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.