Category: Leptin Resistance

March 11, 2018

Long-Term Weight Loss: Why So Many Fail

Over fifty years of data have demonstrated that creating energy deficit through the reduction in caloric intake is effective in reducing weight. . . However, it is only for the short term (1, 2). The biggest challenge physicians face in the treatment of obesity is that calorie restriction fails when it comes to long-term weight loss.

Isn’t Fasting Effective in Long-Term Weight Loss?

With the craze and popularity of intermittent fasting, some have claimed that intermittent fasting is more effective in weight reduction. Recent results demonstrate that this may also be incorrect. In the short term evaluation of caloric restriction and intermittent fasting, reduction in 15-20 lbs of weight is effectively seen and the highly publicized Biggest Loser’s losing ~ 120 lbs. Intermittent fasting and alternate day fasting have been shown to be more effective in lowering insulin levels and other inflammatory markers in the short term.

There is, however, controversy over maintaining weight loss beyond 12 months in the calorie restriction, intermittent and alternate day fasting groups. Forty different studies in a recent literature review, thirty-one of those studies looking at forms of intermittent fasting, demonstrate that the majority of people regain the weight within the first 12 months of attempting to maintain weight loss(3, 5). This is, also, what I have seen for over 18 years of medical practice.

Is Calorie Restriction the Only Way to Lose Fat?

Numerous “experts” claim that the only way to reduce fat is “caloric deficit.” Variations through the use of intermittent, long-term or alternate day fasts can be found all over the internet. In regards to calorie restriction, these “experts” with nothing more than a personal experience and a blog to back their claims preach this louder than the “televangelists” preach religion. Based on the faith that many place in this dogma, it could be a religion. What causes belief in this dogma is that weight and fat loss actually does occur with caloric restriction to a point. The average person will lose 20-25 lbs, however, within 12 months of achieving this goal, most people regain all the weight. (No one ever mentions the almost universal problem with long-term weight loss, especially those “experts.”)

Prolonged calorie restricted fasts, intermittent fasts, and alternate day fasts are often grouped together into the fasting approach, causing significant confusion among those that I speak to and counsel in my office. There is great data that alternate day fasts do not have the reduction in resting energy expenditure that prolonged fasting, intermittent fasting and calorie restriction cause. However, none of these approaches appears to solve the problem of weight re-gain after long-term (12-24 months into maintenance) weight loss (3). And, a recent study of 100 men participating in alternate day fasting showed that there was a 38% dropout rate, implying that without close supervision and direction, maintenance of this lifestyle is not feasible for over 1/3rd of those attempting it.

Long-Term Weight Loss Failure Brings Tears

Failure on calorie restricted diets, low fat diets, and intermittent fasting diets with weight regain at twelve to twenty-four months is the most common reason people end up in my office in tears. They’ve fasted, starved themselves, calorie restricted, tried every form of exercise, and still regained the weight. Trainers, coaches and “experts” have belittled them for “cheating” or just not keeping to the diet. Yet, we know that calorie restriction and intermittent fasting cause a rebound in leptin, amilyn, peptid YY, cholecystikinin, insulin, ghrelin, gastric inhibitory peptide and pancreatic poly peptide by twelve months causing ineffective long-term weight loss (6). The dramatic rise in these hormones stimulates tremendous hunger, especially from ghrelin and leptin.

N Eng J Med 27 Oct 2011. Mean (±SE) Fasting and Postprandial Levels of Ghrelin, Peptide YY, Amylin, and Cholecystokinin (CCK) at Baseline, 10 Weeks, and 62 Weeks.

Although less problematic in alternate day fasting, these calorie restricted approaches also cause dramatic slowing of the metabolism at the twelve month mark. In many cases, the metabolic rate never actually returns to baseline, creating even more difficulty in losing further weight or even maintaining weight (6).

N Engl J Med 27 Oct 2011. Mean changes is weight from 0 – 62 weeks.

Is Gastric Bypass or Gastric Sleeve the Solution?

