I've read a lot on both sides of the debate of low carb vs low fat diets trying to make some sense of what is being proposed. The lipid hypothesis runs roughly along the lines that we have lots of observational epidemiological evidence that eating a high fat diet correlates heart disease/obesity/enter disease of choice.

An alternative hypothesis is that high carbohydrate diets cause these things. Since the studies haven't been done, there is not the correlation to point to. This hypothesis is believable (to some people) due to the well-understood biological pathway: Carbohydrates turn to glucose, which causes an insulin release, and insulin regulates fat storage, so high carbohydrate diets lead to weight gain (see a biochemsitry textbook for a more detailed explanation).

My question is: Does the lipid hypothesis have any biological pathway for which there could be proposed a causal relation rather than just a correlation? Of all the speakers/writers on this topic, the low carb advocates always clearly describe the causal relation, whereas the low fat advocates never say why eating fat should cause weight gain.

Note: I'm not interested in discussing the merits of the studies, but rather the proposed causal mechanism.


3 Answers 3


I think you're confounding two separate things.

The Lipid Hypothesis is about the creation of atherosclerosis (only atherosclerosis) and was proposed as an explanation for why plaques of cholesterol, fatty acids, and somatic cells form in arteries. It does not try to explain adipocyte behavior, which would result in weight gain.

For the Lipid Hypothesis, after the glycerol has been removed from fatty acids, they are free to diffuse into the blood and can start plaques.

Weight Gain/Loss due to adipocyte behavior is significantly more complicated. One of the weight-related regulatory hormones present in adipose tissue is Leptin: http://en.wikipedia.org/wiki/Leptin

And a more scholarly article from 1995 discussing Leptin:


Leptin helps inhibit appetite, along with Ghrelin and a host of other molecules that control hunger and keep track of nutrient levels. However, as the wiki article states, Leptin and Insulin based activities are the primary functions of adipocytes, so a high-fat diet would conceivably deal with either or both of those molecules.

One of the quirks of Leptin is that fad dieting or starvation techniques have a very undesirable affect on Leptin levels (for years after a starvation diet, sometimes) that cause adipocytes to accumulate lipids that they normally would not have.

Obesity can also cause Leptin resistance (which might be aggravated by Fructose intake: http://www.ncbi.nlm.nih.gov/pubmed/11723062 ), much the same way that a diet rich in simple sugars can cause Type II Diabetes: http://www.ncbi.nlm.nih.gov/pubmed/8532024 The Leptin levels are at the expected concentrations in obese individuals, but the proper neuro-receptor activity isn't taking place.

Come to think of it, this may be what you're after. High fat diets will result in more Leptin and thus quicker/more Leptin resistance. Once Leptin resistance occurs, the mechanisms for controlling hunger are no longer as effective as they once were, resulting in more food intake and more weight gain.

However, the actual satiatory signal of Leptin is still debated. Some researchers have proposed that it's more of a "starvation" signal than a "satiation" signal, and thus Leptin resistance might be a normal condition when energy-dense foods are widely available: http://www.ncbi.nlm.nih.gov/pubmed/19644451

  • $\begingroup$ Ah. Interesting. I'm going to be a pain. I understand the Lipid Hypothesis was originally about atherosclerosis, but due to the strong correlation between obesity and heart disease most (all?) proponents of low fat diets believe that eating fat causes you to get fat. At least this is the widespread U.S. belief. So I think this has been absorbed into the modern lipid hypothesis. You will have answered my question if you point out why eating a high fat diet leads to more Leptin. I had heard that fructose causes Leptin levels to increase, but haven't seen that fat can cause it too. $\endgroup$
    – user1323
    Aug 30, 2012 at 17:03
  • $\begingroup$ If that is all the Lipid Hypothesis really is, then would you consider it fairly well debunked? Our modern understanding describes pretty well that the types of lipoproteins that come out of eating fat are not the type that lead to plaque on the arteries, but the type formed from eating a high carbohydrate and/or high sugar diet are. $\endgroup$
    – user1323
    Aug 30, 2012 at 17:07
  • $\begingroup$ Well, my personal opinion is that the proponents are mistaking a high fat diet for a surplus-Calorie diet high in fats. You can gain weight off of almost any food, but fat has more than double the energy density of carbs and protein (9kcal/g vs. 4kcal/g) - so a "High Fat" diet is probably a "Calorie Surplus" diet to begin with. That said, more fat in your system also means more adipocyte activity, which could include fluctuation in Leptin levels sufficient to trigger resistance. I couldn't find any articles, but it is plausible to me... $\endgroup$
    – MCM
    Aug 30, 2012 at 17:28
  • $\begingroup$ ...for the same reasons that Type II Diabetes, while often seen in obese patients, is not exclusive to obese patients. It's just an over-abundance of simple sugars in your system, combined with genetic predispositions, that results in Insulin resistance. Even if you burned off all of the Calories from sweet foods, if you only ate sweet foods you have a chance at developing Type II. Normal weight people, to the best figures I can find, make up about 10% of newly diagnosed cases. $\endgroup$
    – MCM
    Aug 30, 2012 at 17:31
  • $\begingroup$ Given that possibility, though, my personal opinion is still that it's debunked. A high-fat diet will not make you fat on its own, but it's certainly possible to underestimate the Calories involved. There might be some merit to low-carb diets, which show better weight loss over the short-term, but after 6 months there's no difference besides minor HDL and Triglyceride levels: nejm.org/doi/full/10.1056/NEJMoa022207 $\endgroup$
    – MCM
    Aug 30, 2012 at 17:39

