What Can Physicians Do to Prevent Metabolic Dysfunction?

Major Breakthrough in Obesity Research

Several research centers are now looking at the biochemistry of the obesity epidemic, and the results are quite surprising. The old adage of "energy in" vs. "energy out" is totally wrong! We have completely missed the middle step: hormone-regulated fat storage. Unfortunately, dietary changes over the last few decades have greatly increased our fructose intake, which has led to widespread damage of this finely regulated feedback system. Physicians can now effectively counter the obesity epidemic by learning how obesity and metabolic syndrome are predictable outcomes of biochemical damage and hormone dysregulation.

Dr Robert Lustig, at University of California San Francisco, has outlined the whole process in an article published in Pediatric Annals, December 2006. Below I have summarized the gist of his article.

Hypothalamus-Leptin Feedback Loop

Normally, the hypothalamus regulates the balance between sympathetic output (energy burn) and parasympathetic output (energy conserve). The hypothalamus is modulated by feedback via leptin and other hormones. Leptin is produced by adipocytes (fat cells), and is the primary long-term signal which increases energy use, dependent on adequate or excess fat storage. When the fat cells are "full", more leptin is produced, the hypothalamus shifts to more sympathetic output, which brings about the following series of events: (1) appetite reduction, (2) TSH secretion, increasing thyroid hormone with increased baseline energy expenditure, (3) direct sympathetic stimulation to the skeletal muscles, increasing ATP production and increasing uncoupling proteins in mitochondria, and (4) stimulation of beta-adrenergic receptors in adipose tissue to increase lipolysis. Leptin also tells the hypothalamus to reduce parasympathetic output. When the hypothalamus is in sympathetic mode, a person is more alert, has energy readily available, and experiences a sense of well-being.

When there is a decrease in leptin (or if the leptin receptors are blocked!) the hypothalamus shifts to parasympathetic output (vagus nerve) which results in this series of events: (1) slowing of heart rate and lowering of myocardial oxygen consumption, (2) increased peristalsis and increased intestinal absorption of food, (3) increased insulin secretion, (4) increased insulin receptor sensitivity, which promotes energy storage and fat storage in the adipocytes, and (5) release of the neuro-hormone orexin-A which increases hunger.

Remember that leptin is a long-term hormone, changing gradually over time. In the starvation state, leptin levels would go very low, and the body's metabolic rate can drop 20% lower than baseline (40 kcal/kg vs. 50 kcal/kg). In obesity, the leptin receptors are blocked, and the brain is in a state of starvation! The hypothalamus shifts to parasympathetic mode, and the body experiences increased hunger, low metabolic rate, lethargy, and poor sense of well-being.

Fructose and Insulin Excess Can Block Leptin

"Hypothalamic obesity" is well described, where damage to the hypothalamus destroys its ability to respond to leptin, and the brain remains in a constant starvation state. These patients improve when treated with octreotide, an insulin suppressive agent. This got researchers to look at the action of insulin at the leptin receptor site.

As expected, insulin was found to block the leptin receptor site, in both animal and human studies. Hence, in a hyperinsulin state, the hypothalamus becomes leptin resistant, and is not able to respond to even high levels of leptin. It was recently also discovered that triglycerides block leptin from crossing the blood-brain barrier. This happens normally to a smaller degree during puberty and pregnancy, because the body needs to store extra energy at these times. However, something else has induced the hyperinsulin state in a large percentage of the world's population in the last few decades.

It is now known that excess fructose intake causes elevated triglycerides that block leptin from crossing the blood-brain barrier. Fructose is metabolized by the liver to free fatty acids and triglycerides. Thus, we now know the direct effect of fructose that causes leptin resistance.

Is Fructose the Cause of this Leptin Resistance and Insulin Excess?

The most significant change in our environment in the last 30 years, is the large increase in fructose intake in our diets. Sucrose (table sugar) is 50% fructose, and the very widely used "high fructose corn syrup" is a major ingredient in practically all processed foods (just read the ingredient labels). Kids are drinking tons of soft drinks and fruit juice (very high in fructose). Most soft drinks are loaded with high fructose corn syrup.