Gastric bypass and the gastric sleeve procedures have been touted as the solution to this problem, as they decrease ghrelin, however, 5-10 years later, these patients are also back in my office. They find that 5-10 years after these procedures the weight returns, cholesterol and blood pressure rise, and diabetes returns. These hormones kick into high gear, stimulating hunger in the face of a slowed metabolism, that to date, has been the driver for weight regain in the majority of people. People find it nearly impossible to overcome the hunger. You may have experienced this, I know I have.

It’s the Hormones, Baby!

So, what is the answer? It’s the hormones. (WARNING – You’ll hear that when your wife is pregnant, too, gentlemen). We are hormonal beings, both in weight gain, and in pregnancy. Trying to preach calorie control to a hormonal being is like showing up at the brothel to baptize the staff. You might get them into the water, but you’re probably not getting them returning weekly to church or pay a tithe.

So, how do you manipulate the hormones in a way to control the rebounding hunger and suppression of metabolism? This is where we put a bit of twist on the knowledge we’ve gained from alternate day fasting. Recent research shows that “mild” energy deficit in a pulsatile manner, that has the ability to mimicking the body’s normal bio-rhythm’s is dramatically effective in reducing weight and maintaining normal hormonal function without cause of rebound metabolic slowing (4).

Pulsed Mild Energy Restriction

What does this mean in layman’s terms? It means that if we provide a diet that maintains satiety hormones while providing a period of baseline total energy expenditure needs and a period of mildly reduce caloric intake in a pulsed or cyclic manner, greater weight loss occurs and there is no rebound of weight 1-2 years later.

The main reason I’ve not jumped on the intermittent fasting band wagon is the shift in leptin, amylin, ghrelin and GLP-1 signaling that regularly occurs at the 6-12 month mark. The rebound of these hormones causes weight re-gain and is what prevents successful long-term weight loss. A number of people come to my office and tell me they couldn’t follow a ketogenic diet, so they’re doing intermittent fasting and it works . . . for a while. Then, they end up in my office having hit a plateau or fallen off the wagon and regained all the weight. They are completely confused and don’t understand what happned. Most of them are convinced it’s their thyroid or cortisol and they’ve seen every naturopath and functional medicine doctor in town.

What people really need is a simple approach to long-term weight loss without having to spend the night in the physiology lab every two weeks sleeping under a ventilated hood system.

The Ketogenic Lifestyle is a Pulsed Energy Lifestyle

First, it is essential to turn off the insulin load. Insulin is the master hormone. This is done by a ketogenic lifestyle that restricts carbohydrates.
Second, providing adequate protein to supply maintenance of muscle and testosterone is key.
Third, providing adequate fat is the simple way to maintain leptin, ghrelin, amylin, GLP-1 (among the others) and long-term weight loss. Can you eat too much fat? Of course you can. But, because each of us have differing levels of stress and activity each day, this fat intake becomes the lever for hunger control.
Fourth, the use of exogenous ketones ensures easily accessible ketone (short chain fatty acids) to modulate adipose (white fat) signaling of the liver without large caloric intake through the portal vein by first pass of liver metabolism. The ketones also help stabilize the gut bacteria. The combination of hormone balance between the liver and fat cells and improvement of gut bacteria suppresses key hunger hormones and aids glucose regulation between the fatty tissues and the liver. Ketones, both endogenous and exogenous, suppress production of TNF-alpha, IL-6, resistin, and stabilize production of adiponectin and leptin from the adipose cells (7, 8, 9).

In my office, once we calculate the basic protein needs daily, we start with a 1:1 ratio of protein to fat. Then, the fat is adjusted up or down based on hunger. Remember, hunger occurs, because your body produces hormones. The addition of fat to a diet that is not stimulating large amounts of insulin resets the hormone patterns back to normal without causing weight gain.

Give Obese People Fat Ad Libitum?

“Sure, Dr. Nally, but what about those people who don’t know if they are hungry, bored, stressed or just have a bacon fixation? You can’t just give them all the fat they want?!”

Why not? Implying that people aren’t smart enough to know when they are full is a bit of a fascist philosophy, don’t you think?

Do people over eat? Sure they do. But, I’ve found that when you give people an antidote to hunger (using fat intake in the presence of stabilized insulin levels) over a few months, people begin to recognize true hunger from other forms of cravings. This is especially true when they keep a diet journal. This gives people the ability to begin listening to their own bodies, responding accordingly and governing their stress, eating, exercise and activity. Keeping a diet journal is key to long-term weight loss. And, isn’t helping people use their own agency to improve their health really what we’re trying to do?

