Teaser Appetizer: The Adipose American, A Few Facts

Evolutionary pressures banish unfit biological species into extinction. The American descendents of Homo sapiens species will explode into extinction at the midriff. A walk through Main Street, USA will convince any skeptic of the veracity of this prediction. And it will all happen due to the adipose state of the nation.

Fact: 65% of US population is either overweight or obese.
Fact: The number of obese Americans zoomed from 14.5% in 1976 to 30.5% in 2000.

Millions of Americans are obese, diabetic, hypertensive, hyperlipidemic and succumb to this murderous metabolic syndrome. Strokes, heart attacks, fatty liver, osteoporosis, cancer, depression, arthritis and sleep apnea ravage the obese. The chart below, reproduced from Baylor College of medicine, depicts all havoc unleashed by obesity:


We have an epidemic. We spend $117 billion directly or indirectly on obesity and its complications; we eat more, exercise less and our bodies have become a battleground of conflicting hormones and peptides.

We thought our loads of fat were meant only for aesthetic shame but in 1994 scientists told us that the adipose tissue is an endocrine organ! Yes, an endocrine organ, similar to thyroid and adrenal gland. Like them it secrets into blood, a hormone — in this case, Leptin — which travels to remotely located hypothalamus and suppresses appetite.

In reverse, lack of Leptin stimulates appetite, encourages over eating, thus increasing fat storage. (This probably rendered an evolutionary advantage to help store a reservoir of fat for lean days of starvation.) Leptin deficient mice due to gene depletion (ob-ob mice) are obese and leptin replacement cures their obesity. Leptin gene deficiency and obesity is rare in humans and improves with leptin therapy.

Corollary: if leptin were administered to obese people they should loose weight. So the investigators tried it but only with partial success. It so happens that obese people have high – not low – levels of leptin. Their cells lack the receptors for leptin to attach and are resistant to leptin therapy. Thus, obese are either leptin deficient or leptin receptor deficient.

Leptin is not the only attention grabber; ghrelin entered the stage in 1999. Stomach secrets grehlin in response to hunger; a hungry man has high grehlin. The circulating grehlin stimulates the satiety center in the hypothalamus and grehlin secretion stops. A satiated man has low grehlin. Now add to this complexity insulin, cholecystokinin and GLP-1 Low insulin levels stimulate hunger and initiate the act of eating. The fat and probably protein in the meal stimulates cholecystokinin secretion from the upper small bowel which suppresses appetite and slows gastric emptying causing fullness and satiation. The act of eating stops. GLP-1 oozes out of the lower small bowel to suppress the appetite further.

But that is not all; in science it gets complex before it get simple. See the diagram below reproduced from adipose society of Baylor College of medicine:


Adiposity is regulated by a set of short and long term signals. Those for the short term determine the size of a meal and it frequency; the long term signals determine the fat storage.

The mechanism of appetite regulation and fat deposit is an interaction of competing and feed back signals. The following are some of the mediators:

  1. Neurotransmitters in the hypothalamus, like NPY, AGR,5HT
  2. Gut hormones like leptin , grehlin , cholecystokinin and GLP1
  3. Other circulating hormones like cortisol and thyroxine
  4. Sensory input from stomach and intestines
  5. External input like smell, taste and emotions

Currently the US obesity hormones are in state of misalignment: the USA is a leptin resistant, ghrelin deficient, cholecystokinin inefficient and insulin abundant nation.

And we still don’t know which molecule is the master conductor of this orchestra and how to transform this cacophony into harmony. It is obvious that the mechanism of appetite regulation and fat deposition is complex which leads to general failure of any single mode of therapy. Unrealistic individual goals of weight reduction further thwart the success. The therapy of obesity must include a combination of the following:

  1. Eat less: A daily deficit of 500 to 1000 calories is reasonable. This is the single most important component of therapy and most difficult to adhere to.
  2. Exercise a lot: Strenuous aerobic activity for over 200 minutes per week maintained over a long period of time with calorie restriction is effective. Physical activity conserves fat free mass, improves glucose tolerance and lipid profile. Fact: Moderate exercise like walking 45 minutes a day for 5 days a week has minimal effect on weight loss.
  3. Modify behavior to avoid temptation to engorge on food. This warrants life style change and altering emotional response to food. Self monitoring and social support are essential.
  4. Use drug therapy: Only two drugs have been approved by FDA for long term therapy.
    • Sibutaramine causes anorexia by blocking neuronal monoamine uptake.
    • Orlistat decreases fat absorption
  5. Get surgery if morbidly obese and nothing else helps.
    • Gastric bypass to channel food directly into mid intestine thus decreasing absorption
    • Gastric banding and stapling to diminish the size of the stomach
    • Combination of bypass and stomach size reduction.

Fact: Even moderate weight loss of 5% decreases the complications significantly

The prescription of eat- less-exercise- more-modify- behavior is still the best choice but compliance has been pathetic. On average, a person on a weight reduction diet has tried and failed three to six other diets before. This failure has created an enormous market opportunity for fad diet authors and manufacturers. Some examples:

  1. Eat less carbohydrates ( Atkins, South beach)
  2. Eat less fats ( Ornish, Pritikin)
  3. Eat less of both ( Weight Watchers, Jennie Craig)
  4. Eat very low calorie diet:400 calories ( Optifast, Cambridge)

The failure has also challenged the scientists to discover new therapies and many new drugs are in the various stages of development. One exciting possibility is the recent understanding of the endocannabinoid (endogenous cannabis like molecules) system. When investigators were working to understand the molecular action of Cannabis Sativa they found cannabinoid receptors (CB1) in the central nervous system and in the adipose tissues. Stimulation of CB1 in the brain increases appetite and stimulation in the fat cells increases fat deposition. It seems this system is in perpetual overactive drive in the obese and blockage of the receptors decreases appetite and promotes weight loss. Rimonabant, a drug now in clinical trials blocks the CB1 receptors and will be an exciting new weapon to combat obesity.

Fat20cat_2Many other drugs are under development but only an accurate understanding of the mechanism of obesity will lead to a better therapy. Science travels from metaphorical to mathematical; the journey is both exciting and agonizing. The investigation meanders, looses way, finds it again, and races to the next stop, falters, sprints and trundles along with hope towards exhilarating simplicity and elegance. The investigation of obesity is scurrying through the difficult middle stretch at present. We better arrive soon or the speed of decline of the American civilization will be directly proportional to the rate of expansion of its girth.

The sobering fact is:

I think and breathe and live because I eat
I eat therefore I am
But soon I will not be,
Because I ate.