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.

CNS Neural Pathways

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.

Leptin Effect on Hypothalamus

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.

Most Common Obesity Genetic Disorder

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.

Leptin resistance causes

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.

Triglyceride effect on Leptin

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” 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. Some 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 KetoEnhance. It is my specially formulated multivitamin that contains all of the above supplements, and includes 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.


  1. 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
  2. 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.
  3. Hipkiss AR, Brownson . “Reaction of carnosine with aged proteins: another protective process?” Ann N Y Acad Sci. 2002 Apr;959:285-94.
  4. 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.
  5. 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.
  6. 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
  7. 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.
  8. 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.
  9. 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.

2 Comments on “Fructose and High Triglycerides Lead to Leptin Resistance

  1. Pingback: The Principle Based Ketogenic Lifestyle . . . Part I | The KetoDynamic Antidote

  2. I read this multiple times. I should probably have another go at it later to really make it stick. Leptin was never a part of my education. I didn’t know that leptin upregulated VEGF. I always thought that VEGF’s primary damage was promoting neovascularization. The propensity of retinal “neo” to leak is viewed as an ocular emergency. If leptin causes ischemia and neo, it’s one very mean substance when it’s out of control. I wonder if leptin plays any roll in macular degeneration. By the way I believe you left out the word “not” in the early part of the article when you spoke of glucose not getting through the doorway, but I was reading this pretty closely. Thank you for the excellent information.

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