Interestingly, doing this over the years seems to line up with the findings of this year’s MATADOR study in the International Journal of Obesity. They found that mild intermittent energy restriction of about 30-33% for two weeks, then interrupting this with two weeks of a diet that was energy balanced for needs improved both short and long-term weight loss efficiency (4). In looking at my, and my patient’s diet journals, this energy restriction of about 1/3 of needed calories cyclically seems to happens naturally with a ketogenic lifestyle, without even counting calories. (Calories are a swear-word in my office).

What does the correct long-term wight loss program look like in a diet or meal plan? Well, you’ll have to join the Ketogenic Lifestyle 101 Course to see what that really means to you individually. I look forward to seeing you there.

Want to find out more about the Ketogenic Lifestyle 101 course? CLICK HERE.

Have you read my book The Keto Cure? Get a signed copy from me by clicking HERE.

References:

Bronson FH, Marsteller FA. “Effect of short-term food deprivation on reproduction in female mice.” Biol Reprod. Oct 1985; 33(3): 660-7. https://www.ncbi.nlm.nih.gov/pubmed/4052528?dopt=Abstract&holding=npg
Connors JM, DeVito WJ, Hedge GA. “Effects of food deprivation on the feedback regulation of the hypothalamic-pituitary-thyroid axis of the rat.” Endocrinology. Sep 1985. 117(3): 900-6. https://www.ncbi.nlm.nih.gov/pubmed/3926471?dopt=Abstract&holding=npg
Seimon RV, Roekenes JA, Zibellini J, Zhu B, Gibson AA, Hills AP, Wood RE, King NA, Byrne NM, Sainsbury A. “Do intermittent diets provide physiological beneftis over continuous diets for weight loss? A systematic review of clinical trials.” Mol Cell Endo. 15 Dec 2015. 418(2): 153-172. https://www.sciencedirect.com/science/article/pii/S0303720715300800
Byrne NM, Sainsbury A, King NA, Hills AP, Wood RE. “Intermittent energy restriction improves weight loss efficiency in obese men: the MATADOR study.” Int J Obes. 2018. 42:129-138. https://www.nature.com/articles/ijo2017206
Trepanowski JF, Kroeger CM, Barnosky A. “Effect of Alternate-Day Fasting on Weight Loss, Weight Maintenance, and Cardioprotection Among Metabolically Healthy Obese Adults.” JAMA Intern Med. Jul 2017. 177(7): 930-938. https://jamanetwork.com/journals/jamainternalmedicine/article-abstract/2623528?redirect=true
Sumithran P, Prendergast LA, Delbridge E, Purcell K, Shulkes A, Kriketos A, Proietto J. “Long-term persistence of hormonal adaptations to weight loss.” N Engl J Med. 27 Oct 2011. 365: 1597-1604. http://www.nejm.org/doi/full/10.1056/NEJMoa1105816
Asrih M et al., “Ketogenic diet impairs FGF21 signaling and promotes differential inflammatory responses in the liver and white adipose tissue.” PlosOne. 14 May 2015. Open Access. https://doi.org/10.1371/journal.pone.0126364
Veniant MM et al. “FGF21 promotes metabolic homeostasis via white adipose and leptin in mice.” PlosOne. Jul 2012. Open access. https://doi.org/10.1371/journal.pone.0040164
Whittle AJ, “FGF21 conducts a metabolic orchestra and fat is a key player.” Endocrinology. 1 May 2016. 157(5): 1722-1724.

December 22, 2015

Why the Calorie is NOT King

Today in the office I had the calorie conversation again . . . three times. We have an entire society with a very influential health and fitness industry built around the almighty calorie. Has it helped? Looking at our 5 year obesity outcomes. It hasn’t helped a bit. In fact, it is worse. In 1985 only 19% of U.S. adults were obese.

U.S. Obesity Adult 2011

U.S. Adult Obesity 2014

In 2014, 34.5% of U.S. adults were obese. The numbers this year are approaching 35.6% You can see the dramatic increase in obesity by 1-3% every year for the last 5 years in the CDC images above.

