15

votes

Could this Be the Simple Explanation for a Fructose-Leptin Connection?

Answered on August 19, 2014
Created August 11, 2011 at 7:23 PM

As a preface, let me confess that in spite of the fact that people are talking about leptin everywhere I go on the internet, I have spent zero time looking into it (beyond initially finding a simple definition) until this morning. I've always assumed that fructose intake is at least a primary contributing factor in most cases of type-II diabetes, obesity, hypertension, renal disease, hypertriglyceridemia, atherosclerosis, gout, etc. and that the focus on leptin has been important, but ultimately a red herring. As such, I apologize if this has already been hashed out or disproven.

Now then, a necessary primer for this that everyone should read (if you haven't already) is here: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2917125/

In essence, Johnson et al put forth a theory that our loss of the ability to endogenously create vitamin C (which increases urate excretion) as well as out loss of the uricase enzyme have both evolved as a result of a need to potentiate the lipogenic effects of fructose so as to facilitate fat gain ahead of seasonal lean times. You eat fructose, you get (relative) hyperuricemia and the effect (at some point during our evolution) was crucial. The effects of it now during times of constant fructose exposure are those mentioned above. Basically, it's my belief that if humans still had that 4th stage of vitamin C production and the uricase enzyme, obesity as we know it would be nigh on impossible.

What prompted me to look into this was the video of Lustig's short presentation at the AHS and Guyenet's rebuttal that insulin doesn't block leptin in the hypothalamus. [ http://huntgatherlove.com/node/612#comment-280572317 ] I'm sure he's completely right, but perhaps it's not that persistent hyperinsulinemia coming as the result of fructose intake causes leptin resistance, but rather that the same signal that causes insulin resistance (hyperuricemia) causes leptin resistance as well.

So, doing a bit of digging yields some studies:

Hypothesis: fructose-induced hyperuricemia as a causal mechanism for the epidemic of the metabolic syndrome http://www.nature.com/nrneph/journal/v1/n2/full/ncpneph0019.html

"We recently reported that uric acid reduces levels of endothelial nitric oxide (NO), a key mediator of insulin action. NO increases blood flow to skeletal muscle and enhances glucose uptake. Animals deficient in endothelial NO develop insulin resistance and other features of the metabolic syndrome."

fructose-->urate-->endothelial NO decrease-->insulin resistance-->diabetes/obesity

Serum leptin is associated with serum uric acid concentrations in humans http://www.sciencedirect.com/science/article/pii/S0026049599901634

OK, so we have an association to start with.

Leptin Might be a Regulator of Serum Uric Acid Concentrations in Humans http://www.jstage.jst.go.jp/article/jhj/44/4/44_527/_article/-char/en

That study I believe has proposed cause and effect reversed.

Serum Uric Acid and Plasma Norepinephrine Concentrations Predict Subsequent Weight Gain and Blood Pressure Elevation http://hyper.ahajournals.org/content/42/4/474.short

Elevated serum leptin concentrations in women with hyperuricemia. http://ukpmc.ac.uk/abstract/MED/12238635/reload=0;jsessionid=CB123EAAB50A5E34843FD8F8A4827392

Serum uric acid and leptin levels in metabolic syndrome: a quandary over the role of uric acid http://www.sciencedirect.com/science/article/pii/S0026049507000583

Though that one states "Hormone assays showed an elevation of leptin, immunoreactive insulin (IRI), and HOMA-IR in the hyperuricemia group" it also states that there isn't a correlation.

Uric acid: A new look at an old risk marker for cardiovascular disease, metabolic syndrome, and type 2 diabetes mellitus: The urate redox shuttle http://www.nutritionandmetabolism.com/content/1/1/10

That one gives a huge list of reasons why you don't want hyperuricemia.

Alright, so you eat fructose, a by-product of it being metabolized is urate, that urate decreases endothelial nitric oxide, which causes insulin resistance. I don't know by what specific mechanism urate might act upon leptin but his study:

Pivotal role of nitric oxide in the control of blood pressure after leptin administration. http://diabetes.diabetesjournals.org/content/48/4/903.short

shows that leptin itself increases serum nitric oxide, so maybe there is a tie-in there. It seems that if the first paper is correct, and we become relatively insulin resistant as a result of heavy fruit consumption, but we didn't become leptin resistance, leptin would shut down appetite as fat stores increased (and thus released more of it) and there would be little effect. For this adpatation to be effective, you'd have to see resistance to both hormones.

A counter-argument to the first paper is that frugivorous apes living in tropical climates not subject to the seasonality that many of us are also do not possess the ability to produce vitamin C or have uricase. However, they are consuming fruit that presumably contains significant amounts of vitamin C, which would increase urate excretion. Thus, it may very well be that the harmful effects of a high fructose intake, even if in the form of HFCS-sweetened drinks, could be mitigated by a commensurate increase in ascorbate intake.

