Ideally I could just post the links as a point of reference but the articles are not free. I'll list the citations and if you have acess to a medical library, online or not, you should be able to get your pizza skidders on them. In the meantime, I'll post my thoughts on some of their major points of contention. There is a lot of information to cover so I will post one argument at a time and depending on the response, I might address all five. I will however, flesh out their points in great detail, so prepare for a meaty discussion!
Dr. Lustig gets style points for rebutting Dr. Livesey in a numbered and orderly fashion and I will shamelessly follow his fantastic format. Lustig is an MD and Livesey is a PhD so both of these individuals have likely forgotten more about metabolism than I will ever know. I'm not going to be disputing their thoughts per se but instead playing the voice of reason. In otherwords, I'll weigh in on how much of this information is actually useful outside of academia, with useful being defined as "Does it change how we educate a client?" and how much of this is just some intellectual pissing match.
Dr. Robert Lustig's original article
-Lustig RH. Fructose: Metabolic, hedonic, and societal parallels with ethanol. J Am Diet Assoc. 2010;110:1307-1321.
Dr. Geoffrey Livesey's letter to the editor and Dr. Robert Lustig's response
-Livesey G. More on Mice and Men: Fructose Could put Brakes on a Vicious Cycle Leading to Obesity in Humans. J Am Diet Assoc. 2011;111:986-993.
First Basic Argument:
Does Fructose increase De Novo Lipogenesis (DNL)? (In simple terms, DNL is a metabolic pathway for converting carbohydrate (CHO) to fat.)
-Dr. Livesey: He cites a truckload of studies saying NO or not enough to matter
-Dr. Lustig: Lustig claims that Livesey is not interpreting the results in context and that he (Dr. Lustig) is stating the fructose does indeed increase DNL in: nonfasted state, hypercaloric feeding, obese and insulin resistant individuals, and "most importantly" with glucose. Dr. Lustig is especially concerned with this last point because he states that fructose does not occur alone anywhere in nature, fructose and glucose together have a synergist effect thus tripling DNL compared to fructose alone, and that fructose alone is poorly absorbed while glucose and fructose together have almost 100% absorption.
-My thoughts: my initial reaction to this was "who cares?". To clarify: I'm sure my DNL goes buckwild after I dominate the Chinese Super Buffet but it's not like I'm one crab rangoon away from NAFLD or Type 2 Diabetes. DNL is not a felony record that stays with your body until the end of time. As long as you're not consistently hypercaloric/are eucaloric most of the time, the fat you just created through DNL gets used aka lipolysis and the net balance is zero, all is well, and your butt still fits into your silly-ass hipster jeans.
Or if you prefer the medical version "In humans, de novo lipogenesis was shown to respond to several energy supply scenarios (3, 8). For example, de novo lipogenesis increases linearly with increased energy intakes of 25% and 50% above energy balance and decreases with underfeeding at the same levels of energy deficiency in lean subjects" (http://www.ajcn.org/content/74/6/737.long). I'm sure many will harp on "lean subjects". Yes, DNL does somewhat increase with overfeeding in obese subjects compared to lean but the issue is obesity or more specifically how they got there. This is where we should focus our education and as I've said many a time, I believe it will take a multi-disciplinary approach. Why are we getting wound up on a DNL rate when the real problem is longterm, consistent, hypercaloric feeding that has caused obesity? This is akin to arguing over which level of tire pressure will give you the maximum gas mileage when your air filter is 30K mi past due; change the dang filter!!!!!