For over 50 years we have been told that caloric restriction and fat restriction is the solution. But by the numbers above, the 58 million people in the U.S. utilize a gym or health club to burn off those calories aren’t seeing the success that they should be expecting.

Why? Because the calorie is NOT king. What do I mean by that? We don’t gain weight because of the thermogenic dogma we’ve been taught for the last 50 years. Our weight gain is driven by a hormone response to food. Hear more about why the calorie is NOT king on tonight’s PeriScope. You can Katch it here with all the live stream comments and hearts at Katch.me/docmuscles.

Or you can watch the video without the comments here:

November 25, 2015

Adrenal Insufficiency, Adrenal Fatigue, PseudoCushing’s Syndrome – Oh My!

Adrenal Fatigue? Adrenal Insufficiency? Cortisol? PseudoCushing’s Syndrome? What do these terms mean and why are they all over the internet these days? And, what do they have to do with your weight loss?

This was our topic this evening on PeriScope. Katch Dr. Nally speak about this topic with rolling comments at Katch.me/docmuscles. Or you can watch the video below:

If you’re not sure about what this is, you’re not alone. I think I’ve heard the term “Adrenal Fatigue” at lease four times a day for the last three months. If you ask your doctor, they’ll probably scratch their heads too. The funny thing is that “Adrenal Fatigue” isn’t a real diagnosis, but it is all over the internet and it shows up in the titles of magazines in the grocery store every day. There’s even and “Adrenal Fatigue For Dummies” so it must be real, right?!

No. It isn’t a real diagnosis. It is a conglomeration of symptoms including fatigue, difficulty getting out of bed in the morning, and “brain fog” that have been lumped together to sell an “adrenal supplement.” (Sorry, but that’s really what it is all about.) Do a Google search and the first five or six sites describing adrenal fatigue claim the solution is taking their “special adrenal supplement.”

I know what you’re thinking, “Your just a main stream, Western Medicine doctor, Dr. Nally, you wouldn’t understand.” Actually, I do understand.

Adrenal fatigue has risen in popularity as a “lay diagnosis” because many patients show up at their doctors office with significant symptoms that actually interfere with their ability to function, and after all the testing comes back negative for any significant illness, they are told that they are normal. But the patient still has the symptoms and no answer or treatment has been offered. It’s discouraging. . . very discouraging.

That’s because the symptoms are actually the body’s response to chronic long term stress. Many of my patients, myself included, have found themselves “stuck” in their weight loss progression, feeling fatigued, struggling to face the day, with a number of symptoms including cold intolerance, memory decline, difficulty concentrating, depression, anxiety, dry skin, hair loss, and even infertility in some cases. Is it poor functioning adrenal glands? No, your feeling this way because the adrenal glands are actually doing their job!!

If the adrenal glands weren’t working you’d experience darkening of the skin, weight loss, gastric distress, significant weakness, anorexia, low blood pressure, and low blood sugar. The symptoms are actually called Addison’s disease and it is actually fairly rare (1 in 100,000 chance to be exact). So what is causing the symptoms you ask?

There are a number of reasons, but one that I am seeing more and more frequently is “Pseudo-Cushings’s Syndrome.” Pseudo-Cushing’s Syndrome is a physiologic hypercortisolism (over production of cortisol) that can be caused by five common issues:

Chronic Physical Stress
Severe Bacterial or Fungal Infections that Go Untreated
Malnutrition or Intense Chronic Exercise
Psychological Stress – including untreated or under-treated depression, anxiety, post-traumatic stress, or dysthymia (chronic melancholy)
Alcoholism

The psychiatric literature suggest that up to 80% of people with depressive disorders have increased cortisol secretion (1,2,3). People with significant stressors in their life have been show to have an increased corsiol secretion. Chronic stress induces hyperactivity of the hypothalamic-pituitary-adrenal axis causing a daily, cyclic over production of cortisol and then normalization of cortisol after resolution of the stressor. This cortisol response is not high enough to lead to a true Cushing’s Syndrome, but has the effect of the symptoms listed above and begins with limiting ones ability to loose weight.

I’m convinced that this is becoming more and more prevalent due to the high paced, high-stress, always on, plugged in, 24 hour information overload lives we live.