Fructose does not suppress ghrelin (the hunger hormone), so kids keep eating and drinking more of it without satiety. It is absorbed in the intestine without insulin regulation and is converted to fructose-1-phosphate in the liver. This floods the glycolytic pathway producing excess acetyl-CoA that cannot be handled by the Kreb Cycle, and results in build-up of free fatty acids, VLDL lipoproteins and triglycerides which enter the bloodstream. In addition to adverse effects on the endothelium by all three substances, free fatty acids promote insulin resistance, and hence insulin excess. The triglycerides block leptin from crossing the blood-brain barrier. This starts the vicious cycle of leptin resistance, increased parasympathetic function and further dysfunctional secretion of insulin.

Are There Other Causes of Hyperinsulinemia?

Yes, it appears that high fat diet and low fiber diet are also involved. There is also a question about sugar substitutes being able to stimulate insulin secretion. This appears to be the case in rats, but further study is needed for humans. This could be mediated by a rising sweetness threshold as perceived by feedback to the hypothalamus from tastebuds. In the past, low-fat low-sugar diets have been occasionally successful. Now it appears that fructose is the major target, with high-fiber and low-fat diet as the secondary goal. At some point we may also need to reduce or eliminate the artificial sweeteners as well.

Increased physical activity also lowers insulin levels by increasing insulin sensitivity, so a lifestyle that incorporates daily activity is a definite advantage, but cannot be effective without eliminating the fructose.

Why is There So Much Fructose in our Diets?

Over the last few decades, high fructose corn syrup was discovered to be a cheap source of food flavoring, which also had the marketing advantage of being "addictive" because of the appetite-increasing effects of the parasympathetic shift. This is partly due to its inability to suppress ghrelin, partly due to the higher sweetness threshold, and mostly due to the dysfunctional feedback to the hypothalamus caused by leptin resistance. Today almost all sweet processed foods contain high fructose corn syrup, since it very cheap to produce, moistens foods, increases shelf life and increases sales through its addictive qualities.

Reading labels to look for fructose or high fructose corn syrup can help us spot the foods that should be avoided. Also realize that all table sugar is half fructose, so cut back on regular sugar as much as possible. Most of the food we recognize as "junk food" probably is high in fructose.

Another source of fructose is fruit juice. Many schools have made the misguided choice to remove soft drinks from their vending machines and replace them with fruit juice. The soft drinks do have too much sucrose and high fructose corn syrup, but 100% natural fruit juice has even more fructose than full-sugar soft drinks! The American Academy of Pediatrics has been advising children to severely limit juice intake for several years now. A recent AAP statement advises complete avoidance of juice for all children. Water is always the best fluid to drink.

What Can Physicians Recommend to Get Their Patients' Weight, Lipids and Insulin Levels Down?

Dr Lustig recommends a 4-pronged plan:

1. Get rid of every liquid in the house that contains sugar. This includes juice, as well as sodas, kool-ade, sports drinks, energy drinks, and sweet tea. Two or three glasses of low fat milk a day is allowed (but NOT chocolate or strawberry milk!). Other drinks that are calorie-free (hence fructose-free) are allowed.

2. Eat your carbohydrates with fiber. White foods generally do not contain fiber, so avoid white bread, white rice, pasta, potatoes, etc. Brown foods generally have more fiber, so try to eat brown rice, beans, legumes, etc. Try to get 3 gm of fiber per serving. Look at the labels, if packaged. Fresh fruits and veggies will have enough fiber.

3. Wait 20 minutes for second portions. This gives the food hormone, peptide YY, a chance to act to reduce appetite.

4. Get the TV out of the bedroom. Kids should "buy" their TV time minute-for-minute with physical activity. The AAP recommends no more than 2 hours of "screen time" per day.

Remember this is a lifestyle change, and a change for the long haul. Leptin resistance and hyperinsulin state do not go away overnight. It might take months of low fructose/high fiber diet to get the hypothalamic feedback system operating normally again. Losing weight is a key marker to know if the metabolic regulatory system is starting to function, but weight is just a symptom of the more serious condition (metabolic dysregulation) that leads to heart disease, stroke, diabetes, hypertension, hyperlipidemia, and many other related consequences.