Leptin: A Primer for Weight Control

September 15, 2014

Leptin: A Primer for Weight Control 

 Reference: Annals of the New York Academy of Sciences 

 Just what is leptin?   Nice that you would ask. You have likely heard about it and remain slightly fuzzy. Isn’t it “one of those obesity hormones?” you might ask. Well, yes. It is the hormone made by your fat cells that circulates back to your brain and tells you to stop eating. The bigger your fat mass gets, the more leptin you have circulating in your blood. Your hypothalamus has leptin receptors in it that read the level of leptin and set off a cascade of effects as a result. The net effect is that you turn off appetite and increase activity. All that is well established in mice and rats with proven pathways. 

Is it the same in humans? In humans the connection isn’t quite so sure. There is more inter-person variability than can be explained by fat mass variability, so it’s not quite so tightly linked. And gender is a dramatically different marker in humans. Women have much more leptin than men for any given amount of “fat mass”. Teleologically, we needed women to have sufficient calories in storage (fat mass) to be able to survive a winter while being pregnant. That would mean we would have had natural selection pressure to favor a balance of calories that maintained a certain fat quantity in a woman’s body. 

Leptin is not a satiety factor in humans because changes in food intake do not spark a short-term increase in plasma leptin levels. It’s the total fat mass that matters. The story of leptin may boil down to orexigenic and anorexigenic stimulation. Orixigenic is what you feel when you drive past Kopp’s Icecream. Just being there, your appetite goes up. Leptin down-regulates orexigens. Turns them off. Appetite plunges. Things called NPY (neuropeptide Y), MCH (melanin-concentrating hormone), orexins, and AGRP (agouti-related peptide).   

We humans are pretty complicated. Leptin also turns on or up-regulates your appetite supressors with stimulation of things called alpha-MSH (alpha-melanocyte-stimulating hormone), which acts on MC4R (melanocortin-4 receptor); CART (cocaine and amphetamine-regulated transcript); and CRH (corticotropin-releasing-hormone). Again, appetite plunges. (Remember all these words for the next time you play Scrabble) With all that firepower, how come leptin doesn’t work to down-regulate obesity? 

That’s the big question. Overweight humans have very high leptin but become leptin resistant. If you give leptin to overweight folks, they don’t lose weight. And during starvation periods, the fall of leptin levels happens faster than the fall in fat stores. The conclusion is that the leptin system evolved primarily to protect us when we were starving, but doesn’t know what to do with us when we get overweight. 

Most of human history has had a 6 month period of calorie challenge (dry season in Africa, cold in Asia) during which we had to have a supple system of energy conservation. Now, in energy abundant times, we don’t have the natural endocrine system inside us to resist food signals. Our feedback system just doesn’t work at the top end of calorie excess. 

 WWW. What will work for me? Leptin had some promise a few years ago. It’s talked about a lot but hasn’t quite produced the results we want. I suspect there will be some connection to the wicked effects of sugar somewhere, but that remains a suspicion, not a proven fact. For now, we are left painting the bigger picture, and trying to understand the continuing puzzle. It’s a topic you should just know on general principles.   Pop Quiz

  1. Leptin is the hormone that fat cells put out to tell the brain that there is enough energy being stored? T or F                       Answer:  Perfect
  1. Leptin levels rise with obesity, T or F                     Answer:  True
  1. Orexigens are internal hormones that stimulate appetite. T or F.                 Answer:  True
  1. Leptin is turned off with starvation and weight loss, allowing appetite to soar and food intake to increase. T or F                     Answer;  That’s it. You have felt all that.
  1. The administration of leptin to overweight folks hasn’t resulted in weight loss. T or F          Answer:         Again, true.