What is cortisol? It is a steroid hormone made naturally in the body by the adrenal cortex (outer portion of the adrenal gland). Cortisol is normally stimulated by a number of daily activities including fasting, awakening from sleep, exercise, and normal stresses upon the body. Cortisol release into the blood stream is highest in the morning, helping to wake us up, and tapers into the afternoon. Cortisol plays a very important role in helping our bodies to regulate the correct type (carbohydrate, fat, or protein) and amount of fuel to meet the bodies physiologic demands that are placed upon it at a given time (4,5,6).

Under a stress response, cortisol turns on gluconeogensis in the liver (the conversion of amino acids or proteins into glucose) for fuel. Cortisol, also, shifts the storage of fats into the deeper abdominal tissues (by stimulating insulin production) and turns on the maturation process of adipocytes (it makes your fat cells age – nothing like having old fat cells, right?!) In the process, cortisol suppresses the immune system through an inhibitory effect designed to decrease inflammation during times of stress (7,8,9). If this was only occurring once in a while, this cascade of hormones acts as an important process. However, when cortisol production is chronically turned up, it leads to abnormal deposition of fat (weight gain), increased risk of infection, impotence, abnormal blood sugars, brain fog, head
aches, hypertension, depression, anxiety, hair loss, dry skin and ankle edema, to name a few.

The chronic elevation in cortisol directly stimulates increased insulin formation by increasing the production of glucose in the body, and cortisol actually blunts or block-aids the thyroid function axis. Both of these actions halt the ability to loose weight, and drive weight gain.
Cortisol also increases appetite (10). That’s why many people get significant food cravings when they are under stress (“stress eaters”). Cortisol also indirectly affects the other neuro-hormones of the brain including CRH (corticotrophin releasing hormone), leptin, and neuropeptide Y (NPY). High levels of NPY and CRH and reduced levels of leptin have also been shown to stimulate appetite and cause weight gain (10-11).

How do you test for Pseudo-Cushing’s Syndrome?

Testing can be done by your doctor with a simple morning blood test for cortisol. If your cortisol is found to be elevated, it needs to be repeated with an additional 24 hour urine cortisol measurement to confirm the diagnosis. If Cushing’s Syndrome is suspected, some additional blood testing and diagnostic imaging will be necessary. Pseudo-Cushing syndrome will demonstrate a slightly elevated morning cortisol that doesn’t meet the criteria for true Cushing’s type syndrome or disease.

How do you treat it?

First, the stressor must be identified and removed. Are you getting enough sleep? Is there an underlying infection? Is there untreated anxiety or depression present? Are you over-exercising? These things must be addressed.

Second, underlying depression or anxiety can be treated with counseling, a variety of weight neutral anti-depressant medications or a combination of both. Many of my patients find that meditation, prayer, and journaling are tremendous helps to overcoming much of the anxiety and depression they experience.

Third, adequate sleep is essential. Remove the television, computer, cell phone, iPad or other electronic distraction from the bedroom. Go to bed at the same time and get up at the same time each day. Give yourself time each day away from being plugged in, logged in or on-line.

Fourth, mild intensity (40% of your maximal exertion level) exercise 2-3 days a week was found to lower cortisol; however, moderate intensity (60% of your maximal exertion level) to high intensity (80% of your maximal exertion level) exercise was found to raise it (12). A simple 20 minute walk, 2-3 times per week is very effective. Find a hobby that you enjoy and participate in it once or twice a week. Preferably, a hobby that requires some physical activity. The activity will actually help the sleep wake cycles to improve.

Fifth, follow a low carbohydrate or ketogenic diet. Ketogenic diets decrease insulin and reverse the effect of long term cortisol production. Ketogenic diets a have also been shown to decrease or mitigate inflammation by reducing hyperinsulinemia commonly present in these patients (13).

So, the take home message is . . . take your adrenal glands off of overdrive.