In any case, it seems to me that at the very least there is a compelling argument for fructose avoidance based upon the laundry list of negative health outcomes associated with it. I know from personal experience that my reactive hypoglycemia disappeared when I greatly reduced my fructose intake and that my blood pressure (which was fairly normal before) has dropped down to what western medicine would call "low-normal." On top of that, I've experience an overall increase in satiety, suggesting that leptin sensitivity has increased.

One may take a glance at NHANES and conclude that fructose intake hasn't really increased much since the 70s, but one doesn't become obese overnight. The incubation period is about right and I think we would find that the majority of those who are obese had a period of time of heavy fructose exposure many standard deviations above the mean, or at least that they are especially sensitive to fructose as a result perhaps of a greater expression of PFK. Certainly there is going to be a huge variability in individual fructose sensitivity, which should account for those individuals whose intake of it is large but who do not suffer from at least the visually apparent effects.

Anyway, I'd appreciate any thoughts you might have if you trudged through the above mess.

0dbd7154d909b97fe774d1655754f195

(16131)

on August 11, 2011
at 09:28 PM

120 of sucrose (1/2 glucose 1/2 fructose) like in OJ - Glucose part = 12 calories for the liver 48 for the rest of the body. Fructose = 60 calories right to the liver. If your body is already overwhelmed with carbohydrate, then the fructose can lead to high uric acid and hypertension. (He admits blood pressure doesn't go up a lot, like 3 points but still considers this significant). If you are an athlete and/or are in energy depleted state - fructose can be turned into glucose, the problems arise when you are energy replete and sendentary.

0dbd7154d909b97fe774d1655754f195

(16131)

on August 11, 2011
at 09:27 PM

Lustig note Glucose - when you eat 120 calories - 96 calories go to the body, 24 go to the liver. Those 24 calories in the liver ultimately is stored as glycogen. That's good. Some ultimately goes to fat cells if liver glycogen is full. "You can make fat out of glucose, you just have to eat a whole lot of it." When it is ingested acutely, the insulin release acts on the brain causing a satiety signal. "Nice metabolic pathway." continued...

Medium avatar

(39831)

on August 11, 2011
at 09:21 PM

What's your take on fructose and leptin?

Ed71ab1c75c6a9bd217a599db0a3e117

(25477)

on August 11, 2011
at 09:16 PM

I guess you now understand why leptin is at levee two in the Quilt. It is that important. You just have to make sure your doc gets it to help you help yourself.

Ed71ab1c75c6a9bd217a599db0a3e117

(25477)

on August 11, 2011
at 09:15 PM

i look at it all the time.....anyone with high BP needs it followed. But most docs think its related to high purine dietary intake......not true. Its high fructose most of the time.

Medium avatar

(39831)

on August 11, 2011
at 09:12 PM

That's great; I tried to get uric acid tested but my doctor changed the subject. I think it's a proxy for fructose intake and/or vitamin C status. RJ Johnson (the nephrologist cited above) advocates uric acid testing, but I think most doctors rarely would look at it, or if they did, they wouldn't make the fructose connection. Another upside to not eating anything sweet is that your perception of sweet tastes changes dramatically. I eat plain sweet potato several times a day and it tastes like candy to me whereas before it would have been completely bland.

Medium avatar

(39831)

on August 11, 2011
at 09:10 PM

That's great; I tried to get uric acid tested but my doctor changed the subject. RJ Johnson (the nephrologist cited above) advocates uric acid testing, but I think most doctors rarely would look at it, or if they did, they wouldn't make the fructose connection. Another upside to not eating anything sweet is that you perception of sweet tastes changes dramatically. I eat plain sweet potato all the time and it tastes like candy to me whereas before it would have been completely bland.

Medium avatar

(39831)

on August 11, 2011
at 09:00 PM

Yeah, there's no way that starch alone is going to lead to obesity or diabetes. That being said, there is a metabolic/satiety difference between 200g of net carbs from whole bread vs. sweet potato or even rice.

Medium avatar

(39831)

on August 11, 2011
at 08:58 PM

Yeah, there's no way that starch alone is going to lead to obesity or diabetes. That being said, there is a metabolic/satiety difference between 200g of starch from bread vs. sweet potato or even rice.

Medium avatar

(39831)

on August 11, 2011
at 08:58 PM

Yeah, there's no way that starch alone is going to lead to obesity or diabetes. That being said, there is a metabolic difference between 200g of starch from bread vs. sweet potato or even rice.

A45af235ed4dd0b4f548c59e91b75763

(1936)

on August 11, 2011
at 08:48 PM

That makes sense. I wonder if many of the counter arguments against carbohydrates being the primary cause of obesity could be explained away by the fructose link? For instance, I know that many asian cultures eat a diet high in carbs (like Japan), but much lower in fructose. Even Japanese desserts taste very plain compared to the sweetness of american desserts.

Medium avatar

(39831)

on August 11, 2011
at 08:25 PM

Regarding the "and/or," I'm not sure if leptin resistance occurs without insulin resistance.

