap Notes

Kindke's Scrap Notes: Intermittent Fasting and Diurnal Cortisol

A new study that is the buzz in the media is about how restricting feeding to an 8 hour window ( during the afternoon-night phase ) prevents the progression of obesity on a diet that otherwise induces obesity in the same rodents if they are given Ad Lib access to the same food around the clock.

The intermittent fasting rodents consumed the same number of calories as the Ad Lib fed rodents yet remained much more slim. So yes, this proves a calorie is a calorie btw. /sarcasm

This has come at a time that I was thinking about something mentioned on itsthewooo's blog in the comments about diurnal cortisol. Actually, cortisol essentially makes you quite glucose intolerant, ( like melatonin ), and induces insulin resistance, so it is most likely not a good time to eat food when cortisol is high, like first thing in the morning or immediately after exercise.

This is the daily graph of diurnal cortisol for a normal healthy person. It might be slightly different for an obese person, but it quite clearly highlights the problem with eating food immediately after waking up, especially sugary cereal. You should ideally only be eating when cortisol is low, that means during the late afternoon and evening.

Could this be one of the reasons that helped the rodents in the IF study above resist obesity? ( maybe not, since rodents are nocturnal animals by nature, it makes sense for them only to be eating during the night. )

Posted by Kindke at 17:10