References:

Pfohl B, Sherman B, Schlechte J, Winokur G. Differences in plasma ACTH and cortisol between depressed patients and normal controls. Biol Psychiatry 1985; 20:1055.
Pfohl B, Sherman B, Schlechte J, Stone R. Pituitary-adrenal axis rhythm disturbances in psychiatric depression. Arch Gen Psychiatry 1985; 42:897.
Gold PW, Loriaux DL, Roy A, et al. Responses to corticotropin-releasing hormone in the hypercortisolism of depression and Cushing’s disease. Pathophysiologic and diagnostic implications. N Engl J Med 1986; 314:1329.
Ely, D.L. Organization of cardiovascular and neurohumoral responses to stress: implications for health and disease. Annals of the New York Academy of Sciences (Reprinted from Stress) 771:594-608, 1995.
McEwen, B.S. The brain as a target of endocrine hormones. In Neuroendocrinology. Krieger and Hughs, Eds.: 33-42. Sinauer Association, Inc., Massachusetts, 1980.
Vicennati, V., L. Ceroni, L. Gagliardi, et al. Response of the hypothalamic- pituitary-adrenocortical axis to high-protein/fat and high carbohydrate meals in women with different obesity phenotypes. The Journal of Clinical Endocrinology and Metabolism 87(8) 3984-3988, 2002.
Wallerius, S., R. Rosmond, T. Ljung, et al. Rise in morning saliva cortisol is associated with abdominal obesity in men: a preliminary report. Journal of Endocrinology Investigation 26: 616-619, 2003.
Epel, E.S., B. McEwen, T. Seeman, et al. Stress and body shape: stress-induced cortisol secretion is consistently greater among women with central fat.
Psychosomatic Medicine 62:623-632, 2000.
Tomlinson, J.W. & P.M. Stewart. The functional consequences of 11_- hydroxysteroid dehydrogenase expression in adipose tissue. Hormone and Metabolism Research 34: 746-751, 2002.
Epel, E., R. Lapidus, B. McEwen, et al. Stress may add bite to appetite in women: a laboratory study of stress-induced cortisol and eating behavior.Psychoneuroendocrinology 26: 37-49, 2001.
Cavagnini, F., M. Croci, P. Putignano, et al. Glucocorticoids and neuroendocrine function. International Journal of Obesity 24: S77-S79, 2000.
Hill EE, Zack E, Battaglini C, Viru M, Vuru A, Hackney AC. Exercise and circulating cortisol levels: the intensity threshold effect. J Endocrinol Invest. 2008. Jul;31(7):587-91.
Fishel MA et al., Hyperinsulinemia Provokes Synchronous Increases in Central Inflammation and β-Amyloid in Normal Adults. Arch Neurol. 2005;62(10):1539-1544. doi:10.1001/archneur.62.10.noc50112.

November 20, 2015

How to Stay Motivated on Carbohydrate Restriction

This evening on PeriScope, we talked about the 10 things you can do to stay motivated on your low-carb lifestyle. A number of great questions were asked including:

How much carbohydrate should be restricted?
What labs should you be monitoring regularly?
What’s a normal blood sugar?
Why is Dr. Nally freezing in Denver?
Is fermented food good for you?
Why should you eat pickles and kimchi even when you’re not pregnant?

And, much much more . . . It’s like a college ketogenic course on overdrive . . . for FREE!!!

You can see the PeriScope with the comments rolling in real-time here: katch.me/docmuscles

Or, you can watch the video stream below:

See you next time.

October 1, 2015

Fructose and High Triglycerides Lead to Leptin Resistance

I can’t help myself. Some days I enjoy a good murder mystery, but on others, I enjoy a good journal article elucidating our understanding of leptin. No, leptin is not a tiny Irish folk character or even a superhero. Leptin is a hormone. It’s made by fat cells. Anything made by fat cells becomes fascinating to a “fat doctor.”

Why is learning about leptin illuminating?

Well, if Sir Arthur Conan Doyle was an Obesity Specialist, the mystery would have been that Mr. Plump was killed by the wrench in the kitchen, but the wrench seems to have never left tool case in the garage. No one has been able to figure out how leptin, the allegorical wrench, plays its roll in lepin resistance. We know that a lack of leptin allows hunger to persist and a person without leptin will continue to eat without the sensation of feeling full – leading to obesity. What we haven’t understood is – what causes the brain to no longer sense larger and larger amounts of leptin being produced by those who are obese.

That is . . . we haven’t understood it until now. . .