You are mistaken in that the "lipid hypothesis" has no physiological basis like the carbohydrate biological pathways. Lipids and carbohydrates are produced and catabolized mutually from each other in the body. It's all the calories that matter (okay, proteins have a few too). Once the fat is in the body it gets turned into an energy source but it appears you are more interested what comes before. I'll quote from Wikipedia:

Digestion of some fats can begin in the mouth where lingual lipase breaks down some short chain lipids into diglycerides. The presence of fat in the small intestine produces hormones that stimulate the release of pancreatic lipase from the pancreas and bile from the liver for breakdown of fats into fatty acids. Complete digestion of one molecule of fat (a triglyceride) results in 3 fatty acid molecules and one glycerol molecule.

After that, fatty acids are packed into chylomicrons and transported through the blood to where they are catabolized.

This process, however, is strongly dependend on the right mixture of bile acids and pancreas enzymes. Any deviation from the ideal leads to undigested fat in the intestine, which is usually then partly digested by bacteria (winds as byproduct) or simply excreted as fatty stool.



  • 1
    $\begingroup$ First, nowhere in my question do I say the lipid hypothesis has no physiological basis. If so, I wouldn't ask the question. I said that defenders of the lipid hypothesis do not explain what the pathway is. Second, this explains (as you point out) how lipids are catabolized which I already knew. I'm wondering what the proposed pathway from ingesting fat to fat accumulation is, not how fatty acids are turned into an energy source. It would also be nice for people who stumble on this to be able to read an answer if you understand this rather than dig through a Wikipedia article to find it. $\endgroup$
    – user1323
    Aug 28, 2012 at 16:45
  • $\begingroup$ Now it's getting clearer what you want to know. I'll add to my answer. $\endgroup$
    – R Stephan
    Aug 28, 2012 at 16:53
  • $\begingroup$ Thanks so much for your time! Sorry if the question wasn't clear. $\endgroup$
    – user1323
    Aug 28, 2012 at 17:02
  • $\begingroup$ I think my question is still unclear. It is not about how fatty acids are digested or turn into energy. I think the "Lipid Hypothesis" wasn't explained well enough. The lipid hypothesis says that there is something about eating fat that causes you to get fat, i.e. if you eat the exact same amount of calories, then eating fat will cause you to gain weight (get heart disease, etc). The carb hypothesis has a particular pathway that leads to fat accumulation that does not happen from eating fat. My question is what is a proposed pathway for the lipid hypothesis? $\endgroup$
    – user1323
    Aug 28, 2012 at 21:07

First, dietary fat itself accumulates without big biochemical modifications: indeed dietary triglycerides are preferentially uptaken in white adipose tissue according to Bickerton et al. Diabetes 2007 56(1):168-76. So no complicated pathway: you eat fat, you store fat. If you eat more fat than the amount you dispose, you accumulate fat and get obese.

Second, continuted ingestion of dietary fat, and particularly saturated fat, facilitates insulin resistance. Therefore, insulin is less effective to drive glucose entering in the cells. Sometimes, you may want to eat something sweet as well, but because insulin is less effective, more glucose remains in the blood driving the typical complicances of the metabolic syndrome.

At this point, the increased glycemia causes the same interferences described in the carb hypothesis.

  • $\begingroup$ That second article is pretty horrible. It seems to be a survey of the literature, tons of which find no link between dietary fat and insulin resistance. Moreover, there is no proposed mechanism for why this should happen. I'll need more time to read through the first. $\endgroup$
    – user1323
    Aug 30, 2012 at 18:14
  • $\begingroup$ I cannot subscribe to the statement that all fat is simply absorbed. There are environmental differences in the stomach that influence fat intake like LPL activity. The first article states they modeled after LPL, so they clearly thought of this. Also, there is the symptom of fat stool---how can you get that if all fat goes straight to adipos? $\endgroup$
    – R Stephan
    Aug 31, 2012 at 17:43
  • $\begingroup$ In biology, 'all' does not exist. You may better figure out that some 'excess' fat is accumulated in WAT, some 'excess' in stool, some 'excess' in atheromas etc... $\endgroup$ Sep 1, 2012 at 9:34

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