DNL Lies, Damned Lies, and Statistics
The fructosophobes love to toss out these massive percent increases in DNL with fructose vs. glucose or even fat but let's dig a little deeper shall we? This table (table 6) shows "Daily carbohydrate intake and estimated amounts of absolute fat production from rates of de novo lipogenesis (Table 2) after 96 h of dietary treatment in lean (n = 8) and obese (n = 5) women" and is from the previously cited study. Let's talk about a little thing called percent change. Percent change is figured as new minus old/old. Crank up the fear machine and let's compare just how much fat all this DNL actually turned out in lean subjects in the control group (fed in energy balance) to obese subjects in the 50% overfed group (overfed sucrose). Lean individuals, in the control, in energy balance, busted a whopping 1.79g of fat/d after 96 hrs of dietary treatment vs. obese being overfed 50% with sucrose (remember it's half fructose and as Dr. Lustig points out glucose and fructose have this terrifyingly synergistic relationship) had a heart shattering 7.84g/d so you're essentially saying that if we take lean individuals and feed them a eucaloric diet they synthesize 6 grams of fat LESS per day than obese individuals that we overfeed by 50% with the extra calories being sucrose. Hmmmmphh...that's not very impressive so how about obese individuals overfed 50% with sucrose exhibit a 347% increase in DNL fat production!!!!!!!!!!! ~454 grams is one pound so this obese individual being overfed by 50% with the 50% being sucrose would need almost 58 days to accumulate one pound of bodyfat; WOW that really blows some air up my skirt! You can practice your new found percent change abilities with table 2 in the article. Table 2 actually shows Hepatic DNL rates (who cares?) but we can see from table 6 that very little fat in terms of grams is really produced. I've only cited one study here but if we're going to get bent out of shape on DNL, show me some studies where all this DNL actually significantly contributes to gains in fat AND MOST IMPORTANTLY show me some where the subjects were in caloric balance. Don't waste my time with percents, you can keep those in the back pocket of your skinny jeans...oh yeah, they don't have pockets.
My Liver, My Liver!!
There is no question that NAFLD is on the rise and the carb police are looking to frame fructose for the trend. Dr. Lustig appears to be the lead detective on that raid. In fact, his original article seemed to bash fructose alone although the masses no doubt extrapolated that into a crusade against HFCS. Where it gets interesting is when Dr. Livesey points out things like DNL with fructose ingestion alone is low and subbing fructose for glucose in DM pts might be a good thing given it does not raise blood glucose; Dr. Lustig astutely points out that fructose is not found by itself in nature and thus it is worthless to talk about it's properties in isolation. To clarify; you will be consuming it with glucose which allows fructose to work its voodoo. What this means is Dr. Lustig was really making a case against sucrose (glucose and fructose) or sugar. You can't have it both ways. In othewords, you can't write an article comparing fructose to the evils of alcohol and then when somebody points out the benefits of fructose (in isolation); rebuff them by saying it doesn't occur by itself as a foodstuff.
The Case Against Fructose
1. Fructose is capable of skipping phosphofructokinase 1 and thus creates a massive amount of pyruvate, quickly. Pyruvate heads into the mitochondria and is converted to Acetyl-CoA for the tricarboxylic acid cycle which you can think of as the fuel source for producing ATP. To simplify: too much pyruvate, too soon.
2. Well, the TCA cycle much like the TSA has a set speed and gets overwhelmed easily. When this occurs, extra pyruvate gets their admit bracelet revoked and through a series of events gets converted to citrate and hops the citrate shuttle back into the cytoplasm.
3. Once back in the parking lot/cytoplasm, citrate gets converted to Acetyl CoA by an enzyme called ATP citrate lyase. Then Acetyl Coenzyme A carboxylase, another enzyme, jumps on the newly minted Acetyl CoA, carboxylates it and forms Malonyl-CoA. The individual you just threw out of the club is now going to ensure nobody else gets in.
4. Malonyl-CoA is essentially the cop that you never should have thrown out of the club because now he'll see to it that nobody gets in. Malonyl-CoA stops carnitine acyl-CoA transferase-1 from shuttling in additional fatty acids for beta oxidation. So all the cabs bringing customers to your bar are getting stopped at the entrance to the parking lot and being told there is no entry tonight.
5. Malonyl isn't the end of the problems though. When the pyruvate cap was exceeded you also get fatty acid synthase going to work. FAS takes charge of all this additional acetyl CoA that is now available and adds them to carbon backbones, then esterfies them with a pinch of glycerol and viola! you get triglyceride formation. This is a very short explaination of how a hypercaloric, low fat, high carb diet can raise TG levels; keyword "hypercaloric".
6. Triglycerides then get there marching orders but need a ride so they bind to apolipoprotein B to make VLDL or very low density lipoprotein. The VLDL then hits the road and leaves the liver to find refuge in your body's adipocytes (muffin tops, cottage cheese arms, etc..)