We have known for some time that the hormone leptin is a key hormone produced by the adipose (fat) cells that suppresses hunger. A majority of obese patients in my clinic have elevated circulating leptin levels 2-10 times the normal levels. We know that a lack of leptin leads to obesity, but the patients that I see in the office are producing an over abundance consistent with leptin resistance. The leptin signal is not being recognized by the brain. This is very similar to type II diabetes and insulin resistance. The pancreas is producing an over abundance of insulin, but the cells are recognizing the signal to let the glucose in through the door way.

Three recent and very interesting studies have pointed to the probable cause. First, one of the most common genetic disorders causing human obesity is loss of function of the melanocortin receptor.

Image adapted from 2011 “The Skinny About Fat” presentation – Adam Nally, D.O.

If the MC-4R receptor is broken, suppression of appetite is limited, continued eating occurs and weight gain continues. Leptin, produced by every adipose cell in the body, is carried in the blood stream to the brain and must pass through the blood-brain barrier. Once it crosses the blood-brain barrier and enters the hypothalamus, it has a stimulatory effect on the MC-3R receptor in the Arcuate Nucleus of the hypothalamus causing stimulation of the MC-4R receptor in the Parventricular Nucleus and Lateral Hypothalamus to turn off hunger.

Image adapted from 2011 “The Skinny About Fat” presentation – Adam Nally, D.O.

However, if leptin cannot cross the blood brain barrier, the signal is never received from the adipose cells and continued eating without satiation (feeling full) persists. Studies have shown that dietary fructose ingestion alone or in combination with diets high in fat suppress the transmission of leptin across the blood-brain barrier.

Image adapted from 2011 “The Skinny About Fat” presentation – Adam Nally, D.O.

Fructose is the primary component of high-fructose corn syrup, and makes up 45-50% of every other type of natural form of sugar (sucrose). Yes, it’s the major component found in table sugar, brown sugar, honey, agave, molasses and maple syrup. This is why a Paleolithic Diet isn’t fully effective for people with leptin resistance.

Lastly, anything that raises triglycerides inhibits leptin from crossing the blood-brain barrier.

Image adapted from 2011 “The Skinny About Fat” presentation – Adam Nally, D.O.

Insulin has a direct effect on triglycerides. (See the articles “Insulin Resistance & The Horse,” “Fat Thoughts on Cholesterol,” “Ketogenic Living” and “So, What is this Ketogenic Thing?“). If your insulin levels go up, triglyceride production goes up. The patient with insulin resistance, pre-diabetes, impaired fasting glucose or type II diabetes produces between two to ten times the normal amount of insulin when eating the standard American diet (SAD diet). These patients have significant triglyceride elevation because of the high insulin response to carbohydrates in their diet. (Many of them were told by their doctor that “It’s just genetic so take your Lipitor.”) Statin drugs lower the LDL-C (calculated “bad cholesterol” level), but don’t reduce triglycerides effectively. Inadequate treatment of high triglycerides allows poor blood-brain barrier transmission of leptin and worsening leptin resistance.

In fact, this is the challenge and problem with the “frequent fasting” or “intermittent fasting” fad for weight loss that has been popping up in the blogosphere. If fasting reaches a state of starvation (which is a very fine line metabolically), it stimulates a stress response . . . causing a spike in cortisol, release of glycogen (a form of sugar), a compensatory release of insulin and a spike in triglycerides. If you have tried intermittent fasting and you’ve gained weight, you are probably not “fasting,” your probably “starving.” We’ve known for years that triglycerides are elevated in starvation. This diminishes leptin’s ability to cross the blood-brain barrier and leads to worsening leptin and insulin resistance.

High leptin levels caused by leptin resistance also seems to play a significant role in the development of diabetic retinopathy – damage to the tiny blood vessels at the back of the eye feeding the retina. Diabetic retinopathy starts insidiously without any symptoms initially and can lead to eventual blindness if not treated. Leptin seems to upregulate vascular endothelial growth factor (VEGF) which leads to narrowing of the blood vessels called “ischemia.” Chronic ischemia of the retinal vessels leads to damage to the delicate retinal cells of the eye.

So what do you do if you have leptin resistance. First, eliminate carbohydrates from your diet, especially sugars, high fructose corn syrup and any other form of simple sugar. This is why I am such a big fan of low carbohydrate, high fat diets.