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3 Answers

3
44c0064c835001351885a6d349a2542f

(279)

on August 13, 2011
at 06:32 AM

The most interesting questions often tend to get buried on PH. I could barely find this again today. I'm just wondering if you tested your hypothesis / yourself with a fruit + extra vitamin C challenge? In particular does the extra ascorbic acid ameliorate the hypoglycemia / BP rise?

2
7dc950fc76a046048e683d2a27dced37

on August 11, 2011
at 09:00 PM

What an interesting post! I can't comment authoritatively enough on the feasibility (no Kraken here!), but I find it interesting for two reasons. One, the points that Lustig made in his AHS presentation that fructose is fine if you can utilize it, and that fructose-induced insulin resistance would be advantageous as a method of over-riding leptin seasonally (put on fat before winter).

Two, like you, I have been experiencing an increase in satiety as a result of decreasing NADs (my diet most closely approximates the Jaminet's Perfect Health Diet). Also curious to me is that finally, after many months, my uric acid level is now in my lab's reference range.

Ed71ab1c75c6a9bd217a599db0a3e117

(25477)

on August 11, 2011
at 09:15 PM

i look at it all the time.....anyone with high BP needs it followed. But most docs think its related to high purine dietary intake......not true. Its high fructose most of the time.

Medium avatar

(39831)

on August 11, 2011
at 09:10 PM

That's great; I tried to get uric acid tested but my doctor changed the subject. RJ Johnson (the nephrologist cited above) advocates uric acid testing, but I think most doctors rarely would look at it, or if they did, they wouldn't make the fructose connection. Another upside to not eating anything sweet is that you perception of sweet tastes changes dramatically. I eat plain sweet potato all the time and it tastes like candy to me whereas before it would have been completely bland.

Medium avatar

(39831)

on August 11, 2011
at 09:12 PM

That's great; I tried to get uric acid tested but my doctor changed the subject. I think it's a proxy for fructose intake and/or vitamin C status. RJ Johnson (the nephrologist cited above) advocates uric acid testing, but I think most doctors rarely would look at it, or if they did, they wouldn't make the fructose connection. Another upside to not eating anything sweet is that your perception of sweet tastes changes dramatically. I eat plain sweet potato several times a day and it tastes like candy to me whereas before it would have been completely bland.

0dbd7154d909b97fe774d1655754f195

(16131)

on August 11, 2011
at 09:27 PM

Lustig note Glucose - when you eat 120 calories - 96 calories go to the body, 24 go to the liver. Those 24 calories in the liver ultimately is stored as glycogen. That's good. Some ultimately goes to fat cells if liver glycogen is full. "You can make fat out of glucose, you just have to eat a whole lot of it." When it is ingested acutely, the insulin release acts on the brain causing a satiety signal. "Nice metabolic pathway." continued...

0dbd7154d909b97fe774d1655754f195

(16131)

on August 11, 2011
at 09:28 PM

120 of sucrose (1/2 glucose 1/2 fructose) like in OJ - Glucose part = 12 calories for the liver 48 for the rest of the body. Fructose = 60 calories right to the liver. If your body is already overwhelmed with carbohydrate, then the fructose can lead to high uric acid and hypertension. (He admits blood pressure doesn't go up a lot, like 3 points but still considers this significant). If you are an athlete and/or are in energy depleted state - fructose can be turned into glucose, the problems arise when you are energy replete and sendentary.

1
A45af235ed4dd0b4f548c59e91b75763

(1936)

on August 11, 2011
at 08:07 PM

I hate to answer a question with a question, but I'll do it anyhow.

Could one simplify this concept to state that consumption of fructose, via an increase in insulin and/or a decrease in leptin cause obesity? (Due to a genetic adaptation allowing humans to survive food shortage).

So the crux would be that fructose would be the underlying cause of obesity?

Medium avatar

(39831)

on August 11, 2011
at 08:58 PM

Yeah, there's no way that starch alone is going to lead to obesity or diabetes. That being said, there is a metabolic/satiety difference between 200g of starch from bread vs. sweet potato or even rice.

A45af235ed4dd0b4f548c59e91b75763

(1936)

on August 11, 2011
at 08:48 PM

That makes sense. I wonder if many of the counter arguments against carbohydrates being the primary cause of obesity could be explained away by the fructose link? For instance, I know that many asian cultures eat a diet high in carbs (like Japan), but much lower in fructose. Even Japanese desserts taste very plain compared to the sweetness of american desserts.

Medium avatar

(39831)

on August 11, 2011
at 08:58 PM

Yeah, there's no way that starch alone is going to lead to obesity or diabetes. That being said, there is a metabolic difference between 200g of starch from bread vs. sweet potato or even rice.

Medium avatar

(39831)

on August 11, 2011
at 09:00 PM

Yeah, there's no way that starch alone is going to lead to obesity or diabetes. That being said, there is a metabolic/satiety difference between 200g of net carbs from whole bread vs. sweet potato or even rice.

Medium avatar

(39831)

on August 11, 2011
at 08:25 PM

Regarding the "and/or," I'm not sure if leptin resistance occurs without insulin resistance.

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