7. Big finish for the jury here! So, in addition to adding to your adipocytes, which in and of itself terrifies most people (although not enough for them to exhibit moderation) it is hypothesized that not all of the fatty acetyl CoA products make it into VLDL and that some escape and stay in the liver, leading to Non-Alcoholic Fatty Liver Disease. Again, fructose is blamed for this because it hits the liver so hard and fast and with so much pyruvate that it can't even keep up with making fat or more accurately, exporting fat. Fat accumulation in the liver is a bad thing for a number of reasons. For one, it lowers hepatic insulin sensitivity. If your liver can't hear insulin, it doesn't get the message to turn down glucose production and this manifests as a high fasting blood glucose. When it is 100-125 we call it pre-diabetes or insulin resistance and when it hits 126 we call it diabetes but it's all the same thing; you're on a path you don't want to be on.
1. While fructose can certainly skip phosphofructokinase 1, it doesn't have to and in the case of caloric balance it can head that way for the formation of glycogen.
2. What may surprise many is that TGs, not glucose, are your body's main source of energy. Glycogen (stored glucose) comes with baggage, specifically about 4 grams of water for every gram of glycogen, so you would need to weigh somewhere in the neighborhood of 4x your current weight if we relied exclusively on glycogen for energy. TG are a convenient and storeable energy source for us. The process of turning these TG into energy is called lipolysis. The fatty acids can be used in beta oxidation to make more acetyl CoA to fuel the TCA and produce more ATP and the glycerol can actually be used to create more glucose.
3. A VERY simplified version of lipolysis goes something like this: We need some ATP so a few hormones get the page to get lipolysis started! Epinephrine and glucagon, among others get busy and through a series of calls ramp up production of cyclic adenosine monophophate or cAMP. Well, cAMP then calls protein kinase A and he gets to work on alerting the various lipases around the body. They begin to break down fat in the adipocytes and TG are transported to via lipoproteins (their ride) to the parts of the body in need of energy. The free fatty acids are used for acetyl CoA and the glycerol portions head back to the liver and kidney where through a series of steps it gets refurbed to go back into the glycolysis/gluconeogenesis pathway for glucose production.
4. As you can see, lipolyis is the balance to lipogenesis and thus whichever one occurs most over a given time frame, wins. For example, if you create 500 grams of bodyfat in 5 days through lipogenesis but you oxidized 501 through lipolysis, you are still losing weight. To clarify, this is why the immediate boost we see in DNL with fructose, no matter how we tease the numbers, is irrelevant because in caloric balance, all that TG formation, will get used up.
5. But don't take my word for it, the Wash U Crew actually did a fantastic study on it comparing different macronutrient ratios and the effects on insulin sensitivity (fatty liver = bad news for insulin sensitivity). They compared a low carb group and a high carb group. Both were on a 1000 calorie/day deficit defined as (REE x 1.3) - 1000. The LC group was 10% CHO/75% FAT/15% PRO and the high carb group was 65%CHO/ 20% FAT/ 15% PRO. The low carb diet lowered intrahepatic TG content 3x more in the first 48 hours BUT....there was no significant difference after 7% weight loss/11 weeks! Like I said, it's lipolysis vs. lipogenesis; DNL ain't permanent!
Please read the full text document to hear about a ton of other interesting findings (their explaination of the Euglycemic Clamp is fantastic!). I've listed the citation below because again, it's not free.
Kirk E, Reeds DN, Fink BN, Mayurranjan MS, Patterson BW, Klein S. Dietary Fat and Carbohydrates Differentially Alter Insulin Sensitivity During Caloric Restriction. Gastroenterology 2009;136:1552-1560.
-Dr. Livesey and Dr. Lustig are both brilliant but I think this spat is more of a pissing match than anything that will change the way we fight Type 2 DM, Obesity, Metabolic Syndrome, NAFLD, etc..
-DNL with fructose alone is relatively low (point to Dr. Livesey) but you aren't going to find it in isolation in nature (point Dr. Lustig) and frankly since it only goes "high"(practice your percent change formula boys and girls!) with overfeeding and is reversible (a la Wash U study), who really cares?
-Excess calories, not fructose or sucrose are the problem or to take it a step further; poverty, various mental health issues, and lack of education are the larger concerns with the obesity epidemic.