Second, lower your triglycerides. This is done through decreasing overall insulin loads and is very effectively accomplished with a ketogenic diet. You can find this in my book, The KetoCure. Some additional great sources are KetoClarity, The Art and Science of Low Carbohydrate Living, and The Ketogenic Cookbook.

Third, use a supplement containing alpha-lipoic acid, carnosine high gamma vitamin E and benfothiamin (derivative of Vitamin B1). These have been demonstrated to decrease inflammation and render protection to the blood vessels.

The use of Epigallocatechin gallate (EGCg), a derivative extract of green tea, has been shown to repress hepatic glucose production, one of the insidious factors of insulin resistance, and may play a role in stabilizing the effect insulin has on production of triglycerides. You should consider using KetoEssentials. It is my specially formulated multivitamin that contains all of the above supplements, and includes methylated folic acid (B9), the necessary vitamin B6 & B12, chromium, vandium & zinc that help to further stabilize insulin resistance.

Fourth, get a good night’s sleep. Lack of sleep causes a stress response, increases cortisol, raises blood sugar and insulin leading to further leptin resistance.

Fifth, mild to moderate resistance exercise has been shown for years to improve insulin resistance significantly. If you’re not exercising, take a 20 minute walk 2-3 times per week, ride a bike for 20 minutes, start a weight lifting program, consider yoga or Pilates, Remember, jumping to conclusions, flying off the handle, carrying things too far, dodging responsibility and pushing your luck don’t qualify as resistance exercise.

Above all, if you’re having trouble losing weight, controlling insulin or leptin, see your doctor. He or she can really help.

References:

Ray F. Gariano, Anjali K. Nath, Donald J. D’Amico, Thomas Lee, and M. Rocio Sierra–Honigmann. “Elevation of Vitreous Leptin in Diabetic Retinopathy and Retinal Detachment.” Invest Ophthalmol Vis Sci. 2000;41:3576–3581
Hammes HP, Du X . “Benfotiamine blocks three major pathways of hyperglycemic damage and prevents experimental diabetic retinopathy.” Nat Med. 2003 Mar;9(3):294-9. Epub 2003 Feb 18.
Hipkiss AR, Brownson . “Reaction of carnosine with aged proteins: another protective process?” Ann N Y Acad Sci. 2002 Apr;959:285-94.
Zachary A. Knight, K. Schot Hannan, Matthew L. Greenberg, Jeffrey M. Friedman. “Hyperleptinemia Is Required for the Development of Leptin Resistance.” PLoS ONE 5(6): e11376. doi:10.1371/journal.pone.0011376.
Min-Diane Li. “Leptin and Beyond: An Odyssey to the Central Control of Body Weight.” The Yale Journal of Biology and Medicine. 2011;84(1):1-7.
Eri Suganami, Hitoshi Takagi,Hirokazu Ohashi, Kiyoshi Suzuma, Izumi Suzuma, Hideyasu Oh, Daisuke Watanabe, Tomonari Ojimi, Takayoshi Suganami, Yasushi Fujio, Kazuwa Nakao, Yoshihiro Ogawa and Nagahisa Yoshimura. “Leptin Stimulates Ischemia-Induced Retinal Neovascularization: Possible Role of Vascular Endothelial Growth Factor Expressed in Retinal Endothelial Cells.” Diabetes. September, 2004. vol. 53 no. 9 2443-2448
Joseph R. Vasselli, Philip J. Scarpace, Ruth B. S. Harris, and William A. Banks. “Dietary Components in the Development of Leptin Resistance.” Adv. Nutr. 2013: 4: 164–175.
Joseph R. Vasselli. “Fructose-induced leptin resistance: discovery of an unsuspected form of the phenomenon and its significance.” Am J Physiol Regul Integr Comp Physiol. 2008 Nov;295(5):R1365-9. doi: 10.1152/ajpregu.90674.2008. Epub 2008 Sep 10.
Waltner-Law ME, Wang XL Epigallocatechin gallate, a constituent of green tea, represses hepatic glucose production. J Biol Chem. 2002 Sep 20;277(38):34933-40. Epub 2002 Jul 12.